Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
xi
Co11leuls X iii
xii Co11twts
Extracellular Matrix 139 PLATE 14. Endochondral Bone Formation II 210 Clinical Correlations: Demyelinating Diseases 297
Connective Tissue Cells 141 PLATE 15. Intramembranous Bone Formation 212 Origin of Nerve Tissue Cells 303
Functional Considerations: The Mononuclear Phagocytotic Organization of the Peripheral Nervous System 303
System 144 organization of the Central Nervous System 311 Integumentary System 4oo
Response of Neurons to Injury 313
Overview of the Integumentary System 400
PLATE 4. Loose and Dense Connective Tissue
PLATEs. Dense Regular Connective Tissue, Tendons,
150
BlooJJ 214
PLATE 23. Sympathetic and Dorsal Root Ganglia 316
Layers of the Skin 401
and ligaments 152 Overview of Blood 214 Cells of the Epidermis 405
PLATE24. Peripheral Nerve 318
PLATE 6. Elastic Fibers and Elastic Lamellae 154 Plasma 215 PLATE 25. Cerebrum 320 Functional Considerations: Skin Color 409
Erythrocytes 217 PLATE26. Cerebellum 322 Structures ofthe Skin 411
Clinical Correlations: ABO and Rl1 Blood Group Systems 219 PLATE 27. Spinal Cord 324 Functiona l Considerations: Hair Growth and Hair
Characteristics 415
Clinical Correlations: Hemoglobin Disord ers 220
Functional Considerations: The Role of Sebum 415
Adipose Tissue 156 leukocytes 221
Clinical Correlations: Sweating and Disease 419
Platelets 229
Overview of Adipose Tissue 156 Clinical Correlations: Skin Repair 421
Formation of Blood Cells (Hemopoiesis) 231
White Adipose Tissue 156 Clinical Correlations: Hemoglobin Breakdown
Cardiovascular System 326
Brown Adipose Tissue 160 and Jaundice 237 PLATE 38. Skin I 422
Overview of the Cardiovascular system 326
Clinical Correlations: Adipose Tissue Tumors 162 PLATE 39. Skin II 424
Bone Marrow 240 General Features of Arteries and Veins 327
PLATE 40. Eccrine and Apocrine Sweat Glands 426
Arteries 328
PlATE 41. Sweat and Sebaceous Glands 428
PLATE 16. Erythrocytes and Agranulocytes 242 Clinical Correlations: Hypertension 336 PLATE 42. Integument and Sensory Organs 430
PLATE 17. Granulocytes 244 Clinical Correlations: Atherosclerosis 337 PLATE 43. Hair Follicle and Nail 432
Cartilage 164 Capillaries 338
Arteriovenous Shunts 340
Overview of Cartilage 164
Veins 341
Hyaline Cartilage 164
Heart 343
Elastic Cartilage 169 Muscle Tissue 246 Clinical Correlations: Ischemic Heart Disease 346 Digestive System 1: Oral Cavity
Fibrocartilage 169
Histogenesis, Growth, and Repair of Hyaline Cartilage 170
Overview and Classification of Muscle
Skeletal Muscle 248
246 Lymphatic Vessels 347
and Associated Structures 434
II
I l tl Functional Considerations: Muscle Metabolism Overview of the Digestive system 434
PLATE 28. Heart 348
PLATE 7. Hyaline Cartilage 172 and Ischemia 250 PLATE 29. Aorta 350 Oral Cavity 435
PLATE 8. Cartilage and the Developing Skeleton 174 Clinical Correlations: Muscular Dystrophy-Dystrophin PLATE 30. Muscular Arteries and Veins 352 Tongue 437
PLATE 9. Elastic Cartilage 176 and Dystrophin-Associated Proteins 254 PLATE 31. Arterioles and lymphatic Vessels 354 ' Clinical Correlations: Inherited Absence of Taste 440
PLATE 10. Fibrocartilage 178 Functional Considerations: The Sliding Filament Model 256 Teeth and Supporting Tissues 440
Clinical Correlations: Myasthenia Gravis 259 Clinical Correlations: Classification of Permanent (Secondary)
Cardiac Muscle 262 and Deciduous (Primary) Dentition 441
Smooth Muscle 265 Functional Considerations: Histologic Preparation of Tooth
Bone 1so Functional Considerations: Complexity of Smooth Muscle l ymphatic System 356 Tissues 449
Innervation 269 Clinical Correlations: Dental Caries 453
Overview of Bone 180 Overview of the Lymphatic System 356
Functional Considerations: Comparison of the Three Muscle Salivary Glands 454
Bones and Bone Tissue 181 lymphatic Cells 357
Types 270 >l fl I
General Structure of Bones 182 Functional Considerations: Origin of the Names T Lymp11ocyte
and B Lymphocyte 361 PLATE 44. lip, A Mucocutaneous Junction 462
Clinical Correlations: Articu lar Cartilage and Joint PLATE 18. Skeletal Muscle 272
Clinical Correlations: Hypersensitivity Reactions 365 PLATE 45. Tongue I 464
Diseases 183 PLATE 19. Musculotendinous Junction and Neuromuscular PLATE 46. To ngue II 466
Cells of Bone Tissue 186 Clinical Correlations: Human Immunodeficiency Virus (HIV)
Junction 274 PlATE 47. Submandibular Gland 468
and Acquired Immunodeficiency Syndrome (AIDS) 367
Bone Formation 193 PLATE 20. Cardiac Muscle 276 PLATE 48. Parotid Gland 470
Lymphatic Tissues and Organs 368
Clinical Correlations: Nutritional Factors in Bone PLATE 21 . Cardiac Muscle, Purkinje Fibers 278 PLATE 49. Sublingual Gland 472
Formation 199 PLATE 22. Smooth Muscle 280
Biologic Mineralization and Matrix Vesicles 200 PLATE 32. Tonsil 388
Physiologic Aspects of Bone 201 PlATE 33. Lymph Node I 390
PlATE 34. Lymph Node II 392
Functional Considerations: Hormonal Regulation of Bone
Growth 201 PlATE 35 . Spleen I 394
Digestive System II: Esophagus
Fractures and Bone Repair 201 Nerve Tissue 282 PLAIT36. Spleen II 396
PLATE37. Thymus 398 and Gastrointestinal Tract 474
overview of the Nervous System 283
PLATE 11. Bone, Ground Section 204 Overview of the Esophagus and Gastrointestinal Tract 475
Composition of Nerve Tissue 283
PLATE 12. Spongy and Compact Bone 206 Esophagus 478
The Neuron 284
PLATE 13. Endochondral Bone Formation I 20B
Clinical Correlations: Parkinson's Disease 292 Stomach 480
Supporting Cells of the Nervous System 293
xiv Co11twts Colllwls XV
Clinical Correlations: Pernicious Anemia and Peptic Ulcer Alveoli 583 Clinical Correlations: Fate of Mature Placenta at Birth 755
Adrenal Glands 661
Disease 487
Clinical Correlations: Emphysema and Pneumonia 588 Functional Considerations: Chromaffin Cells 665 Vagina 755
Functional Considerations: Enteroendocrine Cells, APUD Cells
Blood Supply 590 Functional Considerations: Cholesterol 668 Clinical Correlations: Cytologic Pap Smears 757
and Gastrointestinal Hormones 489
Clinical Correlations: Zollinger-EIIison Syndrome 490 Lymphatic Vessels 590 External Genitalia 757
Nerves 590 PLATE 76. Pituitary I 670 Mammary Glands 758
Small Intestine 491
JlTL I PLATE 77. Pituitary II 672 Functional Considerations: Lactation and Infertility 763
Large Intestine 501 J
Histology
A _TEXT AND ATLAS__
Fourth Edition
Cell and organelle separation by differential centrifugation thinly sliced, 5 to 15 11-m (1 micrometer [J.tm] equals
Specialized microscopic techniques and microscopes 1/l,OOOth of a mil li meter lmm_l; see Table 1.1). T he speci-
T he student may feel removed from such techniques and men is washed after fixation and dehydrated in a series of
1 experimental p rocedures because direct experience with alcohol solutions of ascending concentration up to 100%
them is usuall y not available in current curricula . Never- alcohol to remove water. Organic solvents such as xylol or
t heless, it is important to know something about special- toluol, which are miscible in bot h alcohol and paraffin, are
ized p r ocedures and the data they yield. This chapter pro- then used to remove the alcohol p rior to infiltration of the
vides a survey of methods and offers an explanation of specimen with melted paraffin.
how the data provided by these methods can help the stu- W hen the melted paraffin is coo l and hardened, it is
ceUent preservation of membranes 111 electron micro- a tissue section. Examples of such large macromolecular
graphs. complexes include
Nucleoproteins, formed from nucleic acids bound to
Other Staining Procedures protein
Tntracellular cytoskeletal proteins complexed with other
Hematoxylin and eosin are used in histology primarily to proteins
display structural features Extracellular proteins in large insoluble aggregates,
bound to simila r molecules by cross-linking of neigh-
Despite the merits of H&E sta ining, the procedure does boring molecules, as in collagen fiber formation
not adeq uately reveal certain structural components of his- Membrane phospholipid-protein (or carbohydrate)
tologic sections, including elastic material, reticular fibers, complexes
basement membranes, and lipids. When it is desirable to dis-
p lay these components, other staining procedures, most of For the most part, these molecules constitute the struc-
them selective, can be used. These procedures include the use tme of cells and tissues, in that they make up the formed
of orcein and resorcin-fuchsin fo r elastic material and the use elements of the tissue. They are the basis for the organiza-
of silver impregnation for reticular fibers and basement tion that is seen in tissue with the microscope.
membrane material. Although the chemical bases of many In many cases a structural element is a t the same time a
FIGURE 1.1
staining methods are not a lways understood, they work. functional unit. For example, in the case of proteins that
Hematoxylin and eosin jH&E) staining. The series of specimens photomicrograph the counterstain, eosin, likewise has an overall
from the pancreas shown here are serial (adjacent) sections to demon- staining effect when used alone. Note, however, that the nu clei are Knowing the components a procedure revea ls is more im- make up the contractil e filaments of muscle cells, the fil-
strate the effect of hematoxylin and eosin used alone and hema- less conspicuous than in the specimen stained with hematoxylin only. portant than !mowing precisely how the procedure works. aments are the visible str uctura l components a nd the ac-
toxylin and eosin used in combination. a. This photomicrograph re- After the specimen is stained with hematoxylin and is then prepared tual participants in the contractile process. The RNA of
veals the staining witl1 hematoxylin only. While there is a general for staining with eosin in alcohol solution, the hematoxylin that is not the cytoplas m is visua lized as part of a stru ctura l compo-
overa ll staining of the specimen, those components and structures tightly bound is lost, and the eosin then stains those components to Q HISTOCHEMISTRY nent (e rgastoplasm of gland cells, N issl bodies of nerve
that have a high affinity for the dye are most heav ily stained, e.g., nu- which it has a high affinity. c. This photomicrograph reveals the com- AND CYTOCHEMISTRY cells), while being the actua l participant in the synthesis
clear DNA and areas of the cell containing cytoplasmic RNA. b. In this bined staining effect of H&E. x 480. of protein.
Specific chemical procedures can provide detailed information
about the funct ion of t he cells and extracellular components of Many tissue components are lost during the preparation of
TABLE 1.2 . Summary of Hematoxylin and Eosin (H&E) Staining the tissues HaE-stained sections
Cell and Extracellular Component Stain Reaction H istochemical and cytochemical procedures may be Despite the fact that nucleic acids, proteins, and phos-
Nucleus based on specific binding of a dye, use of a fluorescent pholipids are mostly retained in tissue sections, many are
Heterochromat in Blue dye-labeled antibody to a particu lar cell component, or also lost. Small proteins and small nucleic acids, such as
Euchromatin Negative the inherent enzy matic activity of a cell component. In transfer RNAs, are generally lost during the preparation of
Nucleolus Blue
add ition, many large molecules found in cel ls can be loca l- the tissue. Large molecules also may be lost, for example,
Cytoplasm ized by au toradiograph y, in which radioactively tagged by being hydrolyzed because of an unfavorable pH of the
Ergastoplasm Blue precursors of the molecule are incorporated by cells and fixa tive solutions. Examples of large molecules lost during
General cytoplasm Pink tissues prior to fixa tion. Many of these procedures can be routine fixation in aq ueo us fixa ti ves are
Cytoplasmic filaments Pink
used with both light microscopic and electron microscopic
Extracellular material preparations. Glycogen (a n intracellular storage carbohydrate com-
Collagen fibers Pink Before discussing the chemistry of routine staining and mon in li ver and muscle cells)
Elastic fibersA Pink, but not usually distinguishable from collagen fibers histochem ica l and cytochemical methods, it is useful to ex- Proteoglycans and glycosaminoglycans (extracellular
Reticular fibers" Pink, but not usually distinguishable from collagen fibers complex carbohydrates found in connective tissue )
amine briefly the nature of a routinely fixed and embedded
Ground substance Blue, but on ly if present in farge amounts, as in cartilage matrix
Bone matrix (decalcified) Pink
section of a specimen. These molecules can be preserved, however, by the use
Basement membrane Pink of nonaqueous fixative for glycogen or by the addition to
A Special staining procedu re used for tlleir demonstration, sucll as one containing resorcin-fuchsin or orcein. Chemical Composition of Histologic Samples the fixative solution of specific binding agents that preserve
special staining procedure used for tlleir demonstration, sucll as silver impregnation or periodic acid- Scll lff extracellular carbohyd rate-containing mo lecules. Also, as
(PAS) stain . described a bove, neutral lipids are usually dissolved by tl1e
The chemical composition of a tissue ready for routine staining
differs greatly from living tissue organic solvents used in tissue preparation.
genera lly based on a clear understanding of the chemistry so lve in fa ts must be used; to retain membrane structures, The components that remain after fi xation consist mostly Soluble components, ions, and small molecules are also lost
involved. For instance, the use of alcohols and organic specia l fixatives containing heavy metals, such as perman-
of large molecules that do not readily dissolve, es pecia lly during preparation of paraffin sections
solvents in routine preparations removes neutral lipids. ganate a nd osmium, that bind to the phospholipids must after treatment with the fixa tive. These large molecu les,
To reta in neutral lipids, such as those in adipose cell s, be used. T he ro utine use of osmium tetroxide as a fixative particularly those t hat react with other large molecules to Intermediary meta bolites, glucose, sodium, chloride,
froze n sections of forma lin-fixed tissue and dyes that dis- for electron microscopy is the primary reason for the ex- form macromolecular complexes, are usuall y preserved in and similar substances are lost during preparation of rou-
6 CHA PTE R 1 MrtiJods CHA PTE R 1
tine H &E paraffin sections. Many of these su bstances can The reaction of the an io nic groups varies with pH. Thus A limited number of substances within cells and the tiou, w hich employs a mi ld h ydrochl oric acid hydrol ys is, is
be studied in special preparatio ns, sometimes with consid- extracellular matrix display basophilia used to stain DNA.
At a high pH (about 10), a U three groups are ionized and
erable loss of stru ctural integrity. These small soluble ions
ava ila ble for reaction by electrostatic linkages with the These substances include
and molecules do not make up the formed elements of a The PAS reaction is based on the following facts:
basic dye.
tissue; they participate in synthetic processes or cellular At a slightly acidic to neutral pH (5 to 7), sulfate and Heterochromatin and nucleoli of the nucleus (chiefly be-
reactions. When they can be preserved and demonstra ted cause of ionized phosphate groups in nucleic acids of both ) Hexose rings of ca rbohyd rates contain adjacent car-
phosphate gro u ps are ioni zed and available fo r reacti on
by specific methods, they provide invalu able info rmation with the basic dye by electrostatic linkages. Cytoplasmic components such as the ergastop lasm (also bons, each of wh ich bears a hydroxyl (-OH) grou p.
abo ut cell meta bolism, active tra nsport, and other vita l At low pH (below 4), o nly sulfate gro ups remain ionized because of ionized phosphate g ro ups in ribosoma l RN A) Hexosamines of glycosaminoglycans contain adjacent
cellular processes. Wate1~ a highly versatile molecule, par- Extracellular materials such as the complex carbohy- carbons, o ne of which bears an - OH gr o up, wh ile the
and react with basic dyes.
ticipates in these reactio ns and processes and contributes d rates of tbe matrix of cartil age (beca use of ion ized sul- other bears a n am ino (-NH2 ) group.
to the stabiliza tion of macro mo lecular structure through Therefor e, sta ini ng with bas ic dyes at a specific pH can fate gro ups} Per iodic acid cleaves the bond between these adj acent
hydrogen bo nding. be used to focus on specific anionic groups, a nd because carbon atoms and forms aldehyde gr oups.
the specific an ionic gr oups are fou nd predominantly o n Staining with acidic dyes is less specific, but more substances These alde hyde groups react wi th the Schiff reagent to
certain macromolecul es, the staining serves as an indicator within cells and the extracellular matrix exhibit acidophilia give a distinctive magenta color.
Chemical Basis of Staining of these macromo lecul es.
As mentioned, hematoxylin is not, strictly speaking, a T hese substances include The PAS sta ining of basement membra ne (Fig. 1.2) and
ACIDIC AND BASIC DYES basic dye. It is used with a mordant (i.e., an in termediate reticular fibers is based on the content or association of
link between the tissue component and the d ye). T he mor- Most cytoplasmic filaments, especia ll y those of muscle proteoglyca ns (complex carbo hydrates associated with a
Hematoxylin and eosin are the most commonly used dyes in cells
dant ca uses the sta in to resemble a basic dye. The linkage protein core). PAS staining is an alternative to sil ver im-
histology in the tissue-mordant-hematoxy lin complex is not a sim- Most intracellular membranous components and much pregnation methods, w hich are also based on reaction with
ple electrostatic lin kage, and w hen sections are placed in of the o therwise unspecialized cytoplasm the sugar mo lecules in the proteoglycans.
An acidic dye, such as eosin, carries a net negative wa ter, hematoxylin does not dissociate from the tissue. Most extracellular fibers (primaril y beca use of ionized The Feulgen reaction is based on cleavage of purines
charge on its colored portion and is described by the gen- Hematoxylin lends itself to those staining sequ en ces in amino gro ups) from the deoxyri bose of DNA by mild acid hydro lys is; the
eral formula [Na +dye-]. which it is fo llowed by aqueous solutio ns of acidic d yes. s ugar ring then opens with the for mation of aldehyde
A basic dye carries a net positive charge o n its colo red True basic dyes, as distinguished from hematoxylin , are Certain basic dyes react with tissue components that shift their groups. Agai n, it is the newly for med aldeh yde groups th at
portion and is described by the genera] form ul a [dye+CI - ]. not generally used in sequences wherein the basic dye is normal color from blue to red or purple; this absorbance react with the Schiff reagent to g ive the distinctive m agenta
H em atoxylin does not meet th e definitio n of a strict ba- fo llowed by an acid ic dye. The basic dye then tends to dis- change is called metachromasia color. The reacti o n of the Schiff reagent with DNA is stoi-
sic dye but has properties that closely resemble th ose of a sociate from the tissue duri ng the aqueous solution washes chiometric and can be used, therefore, in spectro photo-
basic dye. T he colo r of a d ye is not related to whether it is between the two d ye solutions . T he underlying mechanism for metachromasia is the m etric methods to q uantify the amo unt of DNA in the n u-
basic o r acidic, as can be noted by tbe examples of basic presence of pol yani o ns within the tissue. W hen th ese tis- cleus of a cell. RNA does not stain w ith the Schiff reagent
and acidic dyes listed in Table 1.3. Acidic dyes react with cationic groups in cells and tissues, sues are stained with a concentrated basic dye solution, beca use it lacks deoxyribose.
particularly with the ionized amino groups of proteins such as toluidine blue, the d ye molecules are sufficiently
Basic dyes react with anionic components of cells and tissue close to fo rm dimeric and polymeric aggregates. The ab-
(components that carry a net negative charge) The reaction of cationic gro ups with an acid ic d ye is sorpti o n properties of these aggregations differ from those
called acidophilia {Gr., add-loving]. Reactions of cell and tiss ue of th e individua l nonaggregated d ye molecules.
Anionic components include the phosphate gro ups of components w ith acidic d yes are neither as specific nor as Cell and tissue structures that have hig h concentra -
nucleic acids, the sulfate groups of glycosaminoglycans, precise as reactions with basic dyes. tions of ionized sulfate and phosphate gro u ps, such as
and the carboxyl groups of proteins. The abili ty of such Altho ugh electrostatic linkage is the major factor in the the gr o und su bstance of carti lage, heparin-containing
anionic gro ups to react wi th a basic d ye is ca lled ba- p rimary binding of a n acidi c dye to the tissue, it is not the gra n ul es of mast cells, a nd rou gh endoplasmic reticultim
sophilia [Gr. , base-loving]. Tiss ue compo nents that stain with o nly o ne; because of this, acidic d yes are sometimes used of p lasm a cells, exhibi t metachromasia. T herefore, tolu-
hematoxyli n a lso ex hibit basophili a. in combinations to color d iffere nt tissue constitue nts selec- id in e blue will appear p urp le to red w hen it sta ins these
ti vely. For exa mple, three acidic dyes are used in the Mal- components .
lory staining technique: anil in e blue, acid fuchsin, and or-
a nge G. T hese dyes selecti vely sta in collagen, ordinary
TABLE 1.3. Some Basic and Acidic Dyes
ALDEHYDE GROUPS AND T HE SCHIFF
cytoplasm, a nd reel blood cells, respectively. Acid fuchsin
REAGEN T
a lso sta ins nuclei.
Dye Color
In other mu ltiple acidic dye techniq ues, hematoxylin is
Basic dyes used to staiJl nuclei first, then acid ic d yes are used to stain cy- The ability of bleached basic fuchsin (Schiff reagent) to react
Methyl green Green FIGURE 1.2
to plasm and extracell ular fibers selectively. The selecti ve with aldehyde groups results in a distinctive red color and is
Methylene blue Blue Photomicrograph of kidney tissue stained by the PAS method. 1111s
Red staining of tissue components by acidic dyes is due to relative the basis of the periodic acid-Schiff and Feulgen reactions
Pyronin G histochemical method demonstrates and localizes carbohydrate and
Toluidine bl ue Blue factors, such as size and degree of aggregation of the d ye carbohydrate-rich macromolecules. The basement membranes are
Acidic dyes molecules and permeability and "compactness" of the tissue. T he periodic acid-Schiff (PAS) 1'eaction sta ins carbohy- PAS positive, as evidenced by the magenta staini ng of these sites. The
Acid fuchsin Red Basic d yes can a lso be used in combination or sequen- dra tes a nd carbohydrate-rich macromo lec ules. It is used to kidney tubules (T) are sharply delineated by the stained basement
Aniline blue Blue tia lly (e.g., meth yl green and pyro nin to stud y protein syn- demonstrate glycogen in cells, mucus in va rio us cells and membrane surrounding the tubules. The glomerular capillaries (C)
Eosin Red
Orange thesis and secretion), but th ese com binations a re not as tissues, the basement membrane that underlies epithelia, and the epithelium of Bowman's capsule (BC) also show PAS-positive
Orange G
widely used as ac idic d ye combinations. and reticula r fi ber s in con nective tiss ue. T he Feulge1t reac- basement membranes. X360.
8 CHAPTER 1 C HAPTER 1 Mrtl!ods 9
eral, a capture reagent, e ither a d ye or a heavy meta l, is sue sections examined in the TEM tha n is possible w ith
used to trap or bind the reaction product of the enzyme by trad it io nal polyclona l a ntibodies.
precipitation a t the site of reaction. In a typical reaction to An a dditional a d vant age of the indirect labeling meth od
Microspectrophotometry
display a hydrol ytic enzyme, the tissue section is placed in is that a single second a r y a ntibody can be used to localize
a solution containing a s ubstra te (AB) a nd a trapping agent the intracellular or tiss ue-specific bi nding of several di f-
Feulgen microspectrophotometry Is a technique that was de-
(T) tha t precipita tes o ne of t he products as fo llows: ferent primary an tibodies. For light microscopic studies,
veloped to study DNA increases in developing cells and to an-
alyze ploidy, i.e., the number of times the normal DNA content the secondary antibody can be conjugated with different
AB + T CII I.YIIIC AT+ B
of a cell is multiplied (a normal, nondividing cell is said to be fluorescent d yes so t hat multiple labels can be shown in
diploid; a sperm or egg cell is haploid). Recently, It has be- w here AT is the trapped end product and B is the hy- the sa me tiss ue section (see page 49).
come a valuable tool for surgical pathologists in evaluating drolyzed substrate.
the metastatic potential of a malignant tumor and In making
By using such m ethods, the lysosome (see page 32),
prognostic and treatment decisions. The technique of static Autoradiography
first identiJied in d iffe renti a l centrifugation studies of
cytometry of Feulgen-stained sections of tumors (contrasted
with pow cytometry, which can only be used on isolated in- cells, was equated with a vacuola r component seen in
e lectron mi crogra phs. [n lig htl y fi xed t issues, th e acid Autoradiography makes use of a photographic emulsion
dividual cells) uses microspectrophotometry coupled with a
hyd rolases a nd este rases contained in lysosomes react placed over a tissue section to localize radioactive material
digitizing imaging system to measure the a bsorption of light at
w ith an appropriate s ubstrat e. The react ion m ixture also within tissues
560 nm by cells and cell clusters in Feulgen-stained sections.
This technique allows the pathologist to describe ploidy pat- co ntains lead ions to precipitate, e.g., lead phospha te de-
terns in specific adenocarcinomas (epithelia l cancers) and has rived fro m the action of acid phosp hatase. The precipi - Many small molecul ar pr ecursors of la rger molecules,
been particularly useful in studies of breast cancer, kidney can- tated reaction product can then be obser ved with both such a s t he a mino acids t hat ma ke up proteins and the n u-
cer, colon and other gastrointestinal cancers, endometrial lig ht a nd e lectron microscopy. cleotides tha t m ake up n ucleic acids, m ay be tagged by in-
(uterine epithelium) cancer, and ovarian ca ncer. Adenocarci- Simj lar light a nd e lectron histoche mica l procedures have corporatio n of a r a d ioactive a tom or a toms into their mo -
nomas that have a largely diploid pattern are said to be well lecular structure. The radioacti vity is then traced to loca lize
been d evelop ed to de mo nstrate alka line p hosphatase, FIGURE 1.3
differentiated and have a better prognosis than the same can- the larger mol ecules in cells and tissues. Labeled precursor
adenosinetriphosphatases (ATPases) of many varieties (in- Electron histochemical procedure for localization of membrane
cers with aneuploidy (nonintegral multiples of the haploid molec ules can be inj ected into a nimals or introd uced into
cluding the Na '"/K' -ATPase t hat is the enzym atic basis of ATPase in epithelial cells of rabbit gallbladder. Dark areas visible on
amount of DNA) and tetraploidy.
the sodium pump in cells and t issues), various esterases, the electron micrograph show the location of the enzyme ATPase.
a nd man y respirato ry enzymes (Fig . 1.3) . This enzyme is detected in the plasma membrane at lateral domains
of epitl1elial cells, which corresponds to the location of sodium
pumps. These epithelial cells are involved in active transport of mol-
Immunocytochemistry ecules across the plasma membrane. x 26,000.
Enzyme Digestion
A foreign protein or other antigen injected into an animal
Enzyme digestion of a section adj acent to one stained for a results in production of antibodies the fluoresce nt dye bound to the a ntibodies (Fig. 1.4). A
specific component, such as glycogen, DNA, or RNA, can be fluor escence microscope is used to dis p lay the flu o rescein
used to confirm the identity of the stained material A n antibody is a protein p ro duced by certai n w hite now attached inilirectl y to the antigen . It is a lso possible to
blood cells tha t b ind s to the fo reign substa nce t hat st imu- conjugate s ubstances s uch as gold or ferritin (an iron-
Intracell u la r mater ial tha t stains w ith t he PAS reaction la ted its production. In the la bo ra tory, a nti bodies can be containing molecule) to the a ntibody mo lecu le. These
ma y be identified as glycogen by pretrea tment of sections purified and conjuga ted (i.e., c hemicall y bound ) to a fluo- markers ca n be vis ua li zed di rectly with the EM.
w ith d iastase or am ylase. Abolition of the staining after rescent d ye s uc h as flu o rescein. This reagent can t he n be
these treatments positively ide ntifies the sta ined ma t er ia l as applied to sectio ns of lightly fixed or fro zen t issue o n glass Enzyme histochemical methods are combined with traditional
g lycogen . slides to locali ze th e a ntigen in cells a nd tissues. The reac- immunocytochemical methods to amplify the localization
Simila r ly, pretreatmen t of t iss ue section s with d e- t ion can th en be exa mined a nd pho togra p hed w ith a flu o- reaction between an antigen and an antibody
oxyribonuclease (DNAse) will abolish the Feulgen stain- rescence microsco pe . FIGURE 1.4
ing in those sections, a nd treatment o f section s of pro- In these meth od s, horserad ish p erox idase en zyme is Microtubules vis ualized by immunocytochemical methods. The be-
te in secretory epithelia with ribonuclease (RNAse) w ill The specificity of the reaction between antigen and antibody is conjuga ted w ith a primary antibody. Following the havior of microtubules (elements of the cell cytoskeleton) obta ined from
abo lish the stain ing of th e e rgasto plasm w ith basic dyes . the underlying basis of immunocytochemistry an tigen- a ntibody reacti o n, the histoche mi cal proced ur e human breast tumor cells can be studied in vitro by measuring their nu-
fo r demonstrating peroxidase activity is run to reveal the cleation activity, which is initiated by the centrosome. This image was
Enzyme Histochemistry In a typica l proced ure, a specific protein, such a s actin, is loca tion of the a ntigen-antibod y complex (direct reac- photographed in the fluorescence microscope. By use of indirect im-
isolated from the muscle cells of o ne s pecies, s uc h as a rat, tion). A fu rther refinement of thi s method a ttaches the munofluorescence techniques, microtubules were labeled with a mix-
Histochemical methods are also used to identify and localize a nd injected in to the c irc ulatio n of another species, such as peroxidase to a n anti-y-glo bulin (secondary antibody) ture of anth:rtubulln and anti- {3-tubulin monoclonal antibodies (pri-
a rabbit. The actin st imulates the for ma tion of antiactin a n- that binds to t he primmy antibody, furt he r amp lifying mary antibodies) and visualized by secondary antibodies conjugated
enzymes in cells and tissues
tibodies t hat circ ula te in the bloodstream of the ra bbit. The with fluorescein dye (fluorescein isothiocyanate-goat antimouse im-
the reaction (ind irect reacti on). Beca use t he e nd prod uct
munoglobulin G). The antigen-antibody reaction, performed directly on
To localize enzymes in tissue sectio ns, specia l ca re must antibodies are then re moved from the blood of the ra bbit, of the perox idase react io n is also visible in th e EM, th is
the glass coverslip, resulted In visualization of tubulin molecules re-
be taken in fi xation to preserve the enzyme acti vity. Us u- conjuga ted w ith a fluorescent dye, a nd used to sta in tissues method is easily adapted to EM immu nocytochemistry. sponsible for the formation of more than 120 microtubules visible on
a ll y, mild aldehyde fi xation is the preferred method. o r cells of t he ra t suspected of con taining actin, such as fi - Monoclonal a nti bodies conj ugated with ferr it in o r gold this image. They originate from the centriole and extend outward ap-
In these procedures, the rea ction product of the enzyme bro blasts in co nnective tiss ue. If actin is present , the a nti - particles may be used a s primar y a ntibody stains to proximately 20 to 25 ~-tm in a uniform radial array. x 1,400. (Photomi-
acti vity, rathe r t han the enzyme itsel f, is visua lized. Tn gen - bodies bind to it , a nd th e reaction is vis ua li zed by virtue of ach ieve even more precise loca liza ti o n of a n tigens in tis- crograpl1 courtesy of Dr. Wilma L. Lingle and Ms. Vivian A. Negron.)
I0 CHAPTER 1 Mrthods CHAPTER 1 Met!Jotls I I
cell o r organ cultures. In this way, synth esis of DNA and beled molecules a re exposed a nd develo ped by t his p roce- Au toradiography c an a lso be carried o ut by using thi n com panion slide to provide semiquantitative informa t ion
subsequent cell division, synthesis and secretion of proteins dure a nd appear as d ark gr a ins overlying the site of the ra- p lastic sections for examination w ith the EM. Essentially on the amount of bone minera l in di ffe ren t parts of the
by cells, and locali zation of sy nthetic prod ucts w ithin cells dioactive emission when examined wi th the light micro- th e sa m e procedures are used, but as with a ll TEM prepa- grou nd section.
a nd in th e extr ace llu lar matrix h ave been studied. scope (Fig. 1.5a). ration techniques, the processes a re much more de licate
Sections of specimens th at have incorpora ted ra d ioactive These grains m ay be used si mply to indicat e the loca- a nd diffic ult; h owever, they also yield muc h great er resolu-
materia l are mounted on slides. In the dark, the slide is
usua lly di pped in a melted photograp hic emulsion, thus
t ion of a substance, or they may be coun ted to provid e tion and m ore precise localization (Fig. 1.5 b ). \1 MICROSCOPY
semiqua ntitative inform ation about the amount of a given
produc ing a thin photographic film on t he surface of the su bsta nce in a specific locati o n. Fo r instance, afte r injec- light Microscopy
slide. After appropriate exposur e in a light-tight box, usu- tion of a n anim a l w ith tritiated thymidine, cells that in-
Historadiography
a lly for da ys to weeks, the exposed emulsion on the slide is A microscope, w hether simple (one lens) or compou nd
corporated th is nucl eo tide into their DNA prior to divid -
d eve loped by standard photographic techniques and p er- Historadiography is the production of an x-ray photograph (multiple lenses), is a n instrument that magnifies an image
ing but t h a t ha ve not yet divided wi ll h ave approximately
manently m o unted with a coverslip. The slides may be (microradiograph) of a specimen on a slide and a llows visua liza tion of g rea te r detai.l than is possible
twice as many silver g rains overly ing their nucle i as
stain ed either before or a fter exp os ure a nd developmen t. w ith the una ided eye. T h e simplest microscope is a m agni -
wil l cells that have di vided after incorporating the la beled
The sil ver g rai ns in the emulsion over th e radioactively Ia- nucleotide. A historadiogmph displays mass just as a regular x-ray fying glass o r a pa ir o f readin g glasses.
does. Although x -rays ca n be used to examine soft tissues, The resolving power o f the human eye, i.e., the distance
thei r greatest utility is in the exa mina tio n of grou nd sec- by which two o bjects must be separated to be seen as two
tions of bone or other miner a lized tissue. In practice, the o bjects (0. 2 mm), is d ete rmined by the sp aci ng of the pho-
gro und sect ion of bone is placed in contact w ith a photo- toreceptor cells in the re t ina. T h e role o f a microscop e is to
gra phic em ulsion on a glass slide and exposed to a bea m o f m agn ify a n image to a level at which the retin a ca n resolve
x-rays. The photogr aphic em ulsion is then developed a nd the information that wo uld o therwise be below its limi t of
viewed w ith a microscope (Fig. 1.6). Standards of known resolut ion . Ta b le 1.4 compares the resolution of the eye
mass can be a dd ed to the slide or t o a simila rl y trea ted w ith that of va rio us instrumen ts.
The microscope used by most students and researchers is the The phase contrast microscope enables examination of In dark-field microscopy, no direct light from the light source is The confocal scanning microscope combines components of a
bright-field microscope unstained cells and tissues and is especially useful for living gathered by the objective lens light optical microscope with a scanning system to dissect a
cells specimen optically
The bright-field microscope is the direct descendant of In dark-field microscopy, only light that has been scat-
the microscopes that became widely availa ble in the 1 800s T he phase contrast m icroscope takes ad vantage of tered or diffracted by structures in the specimen reaches The confocal scanning microscope is a relati vely new
and opened the fust major era of histologic research. The small d iffere nces in the refractive index in different parts the objective. The dark-field microscope is equ ipped w ith microscope system used to study the structure of bio logic
bright-field m icroscope (Fig. 1. 7) essentia lly consists of of a cell or tissue sample. Light passi ng th rough areas a specia l condenser that illuminates the specimen with materials. T he illumina ti ng lase r light system that it uses is
of re latively high refractive index (denser areas) is de- strong, o blique lig ht. Thus, the field o f view appears as a strongly convergent and therefore produces a shallow
Light source for illumination of t he specimen , e.g., a flected and becomes out of phase with the rest of the clark background o n which sma ll particles in th e speci- scanning spot. T he light emerging from the spot is directed
substage lam p beam of light that has passed thro ugh the specimen . The men that reflect some light into the objective appear to a photomultiplier tube, where it is ana lyzed. A mirro r
Condense,- lens to foc us the beam of light at the level of ph ase contrast microscope adds other induced-out-of- bright. system is used to move th e laser beam across the specimen,
the specimen phase wavelengths through a series of optical rings in The effect is similar to that of dust particles seen in the illuminating a single spot at a time (Fig. 1.8 ). The data
Stage on which the slide or other specimen is placed the condenser and objective lenses, essentia ll y a bo lishing light beam emanating from a slide proj ector in a dark- from each point of the specimen scanned by this moving
Objective lens to gather the lig ht that has passed the amplitude of the initia ll y deflected portion of the ened room. The light reflected off the dust pa rticles spot are recorded and sto red in a computer. This informa-
through the specimen beam and producing contrast in the image. Dark por- reaches the retina of the eye, thus mak ing the particles tion is th en displayed on a hig h-resolution video monitor
Ocular lens (or a pair of ocular lenses in the more com- tions of the image correspond to dense portio ns of the visible. to cr eate a visua l image. The ma jor advantage of this sys-
monl y used binocular microscopes) through which the specimen; light portions of the image correspond to less T he resolution of the dark-field microsco pe cannot be tem is its a bility to visualize a specimen in very thi n opti-
image for med by the objective lens ma y be examined d i- dense portions of the specimen. The phase contrast mi- better than that of the bright-field microscope, usi ng, as it cal sectio ns (approximate ly l J.Lm thick). The out-of-focus
rectly croscope is therefore used to examine living cells and does, the sa me wavelength source. Sma ller individual par- regions are subtracted from the image by the computer
tissues, such as cells in tissue culture, and is used ex- ticles can be detected in dark-field images, however, be- program, th us creating an extremely sharp image. In these
A specimen to be examined with the bright-field micro- tensively to examine unsta ined semithin (approximately ca use of the enhanced contrast that is created. aspects, cm1ocal microscopy resem bles th e imaging
scope must be sufficiently thin for light to pass through it. 0.5-p.m) sections of plasti c-embedded tissue. T he dark-field microscope is useful in exam ining au- process in com puted axia l tomography (x-ray) scanning
Although some light is absorbed w hile passing through the Two modifications of d1e p hase contrast microscope are toradiographs, in w hich t he developed silver g rains a ppear (CAT scans). Ordinary or nonconfocallight imaging con -
specimen, the optical system of the bright-field microscope the interference microscope, w hich also a llows quantifica- wh ite in a da rk background. Clinicall y, it is useful in ex- ta ins superimposed in-foc us and out-of-focus specimen
does not produce a useful level of contrast in the unstained tion of tiss ue mass, and th e differential interference mi- am ining urine for crysta ls, such as those of uri c ac id and parts, there by reducing image quality.
specimen. For this reason, the va ri o us staining methods dis- croscope (using Nomarski optics), w hich is especially use- oxalate, a nd in dem onstra ting spirochetes, particula rly Furthermore, by using o nl y the narrow depth of the in-
cussed earlier a re used. Other optical systems, described be- ful for assessing surface properti es of cells a nd other Treponema pallidum, th e o rga nism that ca uses syphilis, a focus image, it is possible to create multi ple images at
low, may be used to enhance the contrast w ithout staini ng. bio logic o bjects. sex ua ll y transmitted disease. varying depths within the specimen. Thus, one ca n li ter-
all y dissect layer by layer through th e thickness of the
The fluorescence microscope makes use of the ability of specimen. It is a lso possible to use the computer to m ake
certain molecules to fluoresce under ultraviolet light three-dimensional reconstructions of a series of these im-
ages. Beca use each individual image loca ted at a specific
A molecule that fluor esces emits light of wavelengths in depth within the specimen is extremel y shar p, the result-
the visible range w hen exposed to an ul traviolet (UV) ing assembled three-d imensiona l image is eq ually sharp.
source. The {lu01'escence microscope is used to display nat-
ura lly occurring fluorescent (a utofluorescent) molecules,
such as vitamin A and some neurotransmitters. Beca use laser
condenser autofluo rescent molecules are not numero us, however, its
lens scanning beam
,.JI-.,r---- --1- specimen -+-- - -
most widespread application is th e display of intro duced mirrors detector
flu o rescence, as in the detection of a ntigens or a ntibodies
electron in immu no cytochemical stai ni ng procedures (see Fig. 1.4).
objective detector Specific fluorescent mo lecu.les can also be in jected into an
lens
animal or d irectly into cells a nd used as tracers. Such meth-
ods have been useful in stud ying intercellular (gap ) junc-
tions, in tracing th e pathway of nerve fibers in neurobio l-
ogy, a nd in detecting fl uorescent growth ma rkers of
projection mineralized tissues.
lens Vario us fil ters ar e inserted betwee n the UV lig ht so urce
FIGURE 1.7
and the specimen to produce monochro matic o r nea r-
Diagram comparing the optical paths
ocular monoch roma tic (single-wavelength or narrow-ba nd-
lens in different types of microscopes.
image on The light microscope (left) is shown as wavelength) light. A second set of filters inserted between
image viewing if it were turned upside down; TEM the specimen and the objective a llows o nl y the narrow
L---------------~ ineye
screen band of wavelength of t he fluorescence to reach the eye
(middle}; and SEM (rigl7t). The speci- FIGURE 1.8
LIGHT MICROSCOPE TRANSMISSION ELECTRON SCANNING ELECTRON men and the projected magnified im- or to reach a photograp hic emulsion or other ana l yt i ~ Diagram of the beam path in the confocal microscope. (Courtesy of
MICROSCOPE MICROSCOPE age are depicted by red arrows. processor. Sarastro, Inc., Ypsilanti, MI.)
14 CHAPTER 1 C H AP TER 1 MeilJOtls I5
Moreover, once the computer has assembled eac h o f the The TEM uses the interaction of a beam of electrons with a tude sma ller or thinner than those used for light microscopy. Uranyl nitrate is o fte n added to the alcoho l solution s
secti o ned images, the reconstructed three-dime nsional specimen to produce an image The TEM, whose electron bea m has a wavelength of ap- used in de hydration to increase t he density of compone nts
image can b e rotated and viewed from any orie ntation proxima tely 0.1 nm, has a theoretical resolution of 0.05 nm. of cell junctions a nd othe r sites. Sequential soakin g i11 solu-
desired. The " optics" of the TEM are, in principle, simila r to Because of the exceptional resolution of t he TEM, the tions of uran yl acetate a nd lead citrate is ro utinely used to
those of the light microscope (see Fig. 1.7), except that th e quality of .fixation, i.e., t he d egree of prese rvation o f sub- stain sections before viewi ng with the TEM to provide
The ultraviolet microscope uses quartz lenses with an TEM uses a beam of electrons ra ther than a bea m of light. cellular structure, must be the best achi eva ble. high-resolution, hig h-contrast electron micrographs.
ultraviolet light source The principle of t he mi croscope is as fo llows:
Routine preparation of specimens for transmission electron Freeze fracture is a special method of sample preparation for
A source, such as a hea ted tungsten fi lament, emits elec-
The image in the ultraviolet (UV) microscope depends microscopy begins with glutaraldehyde fixation followed by a transmission electron microscopy, especially important in the
trons (cathode).
on the a bsorption of UV ligh t by m o lec ules in the speci- buffer rinse and fixation with osmium tetroxide study of membranes
The electrons are attracted towa rd an anode.
men. The UV source has a waveleng th of approximately An electrica l difference between the ca thode cover and the
200 nm. Thus, the lN microscope may achieve a reso lu- G lutara ldehyde, a dia ldehyde, preserves protein con- The tissue to be exa mined may be fi xed or u nfixed; if it
anode impa rts an acce lera ting voltage of between 20,000
tion o f 0.1 J.Lm . In principle, lN microscopy resembles the stituents by cross-linking them; the osmium tetrox ide re- has bee n fi xed, th e fixative is washed out of the tissue be-
and 200,000 volts to the electrons, creating the beam .
workings o f a spectrophotometer; the results are usually acts with lipids, particu larly phospho lipids. The osmium fore proceeding. A cryoprotectant, suc h as glycerol, is a l-
T he beam then passes through a series of electromag-
recorded photograph ica ll y. The specimen can not be in- a lso imparts electron density to cell and tiss ue structures lowed to infiltra te the tissue, an d tl1 e tissue is then rapidly
netic lenses that serve the same function as tbe g lass
spected directly through an ocula r beca use the lN light is lenses of a ligh t microscope.
because it is a heavy meta l, thus e nhanci ng su bsequent im- frozen to about -16oc. Ice crysta l formation is prevented
not visible and is injurious to the eye. age formation in the TEM. by the use of cryopro tectants, rapid freezing, and ex-
The me thod is useful in detecting nucleic acids, specifi- Ideally, tissues should be perfused w ith buffered glu- tremely small tissue sa mples. The frozen tiss ue is the n
The condenser lens shapes an d cha nges the diameter of
cally the purine and pyrimidine bases of the nucleotides. It ta raldehyde before excision from the an ima l. More com- placed in a vacuum in the freeze fract ure a pparatus a nd
the beam that reaches the specimen pla ne. The beam that
is also useful for detecting proteins that con tain certain monly, tissue pieces no more than 1 mm 3 are fixed for the struck w ith a knife edge or razor blade.
has passed through the specimen is then foc used and mag-
amino acids. Using specific illuminating wavelengths, UV TEM (compared with light microscop e specimens, which
nified by an objective le1ts a nd further magnified by one or
spectro photometric measurements a re commonly made ma y be measured in centimete rs). The dehydratio n process The fracture plane passes preferentially through the
more projector lenses. T he final image is viewed on a
through the UV microsco pe to determine quantitatively is identical to th at used in ligh t microsco py, and the tissue hydrophobic portion of the plasma membrane, exposing
phosphor-coated screen. Portions of the specimen t hrough
the amount of D NA and RNA in individu al cells. As de- is infiltra ted with a monomeric resi n, usuall y an epoxy the interior of the plasma membrane
which electrons h ave passed appear bright; those portions
scribed o n page 8, it is used clinically to evaluate the de- resin, which is subsequently polymeri zed .
of the specimen that have absorbed or scattered electrons
gree of ploidy (mu ltip les of normal DNA quantity) in sec- The resulting fracture of the p lasma membrane produces
beca use of th eir inherent density o r beca use of h eavy m et-
tions of tumors . The plastic-embedded tissue is sectioned on specially designed two new surfaces. The surface of the membra ne that is
als added during specimen preparation appear da rk. A
microtomes using diamond knives
photographic plate o r video detector can be p laced above
The polarizing microscope uses the fact that highly ordered or below the viewing sc reen to record the image on the
molecules or arrays of molecules can rotate the angle of the Because of the limited penetrating power of electrons,
screen permanently. sections for routine transmission electron microscopy range
plane of polarized light
fro m 50 run to no more than 15 0 nm. Because a brasives
Specimen preparation for transmission electron microscopy is
T he polarizing microscope is a simple modification of used to sharpen steel knives leave unacceptable scratches
similar to that for light microscopy except that it requires finer
the light microscope, in which a polarizing filter, ca lled the on sectio ns viewed in the TEM, di a mo nd knives with
methods Many of the histochemical methods used in light microscopy
polarizer, is located between the light sou rce and the spec- nea rly perfect sharp ness are used. Sections cut by the dia- have been adapted for electron microscopy. The use of low-
imen, and a second pola rizer, call ed t he analyzer, is located mond knife a re much too thin to ha nd le; t hey are floated molecular-weight dialdehydes, particularly glutaraldehyde, as
The principles used in the preparation o f sectio ns for
between the o bjective lens and the viewer. away from the knife edge o n the surface o f a fluid-filled primary fixatives has allowed application of many of the stan
viewing with the TEM a re essen tia ll y the same as those used
Both th e pola rizer and the ana lyzer can be rota ted ; the trough an d picked up from t he sur face onto plastic-coated dard enzyme histochemical methods to tissue for TEM exami
in ught microscopy, with th e added constraint that at every
difference between th eir ang les of ro tation is used to deter- co pper mes h gr ids. The grids have 5 0 to 400 ho les/inch or nation, often requiring only minor modifications of buffers and
step one must work with specimens 3 to 4 orders of magni-
mine the degree by w hic h a str ucture affects the beam of special slots for viewing serial secti ons. T he beam passes capture reagents. The phosphatase and esterase procedures
pola rized light. The ability of a c rystal or paracrystalline through the holes in the copper grid, th en throug h the spec- have been well adapted for the TEM. The reactions are usually
imen, and the image is t he n focused o n th e vi ewing screen run on 50-J.Lm tissue slices that are subsequently fixed in
a rray to rotate the plan e of pola ri zed lig h t is ca lled bire-
or photograph ic film . osmiu m tetroxide and embedded for TEM sectioning (see
frilzgence (dou b le refraction). Striated muscle and the c rys- Fig. 1.3).
ta llo id inclusio ns in the testicular inters titial cells (Leydig Substitution of a heavy metal-containing compound for
cells), a mo ng other common structures, exhibit birefrin- Routine staining of transmission electron microscopy sections
the fluorescent dye usually conjugated with an antibody has
gence . is necessary to increase the inherent contrast so that the details allowed adaptation of immunocytochemical methods to
The electronic principles of both the TEM and the SEM are sim
ilar to those of a cathode ray tube (CRT), such as those used in of cell structure are readily visible and photographable transmission electron microscopy, as has the ada ptation of
television sets. In fact, the first EMs, built in the early 1930s, the diaminobenzidinebased peroxidase reaction. Similarly,
Electron Microscopy were developed independently in several countries by scien Jn general, transmission electron microscopy sections refinement of techniques has also allowed development of
Two k inds of EMs can p rovide morphologic a nd a na lytic tists and engineers working on the development of television. are sta ined by adding materials of grea t density, such as routine EM autoradiography as an investigative method (see
da ta on cells and tiss ues: the transmissio1t electron micro- Although some viruses and other dried paracrystalline materi ions of heavy metals, to the specimen. H eavy-meta l ions Fig. 1.5b). These methods have been particularly useful in elu
scope (TEM) and the scamting electron microscope als were studied with the EM in the 1930s, it was not until ad may be bound to t he tissues d uring fi xa tion o r dehyd1a- cidating the cellular sources and intracellular pathways of cer
(SEM). The p rima ry improveme nt in the EM vers us th e equate fixation, embedding. and sect.ioning methods were de tion or by soaking the sections in solutions of such ions tain secretory products, the location on the cell surface of
veloped in the 1950s that the TEM could be applied as a after sectioning. Osmium tetroxide, rou tinely used in the specific receptors, and the intracellular location of ingested
light microscope is tha t the wave length of th e EM beam is
routine tool in biologic researcl1. fixat ive, bi11ds to the phospholipid components of mem - drugs and substrates.
approxima tel y l/2,000th that of the light microscope
bea m, t hereby increasing resolution by a factor of 101. branes, imparting additio nal density to the membra nes.
I6 C HAPTER 1 Melhods CHAPTER 1 Mrlilods 17
final image
NONMEMBRANOUS ORGANELLES 45
Microtubules 45
Actin Filaments 48
Intermediate Filaments 51
Centrioles and Microtubule-Organizing Centers 53
Basal Bodies 58
Inclusions 59
Cytoplasmic Matrix 60
NUCLEUS 60
Chromatin 60
Nucleolus 62
Nuclear Envelope 64
Nucleoplasm 68
CELL RENEWAL 68
CELL CYCLE 68 FIGURE 2.1
Mitosis 68 Different histologic features of different cell types. These three pllo- chromatic) nuclei (N) with distinct nucleoli. Each ganglion cell is sur-
Meiosis 69 tomicrographs show different types of cells in three different organs rounded by flattened satellite cells (S). Tile size of the ganglion cell
Prophase I 72 of the body. The distinguishing features include size, shape, orienta- and tile presence of a euchromatic nucleus, prominent nucleolus, and
Metaphase I 72 tion, and cytoplasmic contents t11 at can be related to each cell's spe- Nissl bodies (rough-surfaced endoplasmic reticulum lrERI visible as
Meiosis II 72 cialized activity or function. a. Epithelial cells in the kidney. Note sev- darker granules within tile cytoplasm) reflect the extensive synt11etic
eral shapes of epithelial cells: columnar cells with well-defined activity required to maintain tile exceedingly long processes (axons)
CELL DEATH 72 borders in collecting duct (CD), squamous cells in tile thin segment of t hese cells. x 380. c. Smooth muscle cells of t11e small intestine.
(TS) of nephron, and even more flattened cells lining blood vessels, Note that these cells are typically elongated, fusiform-shaped, and
BOX the vasa recta in t11e kidney (VR). x380. b. Dorsal root ganglion cells. organ ized in a parallel array. Tile nuclei are also elongated to con-
sox 2.1. Clinica l Correlations: Abnormalities in Microtubules Note the large size of these nerve cell bodies and the large, pale (eu- form to tile general shape of the cell. x 380.
and Filaments 55
18 19
1Q CHAPTER 2 The Cell C HAPTER 2 TIJe Cell :2 I
Inclusions are materials in the cytoplasm that may or tion is sorting proteins de li vered to them via endocytotic microscope (TEM) , it appears as two electron-dense layers
may not be surrounded by a membrane. They comprise vesicles and redi recting them to different cellular com- separated by an intermediate, electron-lucent (nonstaining}
such diverse materials as secretory gran ules, pigment, neu- partments for their final destination. layer (Fig. 2.2). T he total thickness of the plasma mem-
tral fat, glycogen, and stored waste products. Lysosomes, small organelles containing digestive en - brane is about 8 to 10 nm.
The cytoplasmic ground substance was called cytosol in zymes; their derivatives include phagosotnes, phagolyso-
older texts because it was believed to be an amorphous somes, autophagosomes, and autophagolysosomes. The plasma membrane is composed of amphipathic lipids and
fluid. The term cytoplasmic matrix is now used to empha- Transport vesicles, which inc! ude pinocytotic vesicles, two types of proteins
size that it is a concentrated aqueous gel of different-size endocytotic vesicles, and coated vesicles. These vesicles
molecules and has an organized structure. are involved in both endocytosis and ex ocytosis and The current interpretation of the molecular organization
vary in shape and the material that they transport. of the plasma membrane is referred to as the modified
Intracellular membranes increase surface area and delimit Mitochondria, organelles that provide most of the en- fluid-mosaic model (Fig. 2 .3) . The membrane consists pri-
compartments ergy to t he cell by producing adenosine triph osphate marily of phospholipid, cholesterol, and protein molecules.
(ATP ) in the process of oxidative phosphorylation . The lipid molecules form a lipid bilayer with an amphi-
Many organelles and inclusions are membrane-limited Peroxisomes, small organelles involved in the production pathic character (it is both hydrophobic and hydrophilic).
structures; i.e., they are surrow1ded by a membrane. The and degradation of H 2 0 2 and degradation of fatty acids. T he fatty acid chains of the lipid molecules face each other,
membranes form vesicular, tubulat~ and other structural making the inner portion of the membrane hydrophobic
patterns that may be convoluted (as in the case of the The nonmembranous organelles include (i.e., having no affinity for wa ter). The surfaces of the
smooth-surfaced endoplasmic reticulum [sERJ) or plicated Microtubules, which together w ith actin and intermedi- FIGURE 2.2 membrane are formed by the polar head groups of the lipid
(as in the case of the inner mitochondrial membrane). ate filaments fo rm elements of the cytoskeleton. Micro- Absorptive cells of the small intestine. This electron micrograph molecules, thereby making t he surfaces hydrophilic (i.e.,
These membrane configurations greatly increase the sm- tubules continuously elongate (by add ing tubulin shows the apical portion of absorptive cells with microvi lli. X29,000. having an affinity for water} .
face area on which essential physiologic processes and bio- Inset. Higher magnification of the area within the eire/e. Note that at In most plasma membranes, protein molecules consti-
dimers ) and shorten (by removing tubu lin dimers ), a
chemical reactions take place. tl1is magnification the plasma membrane displays its characteristic tute approximately half of the total membrane mass. Most
property referred to as dynamic instability.
Moreover, the spaces enclosed by membranes constitute appearance, showing two electron-dense lines separated by an
Filaments, wh ich are also part of the cytoskeleton. In electron-lucent intermediate layer. x 95,000.
intracellular m i.c rocompartments in which substrates, prod- general, filaments can be classified into one of two
ucts, or o ther substances are segregated or concentrated. groups: actin filaments, wh ich are flexible cha ins of
For example, the enzymes of lysosomes are separated by a globular actin molecules, and intermediate filaments,
membrane from the cytoplasmic matri.x because their hy- w hich are rope-like fibers formed from a variety of pro-
drolytic activi ty would be detrimental to the cell . teins. Both provide tensile strength to w ithstand tension
and confer resistance to shearing forces.
organelles are described as membranous (membrane-limited) Centrioles, short, paired cylindrical structures found in
or nonmembranous the center of the centrosome. Derivatives of centrioles
give rise to basal bodies of cilia. cholesterol
All cells have the same basic set of intracellular or- Ribosomes, structures composed of ribosomal RNA molecule
ganelles, which can be classified into one of two groups: (rRNA} and ribosomal protein s (including proteins at-
(1) membranous organelles with plasma membranes that tached to membranes of the rER and proteins free in the
separate t he internal environment of the organelle from the cytoplasm). Ribosomes are essential for protein synthesis.
cytoplasm, and (2) 1wnmembranous organelles w ithout
plasma membranes. An outline of the key features relating to t he identifica-
tion of cell organelles and inclusions is provided at the end hydrophobic
The membranous organelles include fatty acid
of the chapter (see Table 2.3, page 76) . The normal func-
chain
Plasma (cell ) membrane, a lipid bilayer that forms the tion and the re lated pathologies aJ:e also summarized (see
cell boundary as wel l as the boundaries of many or- Table 2.4, page 77}.
ganelles with in the cell.
Rough-surfaced endoplasmic reticulum (1-ER), a region
of endoplasmic retic ulum associated with ribosomes. It 9 MEMBRANOUS ORGANELLES
is the site of protein synthesis and modification of newly
synthesized proteins. Plasma Membrane
Smooth-su1faced endoplasmic reticulum (sER), a region hydrophilic polar head
of endoplasmic reticulum involved in lipid and steroid The plasma membrane is a lipid-bilayered structure visible
FIG URE 2.3
synthesis. It is not associated w ith ribosomes. with transmission electron microscopy
Diagram of a plasma membrane showing the modified fluid-mosaic within the gaps between phospholipids equally on both sides of the
Golgi apparatus, a membranous organelle composed of
model. The plasma membrane is a lipid bilayer consisting primarily membrane. Note the asymmetric distribution of specific phospho-
multiple flattened cisterna e res ponsible for modifying, The plasma membrane (cell membrane) is a dynamic
of pl1ospl1olipid molecules, cholesterol, and protein molecules. The lipids in the membrane bilayer (indicated by the different colors of the
sorting, and packaging proteins and lipids for intracell u- structure t bat actively participates in many physiologic and hydrophobic fatty acid chains of pllospholipids face each other to plwspl1olipid heads). Tile diagram also shows integral membrane pro-
lar or extracellular transport. biochemical activities essential to cell function and survival. form the inner portion of the membrane, while the hydrophilic polar teins and peripheral membrane proteins. carbohydrate cha ins attach
Endosomes, membrane-bounded compartments inter- When the plasma membrane is properly fixed, sectioned, heads of the phospholipids form the extracellular and intracellular to both integral and peripheral membrane proteins, forming glyco-
posed within endocytotic pathways. Thei r major func- stained, and viewed on edge w ith th e transmission electron surfaces of the membrane. Cholesterol molecules are in corporated proteins, and to polar pllospholipid heads, forming glycolipids.
'22 CHAPTER 2 T!Je Cell CHAPTER 2 The Cell 23
of the proteins are embedded within the lipid bilayer or oute r leaflet integral FIGURE 2.5
pass through the lipid bilayer completely. T hese proteins of lipid bilaye r membrane proteins Freeze fracture examination of the plasma membrane. a. View of
are called integral membrane pmteins. Integral membrane the plasma membrane seen on edge, with arrow indicating the pref-
proteins ca n move within the plane of the membrane; this erential plane of splitting of the lipid bilayer through the hydrophobic
m ovement can be compared to the movement of icebergs portion of the membrane. When the membrane splits, some proteins
floating in the ocean (see Fig. 2.3). The other types of pro- are carried with the outer leaflet, though most are retained within the
inner leaflet. b. View of the plasma membrane with the leaflets sepa-
tein, called peripheml membrane proteins, are not embed-
rating along tl1e cleavage plane. The surfaces of the cleaved mem-
ded wi thin the lipid bilayer. They are associated with the
brane are coated, forming replicas; the replicas are separated from
plasma membrane by strong ionic interactions, mainly the tissue and examined with the TEM. Proteins appear as bumps.
w ith integral proteins on both the extracellular and intra- The replica of tile inner leaflet is called the Pface; it is backed by cy-
cellular surfaces of the mem brane (see Fig. 2 .3 ). In addi- toplasm (wotoplasm). A view of the outer leaflet is called the Eface;
tion, on th e extracell ular surface of the plasma membrane, inner leaflet it is backed by gxtracellular space. c. Electron micrograph of a freeze
carbohydrates may be attached to proteins, thereby fo rm- of lipid layer a
fracture replica shows the E-face of the membrane of one epithelial
ing glycoproteins, or to lipids of the bilayer, thereby form- peripheral cell and the P-face of the membrane of the adj oining cell. The cleav-
ing glycolipids. These surface molecules constitute a layer membrane depression left by age plane has jumped from the membrane of one cell to the mem-
at the surface of the cell , referred to as the cell coat o r gly- proteins P-lace protein brane of the other cell, as indicated by the clear space (intercellular
cocalyx (Fig. 2.4 ). They help establish extracellular mi- space) across the middle of the figure. Note the paucity of particles in
the E-face compared with the Pface, from which t he majority of the
croenvironments at the memb rane surface that have spe-
integral membran e proteins project. (Courtesy of Dr. Giuseppina d'Eiia
cific functions in metabolism, cell recognition and cell Raviola.)
associat io n, and serve as r eceptor sites for hormones.
m
cytoplasm
pared for electron microscopy by the freeze fracture o
process (Fig. 2.5a), membranes typically split o r cleave b
a lo ng the hydroph obic plane (i.e., between the two lipid i'f---'.Q----\t;'i--------{
layers) to expose two interior faces of the membrane, an E- 0~ ((~
K+ o channels:
face and a P-face (Fig. 2.5 b). pu mps
TheE-face is backed by extracellular space, whereas the receptors
P-face is backed by cytoplasm (protoplasm). The numer-
ous particles seen on the E- and P-faces with the TEM rep- structural proteins
resen t the integra l pr oteins of the membrane. Usually, the FIGURE 2.6
P-face displays mo re particles, thus more protein, than the Different functions of integral membrane proteins. The six major
E-face (Fig. 2.5c). categories of integral membrane proteins are shown in this diagram.
These are pumps, channels, receptors, linkers, enzymes, and struc
Integral membrane proteins have important functions in cell tura l proteins. These categories are not mutually exclusive. A struc-
m etabolism, regulation, and integration tural membrane protein involved in cell-tocell junctions might simul
taneously setve as receptor, enzyme, linker, or any combination of
FIGURE 2.4 these functions.
Six broad categories of membrane proteins have been de- Electron micrograph of microvilli on the apical surface of an ab-
fined in terms of their function: pumps, channels, receptors, sorptive cell. The glycoproteins of the glycocalyx ca n be seen ex-
linkers, enzymes, and structural proteins (Fig. 2.6) . T he cat- tending from the tips of t he microvilli into the lumen. At this magni-
egories are 110t mutually exclusive; e.g., a structura l mem- fication, the relationship between the outer plasma membrane
brane protein may simultaneo usly serve as a receptor, an leaflet and the glycocalyx is particularly well demonstrated. Glyco-
enzyme, a pump, o r any combination of these functions. proteins of the glycocalyx include terminal digestive enzymes sucl1 passive diffusion . Gap junctions formed by aligned
as dipeptidases and disaccharid ases. x lOO,OOO. (Courtesy of Dr. Ray channels in the membr anes of adjacent cells permit pas-
Pumps serve to transport certain io ns, such as Na+, ac- C. Henrikson.) sage of io ns and small molecu les from the cytoplasm of
ti vely across membranes. Pumps also transport meta- one cel l to the cytoplasm of the adj acent cel ls.
bo lic precursors of macromolecules, such as amino acids Receptor proteins allow recognition and localized bind-
and sugars, across membranes, either by themselves o r ing of ligands (mo lecules that bind to the extracellula r
lin ked to the Na + pump. surface of the plasma mem brane) in processes such as
Channels allow the passage of sma ll ions and molecules hormonal stimula tion, coated-vesicle endocytos is, and
across the plasma mem brane in either directio n, t.e., c antibody reaction s.
J4 C H APTE R 2 n . c e11 CHAPTER 2 Tile Cell ~ 5
Linher pmteins anchor th e intracellular cytoskeleton to MEMBRANE TRANSPORT AND V ESICULAR ener gy for active tmnspo1't o f molecules agai nst their EXOCYTOSIS
th e extracellula r matrix. Exa mples of linker pro teins in- TRAN SPO RT concentratio n gr ad ient. Other carrier proteins, such as
clude the family of in tegrin s th at link cytoplasmic ac tin glucose carriers, d o not require energy and participate in
filam ents to an extracellular matrix pro tein (fib ro- Subst an ces that enter or leave the cell must traverse the passive tmnsport.
necti n) . plasma membrane Channel proteins a lso transfer small, wa ter-soluble mo l-
Enzymes have a va ri ety of ro les . Adenosine trip hos- ecules. Channel protein s create hydrophilic cha nnels
phatases (ATPases) have specific roles in ion p um ping: So me substances (fat-so luble an d sma ll, uncharged mo l- through the plasma membrane that r egula te th e trans-
ATP synth ase is the major protein of the inner mito- ecul es) cross the plasma membrane by simple diffusion port of the molec ule (Fig. 2. 7c) . They are io n selective
chondrial membr ane, and digestive enzymes such as di- down their concentra tion gradient (Fig. 2.7a) . All oth er a nd are regulated on the basis of the cell's needs. Cha n-
sacd1 a rid ases and dipep tidases ar e integra l membrane molecules require membrane tmnsport proteins to provide nel pro tein transport ca n be regulated by membrane po-
proteins. them with individual passage across the plasma membrane. tent ia ls (e.g., voltage-gated ion channels in neurons),
Structural proteins ar e vis ua lized by the freeze fracture There are generally two classes of tra nsport p roteins: ne uro transmitter s (e.g. , ligand-gated ion channels such
method, especiall y w here th ey fo rm junctio ns with as acetylcholine receptors in muscle cells), or mechanical
Carrier proteins transfer small, wa ter-soluble molec ules.
neighbo ring cells. O ften, certain proteins and lipids are stress (e.g., stress-activated channels in the inner ear) .
They are highly selective, often transporting only o ne
concentrated in loca lized regions of the plasma mem- type of molecule. After binding to a mo lecule designated
brane to carry o ut specific functions. Exa mples of such Vesicular t ranspor t maintains t he integrity of the plasma
for transport, the carrier protein undergoes a series of
regio ns can be recogni zed in polarized cells, such as ep- membrane and also provides for t he transfer of molecules
conformational changes and releases the m o lecule o n
ithelial cells. between different cellular compartments
the other side of the membra ne (Fig. 2.7 b). Some carrier
proteins, such as the Na ~/K ' pump or H ' pum p, require
Integral membrane protei ns move within the lipid bilayer Som e su bstances enter and leave cells by vesicular trans-
of the membrane port, a process that involves conformational changes in the
plasma membrane at localized sites and su bsequ ent fo rma-
The fluidity of the plasma mem br ane is no t revealed in tion of vesicles from the membrane or fusion of vesicles
static electron micrographs. H owever, exp eriments show A B c with the membr ane (Fig. 2.8).
that the mem brane beha ves as tho ugh it were a two- The ma jor m echanism by w hich large mo lecul es entet;
SIMPL E CARRIER CHANNEL transport
dimensional lipid fluid . Proteins with their hydroph o bic re- leave, and move withi n the cell is called vesicle budding.
DIFFUSION PROTEIN PROTEIN vesicle
gions loca li zed in the interi or of the lipid bilayer ar e free to Vesicles formed by budding fro m the plasm a mem brane of
o ne compa rtment fuse with the plas ma membrane of an- ENDOCYTOSIS
d iffuse laterally.
Particles bound to the m embrane can move o n the surface other compartment. W it hi n the cell, this process ensures FIGURE 2.8
intercompartmenta l transfer of the vesicle contents. Endocytosis and exocytosis are two major forms of vesicular trans-
of a cell; even integra l membrane proteins, such as enzymes,
Vesicul ar transport invo lving the cell mem bra ne may port. End ocytosis brings molecules and other substances into the cell.
may move fro m one cell surface to another, e.g., from apica l
In exocytosis, synthesized molecules and other substances leave th e
to lateral, w hen barriers to \ow, such as cell junctio ns, ar e also be descr.ibed in more specific terms:
cell. Endocytosis is associated with the formation and budding of vesi-
disrupted . T he fluidity of the membrane is a function of the Endocytosis is the general term fo r processes of vesicu- cles f rom the plasma membrane; exocytosis is associated with the fu-
types of p hospholipids in the membrane and variatio ns in lar tra nsport in w hich su bstances enter the cell. sion of vesicles originating from intracellular organelles w ith th e
their loca l concentration. Exocytosis is the general term fo r processes of vesicular plasma mem brane and is a primary secretory modality.
Integral mem brane p ro teins may m ove to mediate a transport in w hich su bstances leave the cell.
hormone r esponse o r to so rt (or move) to a diffe rent region I
of the plasma mem bran e. The lateral diffusion of proteins I I Both processes can be visualized with th e electro n m iCl:o-
is often limited by physical connections between mem- 1- MEMBRANE TRANSPORT - 1 sco pe.
bra ne pro teins and in trace llular or extracelJular structures. FIGU RE 2.7
Such connecti o ns may exist Movement of molecules through the plasma membrane. a. Fat- fo rmed by virtually every cell in th e organism , and it is
EN DOCYTOSIS
soluble and other small uncharged molecules (in green) cross t11e constitutive; i.e., it involves a cont inuou s dynamic fo r-
plasma membrane by simple diffusion down their concentration gra- mati o n of sm all vesicles at the cell surface (Fig. 2.9a) .
Between proteins associated with cytoskeleta l filaments Uptake of fluid and macromolecules during endocyt osis
dient. b. Other molecules req uire membrane transport proteins to pro- Recent studies indicate that m ec hanoenzymes suc h as
and portions of the mem brane proteins that extend in to vide them with individual passage across the plasma membrane.
depends on three different mechanisms
GTPase (d yn am in) are involved in pinocytotic vesicle
the ad jacent cytoplasm Small water-soluble molecules (in blue) require highly selective carrier scissio n (the process o f pinchi ng o ff fro m the plasm a
Between the cytopl asmic doma ins of mem brane proteins proteins to transfer them across the plasma membrane. After binding Som e of the endocyto tic mechan isms require special pro-
membrane) . Pinocyto tic vesicles a re visible with t he
Between perip hera l proteins associated with the extra- with a molecule, the carrier protein undergoes a series of conforma- teins during vesicle fo rmatio n. The best k nown protein
TEM, and they have a sm ooth surface. These smooth
cellul ar matrix and the integral mem brane pro tein s that tional c11anges and releases the molecule on the other side of the that interacts with the plasma membra ne in vesicle for ma-
pinocyto tic vesicles a re especia lly numero us in the en-
extend from th e cell surface, i.e., the extracell ul.ar do- membrane. If the process req uires energy, it is called active transport tion is clat/?1--in. T herefo re, endocytos is can be also be clas-
(e.g., transport of W ions against their concentration gradient). The
do thelium of blood vessels (Fig. 2.9b) and in smooth
mam sil1ed as either cl athrin dependent or clathrin independ ent.
process is called passive transport when energy is not required (e.g., muscle cells. Pinocytosis does not require clathrin and
In genera l, three mechan isms o f end ocytosis are recogn ized
glucose transport). c. Ions and other small charged molecules (in red ) therefor e m ay be r eferred to as clathrin-indefJendent en-
in the cell:
Thro ugh these con necti ons, proteins can be localized o r re- are transported through the plasma membrane by ion-selective chan- docytosis.
stricted to "specia lized " regions of the plasma mem bran e nel proteins. In neurons, for instan ce, ion transport is regulated by Pinocytosis {Gr., cell drin/(ingj is the ingestion o f fl uid a nd RecefJtor-mediated endocytosis allows entry of specific
o r act as transmembra ne linkers between intracel lular and membrane potentials (voltage-gated ion channels); in skeletal muscle sm a ll protein molecu les via sma ll vesicles, usuall y mo lecul es in to the cell. ln this mechanism, recep tors fo r
extracellula r filaments (see below). cells, neuromuscular junctions possess ligand-gated ion channels. small er tha n 150 nm in d ia meter. Pinocytosis is per- speci fic mo lecules, ca lled cmgo 1'eceptors, accumulate in
26 CHAPTER 2 The Crll
CD
0 -cargo formation of formation of
0 0 protein coated pit coated vesicle
cargo receptor
!
c-- adaptin
I
e Q
clathrin --=o00
oooo
~ 0
000
a
PINOCYTOSIS
FIGURE 2.9
Pinocytosis. a. Pinocytosis involves the dynamic
formation of small vesicles at tile cell surface.
First, substances to be pinocytosed (e.g., small
soluble proteins, colloidal tracers) make contact
with tile extracellular surface of the plasma FIGURE 2.10
membrane; next, the surface becomes indented; Receptor-mediated endocytosis. a. This diagram shows the steps in proteins and their receptors are thus pulled from the extracellular
and finally, the invaginated portion of tile mem- receptor-mediated endocytosis, a transport mechanism that allows space into the lumen of a forming coated vesicle. After budding and
brane pinches off from tile membrane to be- selected molecules to enter tile cell. CD Cargo receptors recognize and internalization of the vesicle, the coat proteins are removed (5) and
come a pinocytotic vesicle within the cell. b. This bind specific molecules that come in conta ct wit h the plasma mem- recycled for further use. Tile uncoated vesicle travels to its desti-
electron micrograph shows numerous smooth- brane. Cargo receptor-molecule complexes are recognized by nation to fuse with a cytoplasmic organelle. b. Electron micrograph of
surfaced pinocytotic vesicles witl1in the cyto- adaptin, a protein that helps select and gather appropriate complexes the cytoplasmi c surface of the plasma membrane of A431 cells pre-
plasm of endothelial cells of a blood vessel. in specific areas of the plasma membrane for transport into cells. pared by the quick-freeze deep-etch techniqu e. This image shows
X60,000. CD Clathrin molecules tl1en bind to the adaptin-cargo receptor- coated pits and clathrin-coated vesicles in different stages of their for-
molecule complex to assemble into a shallow basket-like cage, form- mation. Note that the coated pits and clathrin-coated vesicles are
ing a coated pit. @ Ciath rin interactions th en assist the plasma mem- formed in areas devoid of actin filaments. The small uniform pinocy-
bra ne to change shape to form a deep depression, a fu lly formed totic vesicles do not have a clathrin coat and are located in close
coated pit that then pinches off from the plasma membrane as a proximity to actin filaments. X200,000. (Courtesy of Dr. John E.
coated vesicle @ (i.e., budding from the membrane). Selected cargo Heuser, Washington University School of Medicine.)
well-defined regions of the cell mem brane. These regions as a result o.f receptor-media ted endocytosis is referred
eventually become coated pits (Fig. 2.1 0a) . T he name to as a coated vesicle, and the process itself is known as
"coated pit" .is derived from their appea ra nce in the elec- clathrin-dependent endocytosis. Clathrin-coated vesi- FIGURE 2.11
tron microscope as a n accumulation of electron-dense cles are also involved in the movement of the cargo ma- Phagocytosis. a. This drawing shows tile
material that represents aggregation of clathrin mole- teri al from the plasma membrane to endosomes and bacterium steps in the phagocytosis of a large parti-
cules on the cytoplasmic surface of the plasma mem- from the Golgi apparatus to the plasma mem brane. non bio logic material
actin filaments of cle, such as a bacterium that has been
bra ne. Cargo receptors recognize and bind to specific Phagocytosis [Gr., cell eating] is th e ingestion of large terminal web killed as a result of an immune response.
molecules that come in contact with the p lasma mem- particles such as cell deb ris, bacteria, and other for- The bacterium is surrounded by antibodies
brane. Clathrin m olecules then assemble into a basket- eign ma terials. In this process, la rge vesicl es (la rger attached to the bacterial surface antigens.
li ke cage that helps change the shape of the plasma than approxima tely 25 0 nm in diameter) ca ll ed phago- F, receptors on the surface of the plasma
membrane at that site into a vesicle-li ke invagination somes are produced. Ph agocytosis is perfo rmed mainly membrane of the phagocytotic cells recog-
nize the F, po1iion of the antibodies. This
(Fig. 2.10b). C lathrin interacts with the cargo receptor by a specia li zed group of ce lls belonging to the phagosome
interaction triggers formation of phage-
via another coating protein, adaptin, which is instru- mononuclear p hagocytotic system (MPS) . Phagocyto-
somes and intracellular destruction of the
mental in selecting appropria te cargo molecules for sis is genera ll y a receptor-mediated process in which
microorganism. Because of the large size
tra nsport into the cells. Thus, selected cargo proteins receptors on the cell surface recogni ze non-a ntigen- of the phagosomes, the actin cytoskeleton
and their receptors are pulled fro m the extracell ular binding domains (Fe fragments) of antibodies coating is rearranged by depolymerization and re-
space into the lumen of a forming vesicle. The large the surface of an invading microorgani sm or cell (Fig. polymerization of actin filaments. b. Non-
(100-kDa) mechanoenzyme (GTPa se, also called dy- 2.11 a). H owever, nonbiologic materi als s ucb as in- biologic materials such as inhaled carbon
namin) mediates the li beration of for ming clathrin- haled ca rbon particles, inorganic dusts, and asbestos particles, inorganic dusts, and asbestos
coated vesicles from the plasma membrane during fibers, as well as bi ologic debris from inflammation , fibers, as well as cellular debris resulting
receptor-mediated endocytosis. The type of vesicle formed wo un d healing, and dead cells, are sequestered by cells from inflammation, are internalized with-
b out involvement of antibodies and F, re-
ceptors. l11ese pa1iicles are bound to mul-
phagolysosome lysosome tiple receptors on the plasma membrane.
18 CHAPTER 2 Tilr Cr/1 CHAPTER 2 Tile Cr/1 '29
of the MPS without invol vement of Fe receptors (Fig. ligand In the maturation model, early endosomes ar e formed
2.11b). T his process does not require clathrin. How- de novo fro m endocytotic vesicles originating from the
ever, because of the large size of the vesicle, the actin
cytoskeleton m ust be rearranged in a process that
plasma membrane. T herefore, the composition of the
ea rly endosoma l membrane changes progressively as
requires dep olymeriza tion and repolymerization of the some components are recycled between the cell su rface
actin fi lam ents. Thus phagocytosis is referred to as an d the Golgi apparatus. T his maturation process leads
clathrin-ittdependent and actin-dependent endo- to for mation of late endosomes and then to lysosomes.
cytosis. Specific receptors present on earl y endosomes, e.g., for
coated vesicles, are removed by recycling, degradation,
EXOCYTOSIS
constitutive
secretory
Q o r inactivation as this compartment matures.
pathways Both models actua lly complement rather than contrad ict
Exocytosis is the process by which a vesicle moves from the each o th er in descri bing, identifying, and stud ying th e
cytoplasm to the plasma membrane, where it discharges its pathways of internalized molecules .
contents to the extracellular space
Endosomes destined to become lysosomes receive newly
A variety of molecules prod uced by the cell for export synthesized lysosomal enzymes that are targeted via the
a re ini tia lly delivered from the site of their formation to the mannose-6-phosphate receptor
Golgi appa ratus. The next step involves sorting a nd pack-
aging the secr etory product into transport vesicles that are Some endosomes also communicate with the vesicular
destined to fuse with the p lasma membrane in a process transport system of the rER. This pathway provides
known as exocytosis. The molecules that travel th is route constant delivery of newly synthesized lysosomal enzymes,
are often chemically modified (e.g., glycosylated, sulfated ) o r hydro lases. Hydrolases are synthesized in the rER and
as they pass through different cellular compartments. The are glycosylated. The protein then fo lds in a specific way
membrane that is ad ded to the plasma membrane by exo- so that a signal patch is formed and exposed on the sur-
cytosis is recovered into the cytoplasm ic compartment by FIGURE 2.12 face of the molecule. T his recognitio n signal is created
Photomicrograph of secretory cells of the pancreas. Note that secre-
an endocytotic process. There are two gener a l pa thways of w hen specific amino ac ids are brought into close proxim-
tory vesicles containing protein ready for secretion fill the apica l por-
exocytosis: ity by th e three-d imensional foldin g of the protein. The sig-
tion of the cells. This process req uires an external signaling mecha-
In the constitutive pathway, substances designa ted for nism for the cell to discharge the accumulated granules. x 860.
rER
export are continuously delivered in transport vesicles to
the plasma membrane. Protei ns that leave the cell by this
pr ocess are secreted inunediately after their synthesis
and exit from the Golgi apparatus, as seen in the secre- Endosomes
tio n of immu noglobulins by plasma cells and of The TEM reveals the presence in the cytoplasm of mem-
tro pocollagen by fibroblas ts. T his pathway is present to brane-enclosed compartments associated with a ll the endo- FIGURE 2.13
some degree in a ll cells. T he TEM revea ls that these cells cytotic pathways described above (Fig. 2. 14). These com- Diagram showing two pathways for exocytosis. Newly synthesized
proteins are synthesized in the rER. After their initial posttranslational
lack secretory granules. partments, called early endosomes, are restricted to a
modification, they are delivered in COP-11-coated vesicles to the Golgi
In the regulated secreto1y pathway, specia lized cells, portion of the cytoplasm nea r the cell membrane where vesi-
apparatus. After additional modification in the Golgi apparatus, sorting,
such as endocrine and exocrine cells and neurons, con- cles origin ating from the cell membrane fuse. From here, and packaging, the final secretory product is transported to the plasma
centrate secretory proteins and tra nsientl y store them in many vesicles return to the plasma mem brane. However, membrane in vesicles that form from the trans-Golgi network (TGN).
secretory vesicles w ithin th e cytoplasm (Fig. 2. 12). In large mun bers of vesicles originating in ea rly endosomes Two distin ct pathways are recognized. Blue arrows indicate the consti-
this case, a regulatory event (h ormo na l or neura l stimu- travel to deeper structures in the cytoplasm, called Late en- tutive pathway in which proteins leave the cell immediately after tl1eir
lus) must be activated for secretion to occur, as ill there- dosomes. The latter typica lly develop into lysosomes. synthesis. In cells using this pathway, little secretory product accumu-
lease of zy mogen granules by chief cells of the gastric lates, and thus few secretory vesicles are present in the cytoplasm. Red
mucosa and by acinar cells of the pancreas . T he signal- Endosomes can be v iew ed either as stable cytoplasmic arrows indicate the regulated secretory pathway In which protein se-
ing stimu lus causes a transient influx of Ca 2 + into the cy- organelles or as transient structures formed as the result of cretion is regulated by hormonal or neural stimuli. In cells using this
toplasm, w hich in turn stimulates secretory vesicles to pathway, such as the pancreatic acinar cells in Figure 2.12, secretory
endocytosis
fuse with the plasm a membrane and d ischarge their con- proteins are concentrated and transiently stored in secretory vesicles
within the cytoplasm. After appropriate stimulation, the secretory vesi- FIGURE 2.14
tents (Fig. 2.13 ). Recent experimental observations of endocytotic path- Electron micrograph of an early endosome. This deep-etch electron
cles fuse with the plasma membrane and discharge their contents.
ways conducted in vitro and in vivo suggest two diffe rent micrograph shows the structure of an early endosome in Dic-
In addition to excretor y pathways, proteins ca n be models that explain the orig in and formation of the endo- tyoste/ium. Early endosomes are located near the plasma membrane
transported between the Golgi apparatus and other or- somal compartments in the cell: cell and with the Golgi apparatus. Coated vesicles and have a typical tubuloveslcal structure. The lumen of the endo-
ganelles along end osoma l path ways. T hese pathways are formed at the p lasma membrane fuse only with early en- some is subdivided into multiple compartments or cisternae by the In-
used for delivery of organelle-specific pro teins, such as The stable compm'tment model describes ea rly and late dosomes because of their expression of specific surface vagination of its membrane and undergoes freq uent change in
lysosoma l structura l protein s, into the appropriate o r- endosomes as sta ble cellular organelles connected by receptors. The receptor remai ns a resident component of shape. x l S,OOO. (Courtesy of Dr. John E. Heuser, Washington Univer-
ga nelles. vesicul ar tra nsport with the extern al enviro nment of the the ea rl y endosomal membrane. sity School of Medicine.)
30 C H APTER 2 The Cell CHAPTER 2 Tl!t Cell 3I
receptor
nal patch on a protein destined for a lysosome is t hen mod- additional sig nal s. For that reason, late endosomes are The fate of the internalized ligand- receptor complex depends
ified by several enzymes that attach mannose-6-phosphate a lso called prelysosomes . on the sorting and recycling ability of the early endosome
(M-6-P) to the enzyme surface. M -6-P acts as a ta rget for
specific proteins p ossessing a M-6-P recept01: M -6 -P re- The major function of early endosomes is to sort and recycle The fo llowing pathways fo r processing internali zed
ceptors are present in early and late endosomes, lysosomes, proteins internalized by endocytotic pathways liga nd-receptor complexes a re p resent in th e cell:
a nd the Golgi apparatus that is involved in sorting a nd re-
trieving secreted h ydrolyses destined for transport t o en - Ear ly endo somes sort prot eins that h ave bee n inte rnal- The 1'eceptor is recycled and the ligand is degraded.
d osomes (Fig. 2 .15). ized by endocytotic processes. The m orpholog ic shape Surface receptors a llow t h e cell to br.i ng in s ubstances
and geometry of the tubules and vesicles emerging rom selectively throu gh the process of endocytos is. This
Early and late endosomes differ in their cellular localization, the ea rl y endosome crea te a n environment in w hic h l o- pathway occurs m ost often in the ce ll; it is important
morphology, and state of acidification and fu nction ca lized changes in pH constitute the basis of the sorting because it a ll ows surface r eceptors to be recycle d. Most
mechanism. This mechanism includes dissociatio n of lig- liga nd-rece pto r comp lexes dissociate in the acidic pH
Early an d late endosomes are localized in different a r - ands from th e ir recep tor protein; thus, in the p as t , ea rly o f the early endosome. The recepto r, most likely an in-
eas of the ceiL Ear ly e ndosomes ca n be found in the m o re en dosomes were referred t o as compartments of uncou- tegral membra ne protein (see page 22), is recycled to
periphera l cyt oplasm, w hereas late end oso m es are o ften pling recetJtors and ligands (CURLs) . In add ition, the the surface via ves icles tha t bud off t he ends of narrow-
positioned near the Golgi appara tu s and the nucleus. n arr ow di a m et er of th e tubules a nd vesicles may a lso aid diamet er tubules of the ea rl y end osome. Ligands are
Ea rly end osomes have a tubulovesicular structure: The in th e sorting of large molecules, w hi ch can be m ech ani- u sua lly seq uestered in the spherical vacuolar part of the
lumen is subdivided into cistern ae th at are separate d by ca lly preven te d from en tering speci fic sortin g co mp art- end osome that w ill la ter form MVBs, w hic h will trans-
in vaginati on of its mem bran e. They ex hibit only a ments. After so rting, m ost o f the protein is rap idly recy- port the ligand to l a te end osomes fo r further degrada-
c led, and the excess membrane is re turned to the plasma tion in the lysosome (Fig. 2.17a). This pathway is de-
membrane . scribed for the low-density lipoprotein (LDL)- receptor
coated vesicle
secretory component
LDL receptor
of lgA ~
--..--.,..,
M-6-P receptor
FIGURE 2.16
Schematic diagram of endosomal compartments of the cell. This di
agram shows the fate of protein (red circles) endocytosed from the cell
surface and destined for lysosomal destruction. Proteins are first found
in endocytotic (coated) vesicles that deliver them to early endosomes,
which are located in the periplleral part of cytoplasm. Because of the
sorting capa bility of the early endosomes, receptors are usually recy
cled to the plasma membrane, and endocytosed proteins are trans-
ported via multivesicular bodies (MVB) to late endosomes positioned
near the Golgi apparatus and the nucleus. The proteins transported to
rER
late endosomes eventually will be degraded in lysosomes. Note the
acidification scale (left) that illustrates cha nges of pH from early endo
somes to lysosomes. The acidification is accomplished by the active
transport of protons into endosomal compartments.
lysosome
late endosome a b c lgA receptor d
sl ig htl y m o re acid ic env iro nment (pH 6 .2 to 6 .5) tha n the early en dosome
cytoplas m o f the cell. In contrast, la te end osomes h ave a FIGURE 2.1 7
more com p lex structure and often exhi bit o ni on-lik e in- Fate of receptor and ligand in receptor-mediated endocytosis. This endosome, the tra nsferrin-receptor complex returns to th e cell sur
FIGURE 2.15 ternal mem branes . Their pH is more acid ic, aver agi ng diagram shows fou r major pathways along which the fate of inter- face, where transferrin is released. c. The internalized liga nd-receptor
Pathways for delivery of newly synthesized lysosomal enzymes. 5.5. TEM studies reveal specific vesicles that transport nalized ligand-receptor complexes is determined. a . Tile internalized complex dissociates in the early endosome. The free ligand a nd tile re
Lysosomal enzymes (such as lysosomal hydrolases) are synt11 esized s ubsta nces be tween ear ly and late end osom es. These vesi- ligand-receptor complex dissociates, the receptor is recycled to the ceptor are directed to the late endosomal compartment for further
and glycosylated within the rER. The enzymes then fo ld in a specific cell surface, and tl1e ligand is directed to late end osomes and even- degradation. This pathway is used by many growth factors (i.e., epi-
cles, ca lled multivesiculm- bodies (MVB), are highly se-
way so that a signal patch is fo rm ed, which allows for further modifi- tually degraded within lysosomes. This processing pathway is used by dermal growth factor (EGF)/EGF- receptor.) d. The internalized lig-
lecti ve transporters. With in early end osomes, proteins
cation by tl1e addition of mannose6phospate (M-6-P). M-6-P allows the LDL/ LDL-receptor complex, insulin-GLUT receptor complex, and and-receptor complex is transported through the cell. Dissociation
destined to be transported to late endosom es a re so rted a variety of peptide hormone-receptor complexes. b. Both internal-
the enzyme to be targeted to specific proteins that possess M-6-P re does not occur, and the entire complex undergoes transcytosis and re
ceptor activity. M-6-P receptors are present in the trans-Golgi network an d separated from proteins destined for recycling and ized receptor and ligand are recycled. Ligand-receptor complex dis- lease at a different site of the cell surface. This pathway is used during
(TGN) of the Golgi apparatus, where the lysosomal enzymes are packaging into MVBs (Fig . 2.16) . In gener a l, s ubstances sociation does not occur, and the entire complex is recycled to the secretion of immunoglobulins (secretory lgA) into saliva. Tile antibody
sorted and packaged into vesicles later transported to the early or tra n sported t o late end osornes are eventually degr a ded in surface. An exam ple is t11e iron-transferrin/transferrin- receptor com- lgA-receptor complex is internalized at the basal surface of the secre
late endosomes and lysosomes. lysosomes in a d e fau lt process tha t does not require any plex that uses this processin g pathway. Once iron is released in the tory cells in the salivary gland and released at the apical surface.
3'2 C HAPTER 2 The Cell C HA PTE R 2 Tbc Crll 33
complex, insulin-glucose transporter (GLUT) receptor Lysosomes lysosomal membrane glycoproteins (lgps), and lysoso-
complex, a nd a variety of peptide hormones a nd thei r mal integral membrane proteins (limps). The la mps,
receptors. Lysosomes are digestive organelles that were recognized only lgps, and limps represen t more than 50% of th e total Golgi apparatus
Both receptor attd ligand are recycled. Liga nd- after histochemical procedures were used to demonstrate membrane proteins in lysosomes a nd are highl y g lycosy-
receptor complex dissociation d oes not a lways acco m- lysosomal enzymes lated on the lumina l surface. Suga r molecules cover al-
pany receptor recycling. For exampl e, th e low pH of most th e en tire luminal surfa ce of th ese pro teins, thus
th e endosome dissociates iron from the iron-carrier Lysosomes a re organelles ric h in hydrolytic enzymes protecting them from digestio n by h ydrolyti c enzymes.
protein tra nsferrin, but transferrin remains associated such as proteases, nucl eases, glycosidases, lipases, and The sa m e fam il y of proteins is a lso detected in la te endo-
with its receptor. Once the transferrin-receptor phospholipases. They ar e r es ponsible for degradation of somes. In addition, lysosomes and late e ndosom es con -
complex returns to the cell surface, however, tra ns fer- macromolecu les d erived from endocytotic pathways as ta in proton (H+) pumps tha t transport H + ions into the
r in is released. At neutral extracellular pH, transferrin we ll as frorn the cell itself in a process known as au- lysosomal lumen, mainta ining a low pH (-4.7). The lyso-
must aga in bind iron to be r ecogni zed by a nd bound tophagy (remova l o f cytop lasmic components, particu - somal membrane also contains transport proteins that
to its receptor. A sim il ar pathway is reco gnized for larly me mbra ne-bo unded o rganelles, by digesting them t ransport the fina l products of diges tion (amino acids,
major histocompatibility complex (MHC) l and II within lysosomes). suga rs, nucleotides ) to the cytoplasm, w he re they ar e
molecules, which a r e recycled to the ce ll s urface with The first hypoth esis for lysosomal biogen esis, formu - used in th e synthetic p rocesses of the cell or are exocy-
a foreign antigen protein attached to t he m (Fig . lated a lmost a half cen tury ago, postula ted that lyso- tosed. All membrane proteins d estined for lysosomes
2. 17b). somes arise as comple te a nd fu nctiona l organelles bud- (a nd late endosomes ) are synthesized in the rER, tra ns-
Both receptor and ligand are degraded. This pathway ding from the Golgi a pparatus. These newly formed ported to the Golgi apparatus, a nd reach their destina-
has been identified for e pidermal g rowth factor (EGF) lysosomes were termed primmy lysosomes, in con trast to tion by on e of two pathways:
and its receptor. Like many other pro teins, EGF binds secondary lysosomes, which ha d already fused w ith in-
In the constitutive secretory pathway, li mps that exit the
to its receptor on the cell surface. The complex is inter- coming endosomes. Howeve r, the primary a nd secondary
Golgi appa ratus a re deli vered to the cell surface. From
na lized and carried to the early endosomes. H e re, EGF lysosome hypothesis has proved to have little validity as
here, they are endocytosed and, via the ea rly a nd late en-
dissociates fro m its receptor, and both a re sorted, pack- new research data allow a better und erstanding of the de-
d osomal compa rtments, finally reach lysosomes (Fig.
aged in separate MVBs, a nd transferred to the late en- tails of protein secretory pathways a nd the fate of endo-
2. 19). This pathway does not require the M-6-P rece p-
dosome. From there, both ligand and receptor are cytotic vesicles.
to r targeting mechanism.
transferred to lysosomes, where they are deg rad ed (Fig.
In the Golgi-derived coated vesicle sec1eto1y pathway,
2. 17c) . Lysosomes have a unique membrane that is resistant to the
limps, after sorting and packaging, ex it the Go lgi appa - FIGURE 2.19
Both 1eceptor and ligand are transported through the hydrolytic digestion occurring in their lumen
ra tus in clathrin-coated vesic les (see Fig. 2 .1 9). These Lysosome biogenesis. This diagram shows regulated and constitutive
cell. This pathway is used fo r secre tion of im-
vesicles are d elivered to the ea r.l y a nd/or late endosome patl1ways for delivery of lysosomal specific membrane proteins into
munoglo bulins (secretory IgA) into sali va or secretion Lysoso mes contain a collecti o n of hydrolytic enzymes
in a ma nn er similar to that described for soluble lysoso- early and late endosomes. The lysosomal membrane possesses
of ma te rnal IgG into milk. During this p rocess, com- and are surrounded by a u nique membrane that resists
ma l enzymes; thus, the M -6-P targeting mecha nism is r e- highly glycosylated specific membrane proteins that protect the me m-
monl y referred as transcytosis, substa nces ca n be a l- hydrolys is by th eir own e nzymes (Fig. 2. 1 8). Most of the brane from digestion by lysosomal enzymes. These lysosomespecific
quired for this pa thwa y (see page 29).
tered as th ey a re tra nsported across th e e pithelia l cell structural lysosom a l mem bra ne proteins a re classifi ed proteins are synthesized in the rER, transported to the Golgi appara-
(Fig. 2. 17d). in to lysosome-associated membmne proteins (lamps), tus, and reach their destination by two pathways. Blue arrows indicate
Three different pathways deliver material for intracellular
digestion in lysosomes the constitutive secretory pathway in which certain lysosomal mem-
brane proteins exit the Golgi apparatus and are delivered to the cell
surface. From there they are endocytosed and, via the early and late
Depending on th e nature o f the digested ma teria l, d if-
endosomal compartments, finally reach lysosomes. Green arrows Indi-
fcte nr pathways deliver materia l fo r di gestion within the cate the endosomal Golgiderlved coated vesicle secretory pathway.
lysosomes (Fig. 2.20). In the digestion process, most of the Here, other lysosomal proteins, after sorting and packaging, exit the
digested material comes from endocytotic p rocesses; how- Goigi apparatus In clathrincoated vesicles. These vesicles are deliv-
membrane impermeable to enzymes; ever, t he cell also uses lyso somes to digest its own obsolete ered to the early and/or late endosome by use of the M-6-P ta rgeting
conta ins specific lysosomal proteins, parts, nonfunctiona l organelles, a nd unnecessa ry mole- mechanism.
lamps, limps, a nd lgps
cules. Three pathways fo r digestion exist:
transport Extracellular large particles suc h as bac teri a, cell debris,
protein~ polysaccharides a nd other foreign mate ria ls are e ng ulfed in the process
nucleases & o f phagocytosis. A phagosome, formed as the material is
nucleic ___.Ji related e nzymes Intracellulm pm-ticles such as entire organelles, cytoplas-
internalized w ithi n t he cytoplasm, subseq uentl y fuses
FIGURE 2.18 acids mic p roteins, and other cellula r components are isola ted
phospha tases H+ proton with a lyso some to create a phagolysosome.
Schematic diagram of a lysosome. This aryl from the cytoplasmic matrix by endoplasm ic retic ulum
pump Extracellular small pm-ticles such as extracellular pro-
diagra m shows a few selected lysosomal s ulfatases membr a nes, transported to lysosomes, a nd degraded in
H+ tei ns, plasma membrane proteins, a nd liga nd-receptor
enzymes residing inside the lysosome the process called autophagy (see below).
and their respective substrates. The ma- co mplexes a re interna li zed by en docytosis a nd receptor-
jor lysosomal membranespecific pro- mediated endocytosis. These particles fol low the endo- In addition, some cells (e.g., osteoclasts involved in bone re-
sorption and neutroph ils invo lved in acute inflammation)
teins, as well as a few other proteins as-
sociated with membrane transport, are
I
organic-linked
organic-linked cytotic pathway throug h early and late endosomal com-
partments and are finally delive red to lysosomes for may release lysoso mal enzymes directly into the extracellu-
sulfates
also shown. phosphates deg radation. lar sp ace to digest components of the extracellula r matrix.
34 CHAPTER 2 T/Jr Cr/1 C H APTER 2 TIJr Cd/ 35
cr oa utoph agy, small cytoplasmic soluble p roteins are in- Rough-Surfaced Endoplasmic Reticulum
ternalized into the lysosomes by invagination of t he
lysosomal membrane. The protein synthetic system of the cell consists of the rough
Chaperone-mediated direct tra11sport to lysosomes is endoplasmic reticulum and ribosomes
the only selective process of protein degradation an d re-
quir es assistance from a specific chaperone P1'otein T he cytoplasm of a variety of cells engaged chiefly in pro-
called hsc73. This process is activated during n utrient tein synthesis stains intensely w ith basic dyes. The ba-
deprivation and requ ires t he presence of targeting sig- sophilic staining is due to the presence of RNA. That por-
nals on the degraded proteins and a specific receptor on tion of the cytoplasm that stains w ith the basic dye is called
the lysosom a l membrane. Chaperone-mediated direct ergastoplasm. The ergastoplasm in secretory cells, e.g.,
transport resembles the process of protein import to var- pancreatic acinar cells, is the light microscopic image of t he
ious other cell ular orga nel.les: hsc73 binds to the protein organelle called the mugh endoplasmic reticulum (1-ER).
W it h the TEM, the rER appea rs as a series of in tercon-
nected, membrane-li mited flattened sacs called cisternae,
endoplasmic with pa rticles studdi ng t he exterior smface of the mem-
reticulum
bra ne (Fig. 2.23) . T hese particles, called ribosomes, are at-
FIGURE 2.20
Pathways of delivery of materials for digestion in lysosomes. Most
\ auto phagosome
vacuole
FIGURE 2.22
Electron micrograph of autophagosomes in an hepatocyte. T11is
electron micrograph shows several autopllagosomes containing de-
generating mitochondria. Note the surrounding lysosomes that had
of the material to be digested comes from endocytotic pathways (red been stained w ith acid phosphatase. Xl2,600. (Courtesy of Dr.
arrows). It consists of small extracellular particles that are interna lized MACROAUTOPHAGY
Wi lliam A. Dunn, Jr.)
by both endocytosis and receptor-mediated endocytosis. Large extra-
cellular particles such as bacteria and cellular debris are delivered to
lysosomes v ia the phagocytotic pathway (blue arrows). The cell also and assists in its tr ansport through the lysosoma l mem-
uses lysosomes to digest its own proteins and other intracellular par-
ticles via the autophagic pathway (green arrows). Intracellular particles
brane into the lumen, where it is fin all y degraded .
are isolated from the cytoplasmic matrix by the membranes of the
MICROAUTOPHAGY Lysosomes in some cells are recognizable in the light
endoplasmic reticulum, transported to lysosomes, and subsequently
degraded. microscope because of their number, size, or contents
A
---tf:\
site~
FIGURE 2.25
Summary of events during protein synthesis. Prior to the events de-
picted here, DNA has been 'translated" into mRNA, and t11e large and
small ribosomal subunits have assembled into a ribosome. Notice that
lope (see below). Groups of r ibosomes form short spiral close as 80 nucleotides apart, thus forming a po lyribosome tl1e ribosome has two binding sites: the p site and the ' A" site. 1. Trans
~(~
arrays called polyribosomes or polysomes (Fig. 2 .24), in complex, or polysome. A polysome ca n translate a single fer RNA (tRNA) with a growing peptide chain is bound to the P site of
the ribosome. The initial amino acids of the nascent protein constitute
w hich many ribosomes a1e attached to a thread of mes- mRNA molecule and simultaneously produce many copies
the signal sequence (red). The nascent protein grows by adding amino
senger RNA (mRNA). of a particular protein.
acids at the end of the chain opposite to the signal sequence. 2 . An in
coming tRNA with an amino acid attached binds to the A site. 3. A pep-
Protein synthesis involves transcription and translation Polysomes of the rER synthesize proteins for export from t he tide bond forms between the last amino acid of the growing peptide
cell and integral proteins of the plasma membrane 2 chain and the new amino acid brought to the ribosome by the incom-
The production of proteins by the cell begins w ith tran- ing tRNA. 4. The previous tRNA is released from the P site. 5. The new
scription, in w hich the genetic code for a protein is tran- 4 tRNA with tile growing peptide chain is translocated to the A site, and
As polypeptide chains are synthesized by th e mem- l mRNA 5
signal sequence threaded through tile ribosome moves along the mRNA. 6. The ribosome is attached to
brane-bound polysomes, the protein is injected into the lu- membrane pore the membrane of the rER, and after recognizing the membrane pore
men of the cisterna, where it may be further modified,
proteins, the signal sequence becomes translocated into the lumen of
concentrated, o r carried to another part o f the cell in the protein th readed
through pore the rER. 7. By enzymatic action of a signal peptidase, signal sequence
continuous channels of the rER. The rER is particularly is cleaved from the peptide. 8. After the stop codon is recognized by the
well developed in those cells that synthesize protein des- ribosome, the synthesis is terminated, and both of the ribosomal sub
tined to leave the cell (secr eto ry cells) as well as in cells 0
units dissociate from th e mRNA and the surface of the rER.
with large amounts of plasma membrane, such as neu-
rons. Secretory cells include g land ular cells, fibroblasts, present there; these modifications include core glycosyla-
plasma cells, odontoblasts, ameloblasts, a nd osteoblasts. I
rEA lumen ribosome tion, disulfide and internal hydrogen bond forma tion, fo ld-
The r ER is not limited, however, to secretory cells and dissociates ing of the newly synthesized protein, and partial subunit
~
neurons. Virtually every cell of th e bod y contains profiles assembly. The rER also serves as a quality checkpoint in
ribosome
of rER. However, they ma y be few in number, a reflectio n the process of protein productio n. If the newly synthesi zed
receptor
of the amou nt of protein secretion, and dispersed so that protein is not properly mod ified , it cannot exit the rER.
in the light microscope they are not evident as areas of membrane pore
Except fo r the few proteins that remain permanent resi-
baso philia. dents of the rER membranes and those proteins secreted by
In agreement with the observation that the rER is most the constitu tive pa thway, the newly synthesized proteins
highl y d eveloped in active secretory cells, secretory p ro -
0
~
are normally delivered to the Golgi apparatus w ithin min-
teins are synthesized exclusively by the ribosomes of the utes. In cell s in w hich the constitutive pathway is domi-
rER. In all cells, howeve1~ th e ribosomes of the r ER syn- signal sequence nant, namel y, plasma cells and developing fibro blasts,
thesize proteins th at are to become perm anent components removed completed newly synthesized proteins may accumu late in the rER cis-
of the lysosome, Golgi apparatus, rER, o r nuclear enve lope protein ternae, ca using their engorgement and distension.
(these structures are discussed below) or integral compo-
nents of the plasma membrane. Coatomers mediate bidirectional traffic between the rER and
Golgi apparatus
Signal peptides are attached to secretory proteins and integral
proteins of the plasma membrane Experimental data indicate that t wo classes of coated
Secretory proteins pass through the membrane of the rER to
vesicles are in volved i.n the transport of protein fro m and
If the protein to be synthesized is destined for export or to th e rER. A protein coat similar to clathrin surrounds
its lumen, where they are modified and stored
will become part of the plasma membra ne, the first group vesicles transpo rting proteins between the rER and the
of amino acids that are linked to o ne another form a hy- The h yd rophobic signal dom a in of a formin g secretory Golgi apparatus (page 25) . However, unlike clathrins,
dropho bic signal peptide (signal sequence) that binds to a pr otein attaches to a recepto r on the membrane o f the rER; w hich mediate bidirectional transport from and to the
receptor on th e membrane of the rER (Fig. 2.25). W hen as synthesis proceeds, the protein is inserted into and plasma membran e, one class of proteins is involved only in
the r ibosom e (polysome ) binds to the rER m embrane, the thro ugh th e membrane. Th is process is desc ribed as con- antemgrade transport from the rER to the cis-Golgi net-
FIGURE 2.24 signal peptid e or a s ubseq uent sequ ence instructs the translational insertion of protein into the rER . If t he form- work (CGN), the Golgi cisternae closest to th e rER. An-
Electron micrograph of the rER and polyribosome complexes. This newly fo rm ed peptide to pass th ro ug h th e membra ne into ing protein is no t to be threaded in its entirety thro ugh th e other class of pro teins mediates retmgrade transport from
image shows a sma ll section of the rER adjacent to the nucleus sec- the lumen of th e rER cisterna. For simple secretory pro- th e CGN back to the rER (Fig. 2.26). T hese two classes of
membrane, a new hydrophobic signal doma in stops the
tioned in two planes. The reticulum has turned within the section. proteins a re called coatomers or COPs:
teins, the polypeptide continu es to be inserted in to the lu- thr eading process, permanentl y anchoring the protein in
Thus, in t11e upper right and left, the membranes of the reticulum
men as it is synthesized. For integral membra ne proteins, the membrane at this site. COP-T mediates transport vesicles originating in the
have been cut at a right angle to their surface. In the center, the retic-
ulum has twisted and is shown as in an aerial view (from above the
sequ ences along the polypeptide may instru ct the forming On completion of protein syn t hesis, the ribosome de- CGN back to the rER (Fig. 2.27a). This retrograd e
membrane). The large spiral cytoplasmic assemblies (arrows) are protein to pass back and fo rt h through th e m embrane, taches from the rER membra ne and is again free in the cy- t ransport mediates a sa lvage operation that returns rER
chains of ribosomes that form polyribosomes that are actively en- cTeating the functional dom ains that the pro tein will ex- top lasm . The reg ion of th e newly formed protein th a t ex~ proteins mistakenly transferred to the CGN during nor-
gaged in translation of th e mRNA molecule. x38,000. hibit at its fina l mem brane locatio n. tends into the lumen of the rER is modified by enzy mes mal anterograde transport.
38 C HAPTER 2 Tlu Cell CHAPTER 2 T!Je Cell 39
<1 RETROGRADE TRANSPORT< sER is the principal organelle involved in detoxification and
conjugation of noxious substances
FIGURE 2.26
The sER is particularly well developed in t he liver a nd
Anterograde and retrograde transport between the rER and cis-
contains a variety of detoxifying en zymes related to cy-
Golgi network. Two classes of coated vesicles are involved in protein
transport to and from the rER. These vesicles are surrounded by toc hrom e P450 that are anchored directly into sER plasma
COP-I and COP-II protein coat complex, respectively. COP-II is in membranes. The degree to w hic h the liver is involved in
valved in anterograde transport from the rER to the cisGolgi network detoxification at any given time may be esti m ated by the
(CGN), and COP-I is involved in retrograde transport from the CGN amount of sER present in li ver cells. The sER is also in-
back to the rER. After a vesicle is formed, th e coat components dis vo lved in
soclate from the vesicle and are recycled to their site of origin.
Lipid and steroid me tabo lism
G lycogen metabolism
Membrane fo rmation and recycling
COP-II is respon sible fo r anterograde transport, form-
ing rER transport vesicles dest ined for the CGN (Fig.
2 .27b). COP-II assists in th e physical deformation of
rER m embra nes into sh arp ly c urved buds a nd furthe r
sepa ration of vesicles from th e rER me mbra ne. Most FIGURE 2.28
protein s produced in th e r ER use COP-ll-coated ves icles Electron micrograph of a nerve cell body. This image shows profiles
to reach the CGN. of rER as well as numerous free ribosomes located between the
membranes of the rER. Collectively, the free ribosomes and mem
Shortl y after forma ti on of COP-I- o r COP-II-coated
braneattached ribosomes are responsible for the characteristic cyto
vesicles, the coats dissociate from the newly formed vesi- FIGURE 2.27 plasmic basophilia (Nissl bodies) observed in the light microscope in
cles, a llowing the vesicle to fuse w ith its target. The coat Electron micrograph of COP-I- and COP-11-coated vesicles. a. This the perinuclear cytoplasm of neurons. X 45,000.
components then recycle to the ir si te of o rigi n. image shows COP-1-coated vesicles that initiate retrograde transport
from the cisGolgi network to the rER. In this image, taken of a quick
"Free" ribosomes synthesize proteins that will remain in the freeze deep-etch preparations, note the structure of the cisGolgi net
work and emerging vesicles. X27,000. b. Image of COP-11-coated conta in RNA; it is the phosphate groups of the RNA of the
cell as cytoplasmic structural or functional elements
vesicles that are responsible for anterograde transport. Note tl1at the ribosomes, not the m embranous component o f the endo -
surface coat of these vesicles is different from that of clathrincoated plasm ic reticulum, that accounts for basop hilic sta ining of
Cytoplasmic basoph ilia is a lso associated w it h cells that
vesicles. x so,ooo. (Courtesy of Dr. John E. Heuser, Washington Uni the cytoplasm.
prod uce large a mou nts of p rotein t hat w ill remai n in th e
versity School of Medicine.)
cell. Such cells and their p roducts incl ude d evelopi ng red
blood cells (hemoglobi n ), deve loping muscle cells {the con- Smooth-Surfaced Endoplasmic Reticulum
trac tile p roteins actin and m yo sin) , nerve cells (neurofila-
FIGURE2.29
ments), and keratinocytes of the skin (keratin ). In add it io n, In t his case, t he ribosomes and polysomes are "free" in the sER consists of short a nastomosing tubules that are not Electron micrograph of the sER. This image shows numerous profiles
most enzymes of the mitochond rion a re synthes ized by free cytoplas m ; i.e., t hey are not a ttac hed to membranes of the associated with ribosomes of sER in an interstitial (Leyd ig) cell of the testis, a cell that produces
polysomes and transferred into tha t o rgane lle . endoplasmic reticulum. T he large basop h ilic bodies of steroid hormones. Tile sER seen here is a complex system of anasto
Basophili a in these cells was formerl y ca lled ergasto- nerve cells, called Nissl bodies, consist of both rER a nd Cells with large amounts of smooth endoplasmic reticu- mosing tubules. The sma ll dense objects are glycogen particles.
plasm and is due to the presence of large amou nts of RNA. la rge numbers o f free r ibosomes (Fig. 2.28) . A ll ribosomes lum (sER) may exhibit di sti nct cytoplasmic eosinophilia X60,QQQ.
40 C HA PTER 2 Tl!e Cell CHAPTER 2 Tbe Cdl 4I
Because of these widely disparate functio ns, numerous a series of stacked, flattened, membrane-li mited sacs or
other enzy mes, including hydrolases, meth ylases, glucose- cisternae a nd tu bula r extensions embedded in a networ k
6-phosphatase, ATPases, a nd lipid oxidases, a re associa ted of microru bules near the microtu bule-organizing center
with the sER, dependi ng o n its functiona l ro le. (MTOC) (see page 53) . Small vesicles invo lved in vesicular
transport are seen in association with the cisternae. The
Golgi apparatus is polarized both morphologically and
Golgi Apparatus functi onall y. The flattened cisternae located closest to the
rER represent the forming face, or cis-Golgi network
The Golgi apparatus is well developed in secretory cells and (CGN); the cistern ae located away fro m the rER represent
does not stain with hematoxylin or eosin the maturing face, or trans-Golgi network (TGN) (Figs.
2.31 and 2.32). The cisternae located between the T GN
T he Golgi apparatus was described mo re th an 100 and CGN are commonly referred as the medial Golgi.
year s ago by histologist Camillo Golgi. In studies of os- The Golgi apparatus functio ns in the posttranslationa l
miu m-impregnated nerve cells, he discovered an organelle modifica tion, sorting, and packaging of p roteins
that for med networ ks a round the nucleus. It was also de- Small vesicles called tmnsport vesicles ca rry newly syn-
scribed as well develo ped in secretory cells. Changes in the thesized proteins (both secretory and membrane) from the
shape and location of the Golgi apparatus relative to its se- rER to the CGN. From there, they travel within the trans-
cretory state were described even before it was viewed with port vesicles from o ne cisterna to the next. The vesicles
the electron microscope and its functi o nal relationship to bud from one cisterna and fuse with the adj acent cisternae.
the rER was established. It is active both in cells that se- As proteins and lipids travel th rough the Golgi stacks, they
crete protein by exocytosis and in cells that synthesize undergo a series of posttranslational modifications that in-
large amounts of membrane a nd membrane-associa ted volve remodeli ng of N-li nked oligosaccharides previously
proteins, such as nerve cells. In the light microscope, se- added in the rER.
cretory cells that have a large Golgi apparatus, e.g., plasma In general, glycop ro teins and glyco lipids have their
cells, osteo blasts, and cells of the epididymis, typically ex- o ligosaccharides trimmed and trans located . Glycosylation
hibit a clear area partially surro unded by ergastoplasm of proteins and li pids uses several carboh yd rate-processing FIGURE 2.31
(Fig. 2.30). In electron micrographs, the Golgi appea rs as enzymes that add , remove, and modify sugar moieties of Electron micrograph of the Golgi apparatus. This electron micro- flattened vesicles on the outer convex surface, whereas the flattened
o ligosaccharide chains. M-6-P is ad ded to those proteins graph shows the extensive Golgl apparatus in an Islet cell of the pan- vesicles of the inner convex region constitute the trans-Golgi network
destined tO travel to late endosomes and lysosomes (page creas. The flattened membrane sacs of the Golgi apparatus are (TGN). Budding off the TGN are several vesicles (7 ). These vesicles are
28). In additio n, glycoproteins are phosphory lated and sul- arranged in layers. The cis-Golgi network (CGN) Is represented by the released (2) and eventually become secretory vesicles (3). xss,ooo.
fated. The proteolyti c cleavage of certa in proteins is also
initiated within the cisternae (Fig. 2.33).
Ettdosomes or lysosomes. Most of the proteins bear- concentr atio n are stored in large secretory vesicles.
Four major pathways of protein secretion from the Golgi ing M-6-P ma rkers are destined for th ese sites (see These vesicles eventu ally fuse with the plasma mem-
apparatus disperse proteins to various cell destinations page 28). brane to release the secretory pro duct by exocytosis.
Apical cytoplasm. Protei ns that were aggregated or crys- This type of secretio n is characteristic of secretory cells
As noted, proteins exit the Golgi apparatus fro m the ta llized in the TGN because of changes in pH and Ca 2 + found in exocrine glands.
TGN. T his network and the associated tu bulovesicular ar-
ray serve as the sorting statio n for shuttling vesicles that
deliver proteins to va rio us loca ti ons (Fig. 2.34 ). These lo-
catio ns are
constitutive trans port used in the translatio n of the mi tochon dria l mRNA. acido phi lia of the cytoplasm beca use of the large amount
vesicle Mitochondria possess a complete system for protein sy n- of membrane they conta in. M itochondria may be sta ined
plasma thesis incl uding the synthesis of their ow n r ibosomes. The specifica ll y by histochemical procedures that demonstrate
membrane remainder of the mitocho nd ria l pr oteins are encoded by so me of their constituent enzymes, such as those involved
early nuclear D NA; new polypeptides a re synthesized by free ri- in ATP synthesis and electro n tra nspo rt.
endosome bosomes in the cytoplasm a nd then imported in to mito-
late chondria with the help of pro tein chaperones. Mitochondria possess two membranes that delineate distinct
endosome
compartments
lysosome Mitochondria are present in all cells except red blood cells and
terminal keratinocytes Mitocho ndria display a va ri ety of shapes, including
spheres, rods, el onga ted fila ments, and even coi led struc-
The number, shape, and inter nal structure of mitochon- tures. All mitocho nd ria, un like other organelles described
d ri a are often characteristic for specific cell types . When above, possess two mem branes (Fig. 2.35 ). The inner mi-
present in large num bers, mi tochondria contribute to the tochondria l mem bra ne su rro unds a space called the ma-
FIGURE 2.34
Summary of events in protein trafficking from the trans-Golgi net-
work (TGN). The tubulovesicular array of the TGN serves as the sort-
ing station for transporting vesicles that deliver proteins to four ma-
jor locations in the cell. The constitutive secretory pathway to the
basolateral plasma membra ne (red arrows) uses clathrin-coated vesi-
cles. The endosomal pathway (green arrows) is an organelle-specific
protein delivery system. Another constitutive secretory pathway to
the apical plasma membrane (purple arrows) also uses clathrincoated
vesicles. The regulated secretory pathway (orange arrows) directs pro-
tein to the apical region of the cell, where proteins are stored In large inne r
mitochondrial membrane
secretory vesicles. These vesicles eventually fuse with the plasma
cytochromes
membrane and release the secretory product by exocytosis. dehyd roge nases
flavoproteins
trix. The outer m itochond rial membrane is in close contact concent~;ation of di va lent (and uivalent) cations in- electron-transport chain of respira to ry enzym es (see Fig. present in peroxiso mes ca refully regulates the cellular hy-
w ith the cytoplasm. The space betwee n th e two m em- creases in th e cytoplasm. Mitochondria can accumulate 2.36). The transfer of H across the inner mitochond ria l drogen p eroxide content by breaking dow n h ydrogen per-
branes is caUed the intemtembrane space. The struc tural ca tions against a concentration gradient. Thus, in ad di- membran e establishes an electrochemical proton gradient. ox ide, thus protecting the cell. In addition, peroxisomes
components of mitochondria possess sp ecific cha racteris- tion to ATP prod uc tio n, mitochondria a lso regulate t he This grad ient creates a large pmton motive force that contain D-amino acid oxidases, ,8-oxidation enzymes, a nd
tics related to their function: concentration of certain ions of the cytoplasmic matrix, causes the movem ent of H ' down its electrochemical g ra- n umero us other enzymes.
a role they share w ith the sER. The matrix a lso contains dient through a large, m em brane-bound enzyme called Oxidative enzymes are partic ula rly important in li ver
Outer mitochond1ial membrane. This 6- to 7-nm-tbick mitochondria l D NA, ribosom es, a nd tRNAs. ATP synthase. ATP synth ase provides a pa thwa y across cells (h ep atocytes), where t hey perform a variety of detox-
smooth membrane contains many voltage-dependent t he inner mitochondrial membrane in w hich H~ ions are ification processes. Pe roxisomes in hepatocytes are respon-
anion channels (a lso called mitochondrial porins). These Mitochondria contain the enzyme system that generates ATP used to drive the energetically unfavorabl e reactions lead- sible for detoxifica ti o n of ingested alcohol by converting it
large ch annels {approximately 3 nm in diameter) a re per- by means of the citric acid cycle and oxidative phosphorylation ing to synthesis of ATP. This movement of protons back to to acetaldehyde. {3-0xidation of fatty acids is a lso a m ajor
meable to uncha rged molecules up to 5,000 Da. Thus the mitochondrial ma trix is referred to as chemiosmotic function of per oxisomes. In some cells, peroxisomal fatty
sma ll molecules, ions, and metabo lites ca n enter the in- Mitoch ondria generate ATP in a variety of metabolic coupling. The newly prod uced ATP is tran sp orted from acid oxidation may eq ua l that of mitochondria. The p ro-
termembrane space but ca nnot pe netrate the inner mem- pathways including oxida tive phosphorylation, the citric the matrix to the intermembrane space by the voltage tein s contained in the peroxisome lumen and m embran e
brane. The environment of the interme mb.rane space is acid cycle, a nd {3-oxidation o f fatty ac ids. The energy gen- gradi ent- driven ATPIADP exchange P1'0tein locat ed in the are synth esized on cyt oplasmic ribosomes and impo rted
the refore similar to that of cytoplasm w ith r espect to ions e rated from t hese reactions, w hich take p lace in the mito- inner mitochond rial membra ne. From her e, ATP lea ves the into th e peroxisome. A pro tein d estined for peroxisomes
an d small molecu les. The o uter membrane possesses re- chondrial m a trix, is represented by hydrogen ions (H~ ) de- mitochondria via voltage-dependent anion chan nels in the must h ave a pemxisomal targeting signal a ttached to its
ceptors for proteins and polypeptides that translocate ri ved from reduced NADH. These ions drive a se ries of o uter membrane to enter th e cytoplasm. A t the sam e time, C-termin us.
into the intermembrane space. It also contains severa l en- proton pumps located within the inner mitochondrial ADP produ ced in the cytoplasm rap idl y enters the mito- Although abundant in liver and kidney cells, peroxi-
zymes, including phospholipase A2 , monoamine oxidase, m embrane tha t transfer H~ from the matrix to the inter- cho ndria for rechargin g. som es are found in most other cells. The nu mber of per-
and acetyl co enzyme A (CoA) synthase. membra ne space (Fig. 2 .36). These pumps constitute the oxisomes present in a cell increases in r esponse to diet,
l1mer mitochond1ial membmne. T he TEM revea ls that Mitochondria undergo morphologic changes related to their drugs, a nd hormonal stimulation. In most a nima ls, but not
this membrane is thinner than the outer mitoch ondJ~i al functional state huma n s, peroxisomes a lso contain mate oxidase (uricase),
membrane. It is arranged into numero us folds (cristae) wh ich often appears as a c haracteristic crystalloid inclu-
th a t significantly increase the in ner membran e surface TEM studies show mitoch o ndria in two distinct config- sion (nucleoid) .
area (see Fig. 2.35). These folds project into the matrix urations. In the orthodox configuration, the cristae are Various human metabo lic diso rders are ca used by the in-
that constitutes the inner compartment of t he organelle. prominent and the matrix compa rtm ent occupies a large ability to import peroxisomal proteins into the organelle
In so me cells in volved in steroid meta bolism , the in ne r part of the tota l mitochondrial volume. This configuration beca use of fau lty peroxisomal targeting signa l. Several se-
membra ne ma y form tubu lar o r vesicular projections ADP corresp onds to a low level of oxida tive phosphorylation. vere disorders are associa ted with nonfunctional perox i-
into the matrix. The inne r membrane is ric h in th e ph os- cytoplasm ATP In the condensed configuration, cristae are not easily r ec- somes. In the most common inherited disease r ela ted to
pholipid cardiolipin, which makes the membrane im- ognized, the matrix is concentrated a nd reduced in vol- nonfunctional peroxisomes, Zellweger syndrome, whic h
perm eable to ions. The membrane forming th e cristae
outer
membrane { ume, and the intermembra ne space increases to as much as leads t o early d eath, peroxisomes lose their a bility to func-
conta in s proteins tha t have t hree major functio ns: intermembrane 50% of the total volume. This configu ration co rresponds tion beca use of lack of necessa ry enzym es. Thera pies fo r
(1) performing t he oxidation reactions o f t he respi ratory space@ @ @ to a high level of oxidative phosphory la tion. p eroxisoma l disord ers have been unsatisfactory to date.
e lectron-transport chain, (2) synth esizi ng ATP, and @ @ @
(3) regula ting t ransport of metabolites into and out of Mitochondria decide if the cell lives or dies
th e matrix . The enzym es of t he respira tory cha in a re at-
tached to the inner membrane and project their heads
inner
membrane { Recent experimental stud ies indicate tha t mitoch o ndria
Q NONMEMBRANOUS ORGANELLES
into the matrix (Fig . 2 .35, rectangle). With th e TEM, sense cellula r stress and are capa ble of deciding whether
the cell lives or dies by initiating apoptosis (progra mmed Microtubules
t hese enzy mes appear as tennis racquet-shaped struc-
tures called elementmy particles. Their beads measure /e cell dea th). The m ajor cell d eath event generated by the mi- Microtubul es a re nonbra nching and rigid hollow tubes of
about 10 nm in diameter and contain e nzym es that carr y from _..... NADH tochondri a is the release of cytoc hrom e c from the mito- protein that can r apidly disassemble in o ne locatio n and
o ut oxida tive phosphorylation , w hic h generates ATP. Krebs c hondrial intermembranou s sp ace into th e cell cytoplasm. reassemble in a nothe r. L1 general, they grow from th e
cycle This event, regulated by the Bcl-2 protein fami ly (see page
Jnte1"membrane space. This space is located betwee n the microtubule-organizing center (MTOC) loca ted nea r the
inner a nd outer membranes and conta ins specific e n- 74 ), initia tes th e cascade of proteolyti c e nzym a tic r eactions nucle us (page 53) and extend toward the cell periphery.
zymes th a t use the ATP gene rated in the inner mem- that leads to apoptosis. Microtubules c rea te a system of connections within the
bra ne. These enzymes include creatine kinase, aden ylate cell , freq uentl y compa red to railroad tracks, a long which
kinase, a nd cytochrome c. The latter is a n important fac- Peroxisomes (Microbodies) vesicu la r movement occurs .
tor in initiati ng apoptosis (see page 45).
FIGURE2.36 Peroxisomes are single membrane-bounded organelles
Matrix. T he m itochondrial m a tri x is su rr o unded b y the Microtubules are elongated polymeric structures composed
Schematic diagram illustrating how mitochondria generate energy. containing oxidative enzymes
inner mitocho ndri a l membra ne and contains the soluble of equal parts of a-tubulin and {Nubulin
The diagram indicates the ATP synthase complex and the electron
enzymes o f the citric acid cycle (Krebs cycle) and the en- transport chain of proteins located in the inner mitochondrial mem-
zymes involved in fatty acid {3-oxidation. The major brane. The electron transport chain generates a proton gradient be-
Pemxisomes (microbodies) are sma ll (0.5 JLm dia mete r), Microtubu les measure 20 to 25 run in diameter (Fig.
products of the matri x are C0 2 and reduced NADH, tween the matrix and intennembrane space that is used to produce membra ne-limited sph erical orga ne lles that contain oxida- 2.37). The waU of the microtubule is approximately 5 nm
which is the source of electrons for the electron tra nsport ATP. Numbers represent seq uential proteins involved in the electron tive enzymes, partic ularly catalase a nd other p eroxidases. thick a nd consists of 13 circul a rl y arrayed glo bular dimeric
ch a in. Mitoch o nd ria contain dense matrix granules that transport chain and ATP production: 7, NADH dehydrogenase com- Virtually all oxidati ve enzymes prod uce hydrogen perox- tubulin molecules. T he tubulin dimer has a mo lecular weight
st or e Cal+ a nd other diva lent and triva lent ca tion s. plex; 2, ubiquinone; 3, cytocl1rome b-e, complex; 4, cytochrome c; 5, ide (H20J as a product of th e oxidatio n reaction. Hydro- of 110 kD a and is formed from an a -tubulin and a {3-tubu-
These granules increa se in number a nd s ize w hen th e cytochrome oxidase complex: and 6, ATP synthase complex. ge n peroxide is a toxic substa nce. T he cata lase univer sally lin molecule, each w ith a molecula r weight of 55 kDa. (Fig.
46 CHAPTER 2 Tbe Cdl C HAPTER 2 T!Je Cr/1 47
2.38) . The dimers polymerize in an end-to-end fashion, head The GTP-tubulin compl ex is then polymerized, and at
to tai l, w ith the a molecule of one dimer bound to the f3 mol- some point GTP is hydrolyzed to guanosine diphosphate
ecule of the next dimer in a repeating pattern. The polymer (GDP). As a res ult of this polymerization p attern, each mi-
th us formed is called a protofilament. Axial periodicity seen crotubule possesses a minus (nongrowing) end em bedded
along the 5-nm-diameter dimers corr esponds to the length of in the MTOC and a plus (growing) end elongating toward
the protein molecules. A sma ll, 1-J.Lm segment of micro- the cell periphery. Tubulin dimers dissociate from micro -
tubule contains approximately 16,000 tubulin dimers. tubu les in the steady state, w hich adds a pool of free tubu-
li n dimers to t he cytoplasm. This pool is in eq uilibrium
Microtubules grow from y-tubulin rings within the MTOC that with the polymer ized tubulin in the microtubules; there-
serve as nucleation sites for each microtubule fore, polymerization and depolymerization are in eq uilib-
rium. The equilibrium can be shifted in the direction of d e-
(+end) Microtubu le formation can be traced to hundreds of y- polymerization by exposing the cell or isolated mi cro-
tubu lin rings that form an integral part of the MTOC (Fig. tubules to low temperatures or high pressure. R epeated ex-
oe
2 .39) . The a- and {3-tubulin dimers are added to a y-tubu- posure to a lternating low and high temperature is the basis
lin ring in a n e nd-to-end fashion (see Fig. 2.38). Polymer- of the purification technique for tubulin and microtubul es .
tubulin dimer ization of t u bulin dimers requires the presence of gua nosine
bound to GTP The speed of polymerization or depolymerization can a lso
triphosphate (GTP) and Mg2+ . Each tubulin molecule binds be modified by interaction with s pecific microtubule-
GTP before it is incorporated into t he forming microtubule. associated proteins (.MAPs). These proteins, such as MAP-
1, 2, 3, a nd 4 , MAP-t, a nd TOGp, regulate microtubule as-
sembly and anch o r the microtubules to specific organelles.
MAPs are a lso responsi ble for the existence of stable popu-
lations of nondepolymerizing microtubes in the cell, such as
those fou nd in c ilia and fl agella.
Beca use of the limited resolution of the lig ht microscope, spindle pole past the metaphase plate and overlap with mi- In addition to controlling the rate of polymerization o.f
in th e past microtubules we re erroneously called fibers, crotubules extend ing from the opposite spi ndle pole. Ki- acti n filaments, ABPs are responsible for their organ ization.
such as the " fibers"- of the mitotic spindle. Micwtubules nesins located between these micro t ubules generate a slid- For example, a num ber of pr oteins can mod ify o r act on
ma y now be distinguished from filam entous an d fib rillar ing movement that red uces the overla p, t hereby pushing the actin fi laments to give them various specific characteristics:
cytoplasmic components even at t he light microscopic level two spindle poles apart to each daughter cell (Fig. 2.41 ).
by using anti bod ies to tubulin, the pr imary protein com- Actin-bundling proteins cross-link actin fila ments into
ponent of microtubules, conjugated with flu orescent dyes Actin Filaments parallel arrays, creating actin filament bundles. An ex-
(Fig. 2.39) . ample of this modification occurs inside the microvillus
In genera l, microtubules are fow1d in the cytoplasm, Actin filaments are present in virtually all cell types
where actin filaments are cross-linked by th e actin~
w here they o riginate from the MTOC; in cili a an d flagella, bundling proteins fascin and fimbrin (see Fig. 4.3, page
wh ere they form the axoneme and its anchoring basal Actin molecules (42 kDa) are a bundant and may consti- 92) . This cross-linkage provides support and imparts
body; in centrioles and t he mitotic spindle; and in elongat- tute up to 20% o.f the total protein of some no nmuscle rigidity to the microvilli.
ing processes of the cell, such as those in growing axons. cells (Fig. 2.42). Similar to th e tubulin in microtubul es, Actin filament-severing proteins sever lo ng actin fila-
Microtubules are involved in nu merous essentia l cellula r actin molecules also assem ble spontaneously b y polymer- ments into short fragments. An example of such proteins
func tions: ization into a linear helica l array to form filaments 6 to 8 is gelsolin, a 90-kDa ABP that normally initiates actin
nm in diameter. They are thinner, shorter, and more flexi- polymerization but at high Cal+ concentrations causes
Intracellula r vesicular transport (e.g., movement of se-
ble than microtubules. Free actin molecules in the cyto- severi ng of the actin filaments, con verting an actin gel
cretory vesicles, endosomes, lysosomes)
plasm are referred to as G-actin (globular actin) in con- into a fluid state.
Movement of cilia and flagella
Attachment of chromosomes to the m itotic spind le and trast to the polymerized actin o f the filament, called
their movement during m itosis and meiosis F-actin (filamentous actin). Actin filaments are polarized
Cell elongation and movement (migratio n) structures; their fast-growing end is referred to as the plus
M aintena nce of cell shape, particularly its asymmetry or barbed end, and their slow-growing end is referred to as
the minus or poi1tted end. The dynamic p rocess of actin
Movement of intracellular organelles is generated by polymerization requires the presence of K+, Mg2+, and
molecular motor proteins associated with microtubules ATP, which is hydrolyzed to ADP after each G-actin mole-
cule is incorporated into the filament (Fig. 2.43). The con-
trol and r egulation of the polymerization process d epends FIGURE 2.42
In cellula r activities that involve movement of organelles
on the local concentration of G-actin and t he interacti o n o f Distribution of actin filaments in a human fibroblast in culture. The
a nd other cytoplasmic structures, such as tra nsport vesi-
cell was stained with an actin-specific antibody conjugated with the
cles, mitocho ndria, and lysosomes, microtubul es serve as actin-binding proteins (ABPs), w hi ch can prevent or en-
dye fluorescein. The antigen-antibody reaction, performed directly in
guides to th e appropriate destinations. Molecular motor hance polymerization.
the culture, results in localization of the actin. The actin filaments or-
proteins attach to t hese organelles or structures and ganized In linear bundles fluoresce and thus show their distribution in
ratchet a long t he m icrotubule track (Fig. 2.40). The energy this nonmigrating cell. (Courtesy of Dr. Elias Lazarides_)
required for the ratcheting movement is derived from ATP
endocytotic vesicle
h yd ro lys is. Two fa milies of molecular motors have been
identified that allow for unidirect ional movement:
~+end)3 U
ery towa rd the MTOC. One member of the dynein fam-
i ly, ax01temal dynein, is present in cilia and flagella. It is FIGURE 2.41
(+end)
respo nsible fo r t he sliding of o ne microtubule aga inst an Distribution of k inesin-like motor protein within the mitotic spindle.
adj acent micr otubule of the axoneme that effects t heir This confocal immunofluorescent Image shows a mammary gland ep
movement.
Kinesins, members of the other fa mily, move a lo ng th e
lthelial cell In anaphase of mitosis, Each mitotic spindle pole contains
two centrioles (green). A mitosis-specific klnesln-llke molecule called
EgS (red} is associated with the subset of the mitotic spindle micro-
0
microtubul es towa rd the plus end; therefore, they areca-
pable of moving orga nelles from t he cell center toward
FIGURE 2.40
The molecular motor proteins associated with microtubules. Micro
tubules that connect the kinetochores (white) to the spindle poles. The ICD actin bound to ADP j i [OJactin bound to ATP I
~otor action of EgS is req uired to separate the sister chromatids (blue) pi
t he cell peri phery. tubules serve as guides for molecular motor proteins. These ATP- IIlio the daughter cells. This cell was first lmmunostalned with three FIGURE2.43
driven microtubule-associated motor proteins are attached to moving primary antibodies against EgS (red), centrln (green), and kinetochores Polymerization of actin filaments. Actin filaments are polarized struc-
Both dyneins and ki nesins are involved in mitosis and structures (such as organelles) and ratchet them along a tubular track. (white) and then incubated in three different fluorescently tagged sec- tures. Their fast-grow ing end is referred to as the plus(+) or barbed
meiosis. In these activities, dyneins move the chromosomes Two types of molecular motors have been identified: dyneins that ondary antibodies that recognize the primary antibodies. Chromo end; the slow-growing end Is referred to as the minus (-) or pointed
along the kinetochore microtubules toward the spindle move along microtubules toward their minus (-) end (i.e., toward the somes were stained w ith a fluorescent molecule that intercalates into end. The dynamic process of actin polymeriz<Jiion requires energy in
pole. Kinesins are simultaneously involved in movement of center of the cell) and kinesins that move toward their plus (+ ) end the DNA double helix. x3,500. (Courtesy of Dr. Wilma L. Lingle and the form of an ATP molecule that is hydrolyzed to ADP after a G-actln
polar microtubules. These m icrotu bules extend from one (i.e., toward the cell periphery). Ms. Vivian A. Negron.) molecule is incorporated into t he filament.
CHAPTER 2 T!Jr Cell 5I
50 CHAPTER 2
kidney and intestinal absorptive cells, nerve growth cones, called filopodia, located around their surface. As in lamel-
Actin-capping proteins block further addition of actin lipodia, these protrusions contain loose aggregations of 10
molecules by binding to the free end of an actin filament. a nd inner ear hair cells.
to 20 actin filaments organized in the same direction,
An example is tropomodulin, which can be isolat~d again with their plus ends directed toward the plasma
from skeletal a nd cardiac muscle cells. Tropomodulm Actin filaments participate in a variety of cell functions
membrane. Actin filaments are also essential in cytoplas-
binds to the free end of actin myofilaments, regulating
Actin filaments are often grouped in bundles close to the mic streaming, i.e., the stream-like movement of cyto-
the length of the filaments in a sarcom ere ~ plasm that can be observed in cultmed cells.
Actin cross-linking proteins are respons1ble for cross- plasma membr ane. Functions of these membrane-associ-
linking actin filaments with each o ther. An example of ated actin filaments include
such proteins can be fo und in the cytoske_leton of e~y Anchorage and movement of membrane protein. Intermediate Filaments
throcytes. Severa l proteins, such as _spectnn, ~ dductm, Actin filaments are distributed in three-dimensional b~termediate filaments play a supporting or general struc-
protein 4 .1, or protein 4. 9, are m volved 111 cross- networks throughout the cell and are used as an- tura l role. These rope-like filaments are called "intennedi-
linki ng actin filaments (see Fig. 9.4, pa~e 21~). . chors within specialized cell junctions such as focal ate" because their diameter of 8 to 10 nm is " intermedi-
Actin motor proteins belong to the myosm family, w h1ch ad hesions. ate" between that of actin filaments and microtubu les.
hydrolyzes ATP to provide the energy for movem ent Formation of the structural core of microvilli o n ab- Nearly all intermediate filaments consist of subunits with a
alo ng the actin filament from the minus end to t~e plus sorptive epithelial cells. Actin filaments may also help molecular weight of about 50 kDa. Some evidence suggests
end. Some cells, such as muscle cells, are charactenzed by maintain the shape of the apical cell surface, e.g., the tha t many of the stable structur al proteins in intermediate
the size, amount, and nature of the filaments and actin- apical terminal web of actin filaments serves as tension filaments evolved from highly conserved enzymes, w ith
motor pro teins they contain. There are two types of fila- ca bles under the cell surface. only minor genetic m odification.
ments (myofilaments) present in muscle cells: 6- to 8-nm Locomotion of cells. Locomotion is achieved by the
actin filaments (called thin filaments) (Fig. 2.44) and force exerted by actin filaments by polymerization at Intermediate filaments are formed from nonpolar and highly
15-nm filam ents (called thick filaments ) of myosin n, their growing ends. This mechanism is used in ma ny variable Intermediate filament subunits
which is the predominant protein in muscle cells. Myo~in migrating cells, in particu lar on tra_nsformed ~e lls_ of
II is a double- headed molecule with an elo ngated rod-!tke invasive tumors. As a result of actm polymenzat1on Unlike those of microfilaments and microtub ules, the
tai l. The specific structural and functional relationships at their leading edge, cells extend processes from their protein subunits of intermediate filaments show consider-
among actin, myosin, and other ABPs in muscle contrac- surface by pushing the plasma membrane ahead of able diversity and tissue specificity. In addition, they do not
tion are discussed in Chapter 10 (Muscle Tissue). the growing actin filaments. The leading-edge exten- posses enzymatic activity and form nonpolar filaments. In-
In addition to myosin II, nonm uscle cells contain myosi1~ sions of a crawling cell are called lamellipodia; they termedia te filaments a lso do not typically disappear and FIGURE 2.45
I, a protein with a single globular domain a nd short t_ail contain elongating organi zed bund les of actin fila- re-form in the continuous manner characteristic of most Electron micrograph of the apical part of an epithelial cell. This elec-
that attaches to other molecules or organelles. Extenstve ments with their p lus ends directed toward the p lasma microtubules and actin filaments. For these reasons, inter- tron micrograph, obtained using the quick-freeze deep-etch tech-
studies have revea led the presence of a variety of other membrane. mediate filaments are believed to play a primarily struc- nique, shows the terminal web (TW) of an epithelial cell and underly-
nonmuscle myosin isoforms that are responsi ble for m otor Extension of cell processes. These processes can be. ob- tural role within the cell and to compose the cytoplasmic ing Intermediate filaments (IF}. The long straight actin filament cores
functions in many specialized cells, such as melanocytes, served in many other cells that exhibit small protrusiOns link of a tissue-wide continuum of cytoplasmic, nuclear, or rootlets (R) extending from the microvilli are cross-linked by a
and extracellular filaments (Fig. 2.45). dense network of actin filaments containing numerous actin-binding
Intermedi ate filament proteins are characterized by a proteins. The network of intermediate filaments can be seen beneath
high ly variable central rod-shaped domain with strictly the terminal web anchoring the actin filaments of the microvilli.
conserved glo bular domains at either end (Fig. 2.46). Al- x 47,000. (From Hirakawa N, et al. J Cell Bioi 1983;96:1325.)
though the vario us classes of intermediate filaments diff~r
tropomyosin in the amino acid sequence of the rod-shaped doma in and
molecules show some va riation in molecular weight, they all share a Intermediate filaments are a heterogeneous group of
homologous region that is important in filament self- cytoskeletal elements found in various cell types
assembly. Intermediate filaments are assembled from a pair
of helica l monomers that twist around each other to form Intermediate filaments are organized into four maj or
coiled-coil dimers. Then, two coiled-coil dimers twist classes on the basis of protein composition and cellular dis-
around each other in antiparallel fas hion (parallel but tribution (Table 2.1 ):
pointing in opposite djrections ) to generate a staggered
tetramer of two coiled-coil dimers, thus forming the non- Keratins (cytokeratins), the most diverse group of inter-
b polarized unit of the intermediate filaments (see Fig. 2.46). m ediate filaments, contain more than 50 different iso-
FIGURE 2.44 Each tetramer, acting as an individual unit, is aligned a long forms. Keratin fila ments are formed from a variety of dif-
Thin filament organization and structure in cardiac cells. a. Im- by the fast-growing(+ ) end and the slow-growing(-) end. Only a por- the axis of the filament. The ends of the tetramers are ferent keratin su bunits and are found in different cells of
munofluorescence micrograph of a chick cardiac myocyte stained for tion of the entire thin filament is shown for clarity. Tropomodulin is
bound together to form the free ends of the filament. This epithelial origi n. Specialized keratins called hard keratins
actin (green) to show the thin filaments and for tropomodulin (red} to bound to actin and tropomyosin at the slow-growing (-) end. The tro-
ponin complex binds to each tropomyosin molecule every seven act~n
assembly process pr o vides a sta ble, staggered, helical a rray are found in skin appendages such as hair and nails. Ker-
s11ow the location of the slow-growing (-) ends of the thin filaments. in which fi la ments are packed together and additio nally ati n filaments span the cytoplasm of epithelial cells and,
Tropomodulin appears as regular striations because of the uniform monomers along the length of the thin filament. (Courtesy of Drs. Vella
F. Fowler and Ryan Littlefield.) stabilized by lateral binding interactions between adjacent via desmosomes, connect with keratin fi laments in neigh-
lengths and alignments of the thin filaments In sarcome_re~. b. Dia-
tetramers. boring cells. Keratin subwlits do not coassemble with
gram of a thin filament. The polarity of the thin filament IS mdicated
5J CHAPTER 2 Tbr Cr/1 C HAPTER 2 Tlu Ctll 53
FIGURE 2.46
Polymerization and structure of intermediate filaments. Intermedi- TABLE 2.1. Classes of Intermediate Filaments Based on Their Molecular Structure and Assembly
ate filaments are self-assembled from a pair of monomers that twist
Type Molecular
around each other in parallel fashion to form a stable dimer. Two of Protein Weight (kDa) Cellular Distribution Where Found
coiled-coil dlmers then twist around each other in antiparallel fashion
to generate a staggered tetramer of two coiled-coil dimers. This Class 1: Keratins
monomers
tetramer forms the nonpolarized unit of the Intermediate filaments. Acid cytokeratins 40-64 Cytoplasm All epithelial cells
Each tetramer, acting as an individual unit, aligns along the axis of Basic cytokeratins 52-68 Cytoplasm All epithelial cells
the filament and binds to the free end of the elongating structure.
This staggered helical array is additionally stabilized by lateral bind- Class 2: Vlmentin and Vlmentln-llke
ing interactions between adjacent tetramers. Vimentin 55 Cytoplasm Cells of mesenchymal origin (including endothelial
cells, myofibroblasts, some smooth muscle cells)
and some cells of neuroectodermal origin
Desmin 53 Cytoplasm Muscle cells
Glial fibrillary acidic protein 50-52 Cytoplasm Neuroglial cells (including oligodendroglia,
other types of intermediate filaments; therefore, they form (GFAP) astrocytes, microglia), Schwann cells, ependymal
a distinct cell-specific and tissue-specific system. cells, and pituicytes
Vimentin and vimentin-like filaments represent a di- Peripherin 54 Cytoplasm Neurons
verse family of cytoplasmic filaments found in many cell Synemin 182 Cytoplasm Muscle cells
types. In contrast to keratins, they form homopolymeric Paranemin 178 Cytoplasm Muscle cells
filaments containing only one type of intermediate pro- Nestin 240 Cytoplasm Muscle cells, some cells of neuroectodermal origin
tein. Vimentin is the most abundant intermediate fi la-
Class 3: Neurojllaments
ment found in all mesoderm-deri ved cells. Vimentin-like
filaments include desmin, cha racteristic of muscle cells; Neurofilament L (NF-L) 68 Cytoplasm Neurons
glial fibrillary acidic protei11 (GFAP), found in glial Neurofilament M (NF-M) 110 Cytoplasm Neurons
cells and astrocytes; peripherin, found in many neu- Neurofilament H (NF-H) 130 Cytoplasm Neurons
rons; and syttemin and paranemin, found a lso in mus- Class 4: Lamlns
cle cells.
Larnin A/CA 62-72 Nucleus Most differentiated cells
Neurofilaments are formed from the group of neuro-
filament-triplet (NF} proteins that contain three proteins Lamin B 65-68 Nucleus All nucleated cells
of different molecular weights: NF-L (low-weight pro- Lamln C is a splice product of lamin A.
tein), NF-M (a medium-weight protein) and NF-H (a
high-weight protein ). All three proteins fo rm neurofila-
ments that extend from the cell body into the ends of ax-
ons and dendrites, providing structural support. reins fo rm the attachment plaques for intermediate fila- MTOC is the region where most microtubu les are formed
Lamins, specifically nuclear lamins, are associated with ments, an essential part of desmosomes and hemidesmo- and from which they are then directed to specific destina-
coiled-coil
dimers the nuclear envelope and are formed by two types of somes. The interaction of intermediate filaments with cell- tions within the cell. Therefore, the MTOC controls the
proteins, lamin A and lamin B. In contrast to other types to-cell a nd cell-to-extracellular matrix junctions provides number, polarity, direction, orientation, and organization
of intermediate filaments fo und in the cytoplasm, lamins mecha nical strength and resistance to extracellular forces. of microtubules formed during interphase of the cell cycle.
are located within the nucleoplasm of almost all differ- Table 2 .2 summarizes the characteristics of the three types Development of the MTOC itself depends solely on the
entiated cells in the body. A description of their structure of cytoskeletal filaments. presence of centrioles. When centrioles are missing, the
and function can be fow1d on page 64. MTOCs disappear, and formation of microtubules ts se-
verely impaired.
Centrioles and Microtubule-Organizing Centers
Intermediate filament-associated proteins are essential
for the integrity of cell-to-cell and cell-to-extracellular Centrioles represent the focal point around which the MTOC The MTOC contains centrioles and numerous ring-shaped
matrix junctions assembles structures that initiate microtubule formation
A variety of intermediate filament-associated proteins Centrioles, visible in the light microscope, are paired, T he MTOC contains an amorphous matrix of more
staggered function within the cytoskeleton as integral parts of the short, rod-like cytoplasmic cylinders built from nine mi- than 200 proteins, including y-tubulins that are organi zed
tetramer
molecular architecture of cells. Some proteins, such as crotubule triplets. In resting cells, centrioles have an or- in ring-shaped structures . Each y-tubulin ring serves as the
those of the plectin family, possess binding sites for actin thogonal orientation: one centriole in the pair is arrayed at starting point (nucleation site) for the growth of one mi-
fi laments, microtubules, and intermediate filaments and right angles to the other. Centrioles a re usua lly fo und in crotubule that is assembled fro m rubulin dimers; a- and {3-
are thus importallt in the proper assembly of the cy- close proximity to the nucleus, often partially surrou nded tubulin dimers a re added with specific orientation to the y-
toskeleton. Another important family of intermediate by the Golgi apparatus, and associated with a zone of tubulin ring. The minus end of the microtubule rema ins
filament-associated proteins consists of desmoplakins, amorphous, dense pericentrio lar material. The region of attached to the MTOC, and the plus end represents the
desmoplakin-lil~e proteins, and plalwglobins. These pro- the cell containing the centrioles and pericentrio lar mate- growing end directed toward the plasma membrane (see
ria l is called the MTOC or centrosome (Fig. 2.48). The Fig. 2.48).
54 C H APTER 2 T!JeCrll CHAPTER 2 Thr Cell 55
....... Abnormalities related to the organization and structure of micro- diate filaments. These defects have also been induced experimen-
~ "E
""t !: ' tubules, actin, and intermediate filaments underlie a variety of tally by mutations In intermediate filament genes in laboratory an-
..
"Iii
liT
...
~I I
lid
pathologic disorders. These abnormalities lead to defects in the cy-
toskeleton and can produce a variety of defects related to intracel-
imals. Changes in neurofllaments within brain tissue are character-
istic of Alzheimer's disease, which produces neurof ibrillary tangles
lular vesicular transport, intracellular accumulations of pathologic conta ining neurofilaments and other microtubule-associated pro-
Shape Double-stranded linear helical array Rope-like fibers Nonbranching long hollow proteins, and impairment of cell mobility. teins. A prominent feature of alcoholic liver cirrhosis is the pres-
cylinders
ence of eosinophilic Intracytoplasmic inclusions composed pre-
Diameter (nm) 6-8 8-10 20-25 MICROTUBULES dominantly of keratin Intermediate filaments. These inclusions,
Basic protein subunit Monomer of G-actin (MW 42 kDa) Various intermediate filament Dim ers of a - and {3-tubulin (MW Defects in the organ ization of microtubules and microtubule-asso- called Mallory bodies, are visible in light microscopy within the he-
proteins (MW about 50 kDa) 54 kDa); y tubulin found in ciated proteins can immobilize the cilia of respiratory epithelium, patocyte cytoplasm (Fig. 2.47).
MTOC is necessary for nucleation
interfering w ith the ability of the respiratory system to clear accu-
of microtubules
mulated secretions. This syndrome, known as Kartagener's syn-
Enzymatic activity ATP hydrolytic activity None GTP hydrolytic activity drome (see page 95), also causes dysfunction of microtubules that
Polarity Yes; minus (-) or pointed end Is Nonpolar structures Yes; minus (-) end is nongrowing affects sperm motility, leading to male sterility. It may also cause
slow-grow ing end; plus(+) or end embedded in MTOC; plus (+ ) infertility in females because of impaired ciliary transport of the
barbed end is faster-growing end end is the growing end ovum through the oviduct.
Assembly process Monomers of G-actin are added to Two pairs of monomers form two At the nucleation site, a- and Microtubules are essential for vesicular transport (endocytosis
growing filament; polymerization coiled-coil dimers; then, two coiled- {3-tubulin dimers are added to y and exocytosis) as well as cell motility. Certain drugs, such as
requires the presence of K, Mg2 , coil dimers twist around each other tubulin ring in an end-to-end colchicine, bind to tubulin molecules and prevent their polymeriza-
and ATP, which is hydrolyzed to to generate a staggered tetramer, fashion; each tubulin dimer mol-
tion; this drug is useful in the treatment of acute attacks of gout, to
ADP after each G-actin molecule Is which aligns along the axis of the ecule binds GTP before it be-
prevent neutrophil migration and to lower their ability to respond
incorporated Into the filament filament and binds to the free end comes incorporated into the mi-
crotubule; polymerization also to urate crystal deposits in the tissues. Vinblastine and vincristine
of the elongating structure
requires the presence of Mg 2 ; represent another family of drugs that bind to microtubules and in-
GTP- tubulin complex is polymer- hibit the formation of the mitotic spindle essential for cell division.
ized, and after incorporation, These drugs are used as antimitotic an d antiprollferative agents in
GTP Is hydrolyzed to GOP cancer therapy. Another drug, Taxol, Is used in chemotherapy for
Source of energy ATP N/ A GTP breast cancer. It stabilizes microtubules, preventing them from de-
required for assembly polymerizing (an action opposite to that of colchicine), thus arrest-
Thin, flexible filaments Strong, stable structures Exhibit dynamic instability ing cancer cells in various stages of cell division.
Characteristics
Associated proteins Variety of actin-binding proteins Intermediate filament-associated Microtubule-associated proteins:
ACTIN FILAMENTS
(ABPs) with different functions: proteins: plectins-bind micro- MAP-1, 2, 3, and 4, MAP--r, and
fascin- bundling; gelsolin-filament tubules, actin, and intermediate TOGp regulate assembly, stabilize Actin filaments are essential for various stages of leukocyte migra-
severing; CP protein-cappi ng; filaments; desmopla kins and and anchor microtu bules to spe- tion as well as for the phagocytotic functions of various cells (see
spectrin-cross-linking; myosin I plakoglobins- attach intermediate cific organelles; motor page 28). Some drugs, such as cytochalasin 8 and cytochalasin D,
and 11-motor functions filaments to desmosomes and proteins-dyneins and kinesins- prevent actin polymerization by binding to the plus end of the actin
hemidesmosomes required for organelle movement
fila ment inhibiting lymphocyte migration and phagocytosis. Sev-
Location in cell Core of microvilli; terminal web; Extend across cytoplasm connect- Core of cilia; emerge from MTOC eral toxins of poisonous mushrooms, such as phalloidin, also bind
concentrated beneath the plasma ing desmosomes and hemidesmo- and spread into periphery of the to act in filaments, preventing their depolymerlzation. Prolonged
membrane; contractile elements of somes; in the nucleus just beneath cell; mitotic spindle, centrosome FIGURE 2.4 7
exposure of the cell to these substances can disrupt the dynamic
muscles; contractile ring in dividing inner nuclear membrane Photomicrograph of Mallory bodies. Accumulation of keratin In-
equilibrium between F-actin and G-actin, causing cell death.
cells termediate filaments forming Intercellular inclusions is frequently
Major functions Provide essential components to Provide mechani cal strength and Provide network ' railroad tracks' INTERMEDIATE FILAMENTS associated with specific cell injuries. In alcoholic liver cirrhosis, he-
contractile elements of muscle cells resistance to sheari ng forces for movement of organelles patocytes exhibit such Inclusions (arrows), known as a Mallory bod-
(sarcomeres) within the cell; provide move- As noted, the molecular structure of intermediate filaments is tissue ies. Note that lymphocytes and macrophages responsible for an in-
ment for cilia and for ch romo- specific and consists of many different types of proteins. Several tense inflammatory reaction surround cells containing Mallory
somes during cell division diseases are caused by defects in the proper assembly of interme- bodies. X900.
56 CHAPTER 2 Tlu Cell C HAPTER 2 Tlu Cell 57
-y-tubulin ring Mitotic spindle formation. During mitosis, centrioles are polar microtubule and ru n in sligh tly twisted bundles (Fig. 2.51). The three
necessary for the formation of the MTOC and astral mi- microtubu les of the triplet are fused, with adjacen t micro-
crotubules. Astral microtubules are formed around each kinetochore tubules sharing a com mon wall. The innermost or A mi-
microtu bule MTOC
individual centriole in a star-like fas hion. They are crucial crotubu le is a complete r ing of 13 a- and {3-tubulin dimers;
in establishing the axis of the developing mitotic spindle. astral the middle and outer microtubules, B and C, respectively,
microtubule centriole
In some animal cells, the mitotic spindle itself (mainly appea r C-shaped because they share tubulin dimers with
kinetochore microtubules) is formed by MTOC-independ- each other and with the A microtubule. The microtubules
ent mechanisms and consists of microtubules that origi- of the tr iplets are not equal in length. The C microtubule
nate from the chromosomes. Recent experimental data in- of the triplet is usua lly shorter than A and B.
dicate that in the a bsence of centrioles, astralmicrotubules
fail to develop, causing errors in mitotic spindle orienta-
tion (Fig. 2.50). T hus, the primary role of centrioles in mi-
tosis is to position the mitotic spindle properly by recruit-
FIGURE 2.48
Structure of the microtubule-organizing center (MTOC). This dia
gram shows the location of the MTOC in relation to the nucleus and
the Golgl apparatus. In some species, the MTOC Is tethered to the nu-
clear envelope by a contractile protein, the nucleus-basal body con-
nector (NBBC). The MTOC contains the centrioles and an amorphous
protein matrix with an abundance of y-tubulin rings. Each y-tubulin
ring serves as the nucleation site for the growth of a single micro
tubule. Note that the minus (-) end of the microtubule remains at-
tached to the MTOC and the plus (+ ) end represents the growing end b misoriented spindle
directed toward the plasma membrane. (anastral bipolar spindle)
FIGURE 2.50
Mitotic spindle during normal cell division and in cells lacking cen-
trioles. a. This schematic drawing shows the orientation of the astral
Centrioles provide basal bodies for cilia and flagella and align
bipolar spindle in a normal cell undergoing mitosis. Note the positio.ns
the mitotic spindle during cell division
of the centrioles and the distribution of the spind le microtubules. b. In
a cell that lacks centrioles, mitosis occurs and a mitotic spindle con-
Although centri oles were discovered over a century ago, ta ini ng only kinetochore microtubu les is formed. However, both poles
their precise functions, rep lication, and assem bly remain of the mitotic spindle lack astral microtubules, wl1ich position the
largely unclear. The functions of centrioles can be organ- spindle In proper plane during the mitosis. Such a misoriented spindle
ized into two categories: is referred to as an anastral bipolar spindle. (Based on Marshall WF,
Rosenbaum JL. Curr Opin Cell Bioi 2000;112:119-125.)
Basal body formation. One of the importa nt functions
of the centri ole is to provide basal bodies, wh ich are nec-
essary for the assembly of cilia and flagella (Fig. 2.49). ing the MTOC from w hich astral microtu bules can
FIGURE 2.49 grow and establish the axis for the developing spindle.
Basal bodies are for med by replication of centrioles that
Basal bodies and cilia. This electron micrograph shows the basal bod FIGURE 2.51
give rise to multiple p1'ocentrioles. Each procentriole mi- ies and cilia in cross-sectional profile as seen in an oblique section Electron micrograph showing parent and daughter centrioles in a fi-
grates to the appropriate site on the surface of the cell, The dominant feature of centrioles is the cylindrical array
through the apical part of a ciliated cell in the respiratory tract. Note broblast. Note that the transverse-sectioned centriole in each of the
where it becomes a basal body. T he basal body acts as of t riplet microtubules with associated proteins
the 9 + 2 microtubule arrangement of the cilia. The basal bodies lack pairs reveals the triplet configuration of microtubules. The lower right
the organizing center fo r a cilium. Microtu bules grow the centra l tubule pair. The triplet microtubule configuration in the centriole represents a midlongitudinal section, whereas the upper left
upward fro m the basal body, pushing the cell membrane basal body appears as a more dense structure than the doublet mi- T he TEM reveals that each rod-shaped centri o le is about centriole has also been longitudi nally sectioned, but along the plane
outward, and elongate to form the mature cilium. T he crotubule configuration in the cilia. x 28,000. (Courtesy of Patrice C. 0.2 ,urn long and consists of nine tr iplets of microtubules of its wall. x 90,000. (Cou rtesy of Drs. Ma nley McGill, D. P. Highfield,
process of ciliary fo rmation is descri bed on page 95. AbeiiAieff.) that are oriented p arallel to the long axis of the orga nelle T. M. Monahan, and Bill R. Brinkley.)
'l8 CHAPTER 2 Thr Cell CHAPTER 2 n, Cr/1 59
The microtubule triplets of the centrio le surro und a n in- connections between the centriole pair have been identified centrio le-derived basal body then serves as the organiz- by a plasma membrane; others, e.g., lipid droplets and
ternal lumen. The distal p art of th e lu men (away from the in human lymphocytes. In other organisms, two protein ing cen ter for the assembly of the microtubules of the cil- glycogen, are not and reside within the cytoplasm ic or n u-
n ucleus) contains a 20-kDa Ca2 -'- -bi nding protein, centrin bridges, the proxim al and distal connecting fib ers, connect ium. T he core structure (axoneme) of a cilium is com- clear matrix.
(Fig. 2.52). The pr oximal p a rt of the lumen (close to the each centriole in a pair (see Fig. 2.52). In dividing cells, posed of a complex set of microtubules consisting of two Secretory vesicles and neutral fat often constitute most
nucle us) is lined by 'Y-tubulin, w hicb provides the templa te these connections par ticipate in segregating t he centrioles central microtubules surrounded by nine microtubule of the cytoplasmic volume, compressing the other formed
fo r the arrangement of the triplet mic ro tubules. A group of to each daughter cell. In some organisms, t he pr oximal end doub lets (see Fig. 4.6, page 94 ). T he organizing role of organelles into a thi.n rim at the margin of the cell. This
pro teins generally k nown as pericentrins has a lso been as- of each cen triole is attached to t he n uclear envelop e by the basal bod y differs from that of the MTOC. T he ax- structure is typical of the intestinal goblet cell (see Fig.
sociated w ith the centrioles. N ewly ide ntified protein p210 contractile proteins called nucleus-basal body connectors onemal microtubu le doublets are continuous with the A 16.23, page 497) and the adipose cell of connective tissue
forms a ring o f molecules tha t appea rs to lin k the distal (NBBCs). Their function is to link the ce ntriole to the mi- and B m icr otu bules of the basal body from which they (see Fig. 6.2, page 159). Cells with regulated secretory
end o f the centriole to the plasma membra ne. Fila m ento us totic spin dle poles during mitosis. Jn h uman cells, the cen- deve lo p by addi tion of a- and ,13-tubu lin dimers at the pathways store proteins w ithin large vesicles in their cyto-
tr osom e-nucle us con nection appea rs to be maintained by growing plus end. plasm for hours or even days. These vesicles do not fuse
fila mento us str uctures of cytoskeleto n. A distinctive fea- wit h the plasma membrane until the cell is activated for ex-
t ure o f mamm alia n ce ntrioles is the d ifferen ce between in- ocytosis by an external signaling mechanism (see page 28).
proximal and distal Inclusions Glycoge1t may be seen in the light microscope only after
connecting fibers divi d ual centrioles in t he pa ir. One centr iole (termed t he
(in some species) IMMATURE CENTRIOLE mature cent1iole) contains stalk-like sa tellite processes a nd special fixation and staining procedures. It is usually lost
sh eet-like ap pendages wh ose ftmction is no t k nown (see Inclusions consist largely of secretory vesicles, pigment during routine processing of tissue for light microscopy.
distal granules, neutral fat, other lipid droplets, and glycogen Liver and striated muscle cells, which usually contain large
Fig. 2.52}. The other centriole (termed the immature cen-
ring amounts of glycogen, may display empty regions where the
triole ) d oes no t possess satellites or appendages.
Inclusions are cytoplasmic or nuclear structures with glycogen was localized. Glycogen appears in electron mi-
Prior to cell division, a single new centriole is formed at a right ch aracteristic sta ining properties. T hey are considered crographs as granules 25 to 30 nm in d iameter or as clus-
angle and adjacent to each preexisting centriole "nonliving" com ponents of the cell. Some of them, such ters of such granules that often occupy significant portions
as secretory vesicles and pigment granules, are surrounded of the cytoplasm (Fig. 2.53) .
Prior to cell d ivisio n, wh en DNA is bei ng replicated dur-
ing the S p hase of the cell cycle (see page 68), centrioles
PJ.---41-- triplet also d up lica te. A small mass of g ra nular a nd fi br illa r ma-
distal II microtubules terial, the procentriole, ap pears at the side of each centri-
ole and grad ually enlarges to fo rm a right-angle ap pendage
lumen I proximal
1 /f-- NBBC to the par ent. Microtub ules develop in the m ass as it grows
satellites \ \lumen /; (not in
~ humans) (usuall y d uring the S to late G 2 p hase of the cell cycle), ap-
a ppendages pearing first as si ngle t ub ules, then as dou blets, a nd finally
Lipid inclusions (fat droplets) are also usually ex- and outer membranes separated by a perinuclear cis-
tracted by the organic solvents used to prepare tissues for ternal space and perforated by nuclear pores . The
both light and electron microscopy. What is seen as a "fat outer membrane of the nuclear envelope is contin-
droplet " in light microscopy is actually a hole in the cy- uous with that of the rER and is often studded with
toplasm that represents the site from which the lipid was ribosomes.
extracted. Nucleoplasm, the nuclear contents other than the chro-
Crystalline inclusions contained in certain cells are rec- matin and nucleolus.
ognized in the light microscope. In humans, such inclusions
are found in the Sertoli (sustentacular) and Leydig (intersti-
Chromatin
tial) cells of the testis. With the TEM, crystalline inclusions
have been found in many cell types and in virtually all parts
Chromatin, a complex of DNA and proteins, is responsible for
of the cell, including the nucleus and most cytoplasmic or-
the characteristic basophilia of the nucleus
ganelles. Although some of these inclusions contain storage
material or remnants of cellular structures, the significance
In most cells, chromatin does not have a homogeneous
of others is not clear.
appearance; rather, clumps of densely staining chromatin
are embedded in a more lightly staining background. The
Cytoplasmic Matrix densel y staining material is highly condensed chromatin
called heterochromatin, and the lightly staining material is
The cytoplasmic matrix is a concentrated aqueous gel a dispersed form called euchromatin. It is the phosphate
consisting of molecules of different sizes and shapes groups of the DNA of the chromatin that are responsible
for the characteristic basophilia of chromatin (page 7). The
The cytoplasmic matrix (ground substance, or cytosol) proteins of chromatin include five basic proteins called his-
shows little specific structure by light microscopy or con- tones and other nonhistone proteins. Heterochromatin Is
ventional TEM and has traditionally been described as a disposed in three locations (Fig. 2 .54):
concentrated aqueous solution containing molecules of dif-
ferent size and shape (e.g., electrolytes, metabolites, RNA, Marginal chromatin is found at the perimeter of the nu-
and synthesized proteins) . In most cells, it is the largest sin- cleus (the structure light microscopists formerly referred
gle compartment. The cytoplasmic matrix is the site of to as the nuclear membrane actually consists largely of
physiologic processes that are fundamental to the cell's ex- marginal chromatin).
istence (protein synthesis, breakdown of nutrients). Studies Karyosomes are discrete bodies of irregular size and
with high-voltage electron microscopy (HVEM) of 0 .25- to shape, found throughout the nucleus.
0.5-,um sections reveal a complex three-dimensional struc- Nucleolar associated chromatin is chromatin found In
tural network of thin microtrabecular strands and cross- association with the nucleolus.
linkers. This network provides a structural substratum on
Heterochromatin stains with hematoxylin and basic
which cytoplasmic reactions occur, such as those involving Electron micrographs of nuclei from two different cell types.
dyes; it is also readily displayed with the Feulgen proce-
free ribosomes, and along which regulated and directed cy- The large electron micrograph shows the nucleus of a nerve
dure (a specific histochem ical reaction for the deoxyribose
toplasmic transport and movement of organelles occur. cell. Two nucleoli are included In the plane of section. Tile nu-
of DNA, page 7) and fluorescent vital dyes such as Hoechst
cleus of t11is active cell, exclusive of the nucleoli, is comprised
dyes and propidium iodide. It is the heterochromatin that
almost entirely of extended chromatin or euchromatin.
accounts for the conspicuous sta injng of the nucleus in
9 NUCLEUS hematoxylin and eosin (H &E) preparations.
x lO,OOO. Inset. The smaller nucleus belongs to a circulating
lymphocyte (the entire cell is shown in the micrograph). It is
Euchromatin indicates active chxomatin, i.e., chromatin a relatively inactive cell. Note the paucity of cytoplasm and
The nucleus is a membrane-limited compartment that
that is stretched out so that the genetic information in the cytoplasmic organelles. The chromatin in the nucleus is
contains the genome (genetic information) in eukaryotic cells
DNA can be read and transcribed. It is prominent in largely condensed (h eterochromatin). Tl1e lighter areas repre-
metabolically active cells such as neurons and liver cells. sent euchromatin. x 13,000.
The nucleus of a nondividing cell, also called an inter-
H eterochromati n predominates in metabolically inactive
phase cell, consists of the fo llowing components:
cells such as small circulating lymphocytes and sperm or
Chromatin, nuclear material organized as euchromatin in cells that produce one major product, such as plasma
and heterochromatin. It contains DNA, histones, and cells.
va ri ous nuclea r proteins that are necessary for DNA to Euchromatin is not evident in the light microscope. It The smallest units of chromatin structure are macromolecular (abo ut 146 nucleotide pairs) are wrapped around the core
function. is p resent within the nucleoplasm in the "clear" areas complexes of DNA and histones, called nucleosomes octamer. The DNA extends between each particle as a
Nucleolus (pl., nucleoli), a small dense area within the between th e heterochromatin. In ro utine electron micro- 1.5-nm filament that joins adjacent nucleosomes. The nu-
nucleus that contains RNA and proteins. The nucleolus graphs, there is no sharp delineation between euchro- Nucleosomes are found in both euchromatin and hete- cleosomal substructure of chromatin is often described as
is the site of rRNA synthesis. matin and heterochromatin; both ha ve a granular, fila- rocluomatin and in chromosomes (see below). A nucleo- "beads on a string."
Nuclear envelope, th e membra ne system that sur- mentous appearance, but the euchromatin is less tightl y some is a 10-nm-diameter particle that consists of a core of A long strand of nucleosomes is coiled to produce a unit
rounds the nucleus of the cell. It consists of inner packed. eight histone molecules. Approximately two loops of DNA chromatin (ib1il that is abo ut 25 to 30 nm in diameter. Six
62 C HAPTER 2 The Ceil C HAPTER 2 The Cell 63
nucleosomes form one turn in the coil of the chromatin fib- on a microscope slide, and stained with Giemsa stain is
"-\ { ~~ l;
u},(
ril. Both interphase chromatin and chromosomes are called a metaphase spread (Fig . 2.55a). Such spreads a re
formed from the 25- to 30-nm un it fibril. In beterochro- then photographed. The chromosome pairs are cut from
matin, the unit chromatin fibrils are tightly packed and
folded on each other; in euchromatin, the unit fibrils are
the photograph and sorted according to their mor phol-
ogy to form a karyotype (Fig. 2 .55b). Karyotypes are i~
1
\ \\I' 2"
G\ .
3
u n ... ~
more loosely arranged. This loose arrangement allows used to detect chromosome abno rmalities such as dele-
~ "
DNA polymerases access to the DNA in euchromatin.
l 7 ~ 8
~ ~
~t
9 10
~~
.~ n
11
:
i
A
12
discrete bodies called chromosomes study of localized regions of specific chromosomes to de-
.,
~ ~ {!'
termine duplications or deletions of specific gene sites & .
~
~~
~ {(
~, ~
( '
22
IS
X X
hi
cycle (see page 69), during which DNA is replicated in an- form. One X chromosome of the female is an example of
~
ticipation of the next mitotic division. such a chromosome. This fact can be used to identify the
The area located at each end of the chromosome is called sex of a fetus. This chromosome was discovered in 1949
the telomere. Telomeres shorten with each cell division. Re- 1 I
by Barr and Bartram in nerve cells of female cats, where it
cent studies indicate that telomere length is an important
indicator of the lifespan of the cell. To survive indefinitely
appears as a well-stained round body, now called the Barr a b
body, adjacent to the nucleolus. FIGURE 2.55
(become "immortalized"), cells must activate a mechanism Although the Barr body was origina lly fou nd in sec- Examination of chromosomes. a. Metaphase spread. b. Karyotype of chromosome pair in t11e male. Note in the red box insert below the
that maintains telomere length. For example, in cells that tioned tissue, it was subsequently shown that any relatively a normal female. The paired chromosomes are numbered in the chromosome 21 pair is an example of trisomy 21, an error in chro-
have been transformed into malignant cells, an enzyme large number of cells prepared as a smear (e.g., scrapings karyotype, and the female sex chromosomes are indicated by X and mosome number that causes Down's syndrome. (Courtesy of the Uni
called telomerase is present that adds repeated nucleotide of the oral rnucous membrane from the inside of the cheeks X. The black box insert below the XX chromosomes shows the XV versity of Florida Cytogenetics Laboratory.)
sequences to the telomere ends. Recently, expression of this or neutrophils from a blood smear) can be used to search
enzyme has been shown to extend the life span of cells. for the Barr body. In cells of the oral mucous membrane,
With the exception of the mature gametes, the egg and the Barr body is located adjacent to the nuclear envelope.
sperm, human cells contain 46 chromosomes organized as In neutrophils, the Barr body forms a dr umstick ap-
23 homologous pairs (each chromosome in the pair has pendage on one of the nuclear lobes (Fig. 2.56) . In both
the same shape and size). Twenty-two pairs have identical sections and smears, many cells must be examined to find
chromosomes, i.e., each chromosome of the pair contains those whose orienta tion is suitable for the display of the
the same portion of the genome, and are called autosomes. Barr body.
The twenty-third pair of chromosomes are the sex chro-
mosomes, designated X and Y. Females contain two X
chromosomes; males contain one X and one Y chromo- Nucleolus
some. The chromosomal number, 46, is fou nd in most of
the somatic cells of the body and is called the diploid (2n) The nucleolus is the site of rRNA synthesis and initial
number. Diploid chromosomes have the 2n amount of ribosomal assembly
DNA immediately after cell division but have twice that
amount, i.e., the 4n amou nt of DNA, after the S phase (see The nucleolus is a nonmembranous, intranuclear
page 69). structure formed by fib rillar material (pars fibrosa)
As a result of meiosis (see below), eggs and spenn have and granular material (pars granulosa) (Fig. 2.57). It
only 23 chromosomes, the haploid (l n) number, as well as vaxies in size but is particularly well developed in cells
the haploid (ln) amount of DNA. The somatic chromo- active in protein synthesis. Some cells contain more than
some number and the diploid (2n) amo unt of DNA are one nucleolus. The nucleolus consists largely of DNA
reestablished at fertilization by the fusion of the sperm nu- loops of different chromosomes containing genes fo r
cleus with the egg nucleus. rRNA clustered together, large amo unts of rRNA, and
proteins. FIGURE 2.57
In a karyotype, chromosome pairs are sorted according to their rRNA is present in both granular and fibrillar materia l FIGURE 2.56 Electron micrograph of the nucleolus. This nucleolus from a nerve cell
size and shape and is orga nized, respectively, as both granules and ex- Photomicrograph of a neutrophil from a female blood smear. The shows the fibrillar (F) and granular (G) materials. Such a network of
tremely fine fila ments packed tightly together. T he net- second X chromosome of the female is repressed in the interphase both materials is referred to as the nucleolonema. The rR NA, DNA-con
A preparation of chromosomes derived from mechani- wor k formed by the gran ular and the fibrillar materials is nucleus and can be demonstrated in th e neutrophil as a drumstick- taining genes for tile rRNA, and specific proteins are localized in the
cally r uptured, dividing cells that are then fixed, pla ted called the nucleolonema. DNA containing genes for the ri- appearing appendage (arrow) on a nuclea r lobe. x250. interstices of the nucleolonema. x 15,000.
64 C H APTER 2 T!Jr Cr/1 CHAPTER 2 T!Je Cell 65
bosomal subunits is localized in the interstices of this net- Nuclear Envelope uous with rER membrane (see Fig 2.58). Polyribosomes the m embrano us component of the nuclear envelope is dis-
work. are often attached to ribosoma l docking proteins present rupted by expos ure to detergent, the fi brous lamina re-
rRNA genes are tra nscribed by RNA polymerase I, and The nuclear envelope, formed by two membranes with a on the cytoplasmic side of the outer nuclear membra ne. mains, and the nucleus retains its shape.
subunits of rRNA are assembled using ribosomal proteins perinuclear cisternal space between them, separates the T he inner nuclear membrane is supported by a rigid net- The major compo nents of the la mina, as determined by
imported from the cytoplasm. The partially assembled ri- nucleoplasm from the cytoplasm work of protein filaments attached to its inner surface, biochemical isolation, are nuclear lamins, a specialized
bosomal subunits leave the nucleus via nuclear pores (see called the nuclear lamina. In addition, the inner nuclear type of nuclear intermediate filament (see page 53), and
below), to be fully assembled into ribosomes in the cyto- The nuclear envelope is assembled from two (o uter and membr ane contains specific lamin receptors and several lamina-associated proteins (Fig. 2.59). Unlike o ther cyto-
plasm. inner) nuclear membranes containing a perinuclear cister- lamina-associated protein receptors that bind to chromo- plasmic intermediate filaments, la mi ns disassemble during
nal space between them. T he nuclear envelope encloses the somes and secure the attachment of the nuclear lamina. mitosis and reassemble when mitosis ends. The nuclear
The nucleolus stains intensely with hematoxylin and basic
chromatin, defines the nuclear compartment, and serves as lamina appears to ser ve as a scaffolding for chromatin,
dyes and metachromatically with thionine dyes
a membranous boundary between the nucleoplasm and the The nuclear lamina lies adjacent to the inner surface of the cluom atin-associated proteins, nuclear pores, a nd the
cytoplasm. The perinuclear clear cisternal space is contin- nuclear envelope, between the membrane and the marginal membranes of the nuclear envelope. In addition, it is in -
That the basophilia a nd metachromasia of the nu- uous with the cisternal space of the rER (Fig. 2.58). The heterochromatin volved in nuclea r organization, cell cycle regulation, and
cleolus are d ue to the phosphate groups of the nucle- two membranes of the envelope are perforated at intervals differentiation. Impairment in nuclear lamina architecture
olar RNA is confirmed by pred igestion of specimens by nuclear pores that med iate the active transport of pro- The nuclear (fibrous) lamina, a thin, electron-dense pro- or functio n is associa ted with certain genetic diseases and
with ribonuclease (RNAse), which abo lishes the staining. teins, ribon ucleoproteins, and RNAs between the nucleus tein layer, has a supporting or "nucleoskeletal" function. If apoptosis.
D N A is present in the nucleolus but in such sma ll and cytoplas m. The membranes of the nuclear envelope
a mou nts that it appears Feulgen negative when ex am- differ in structure and functions: rough endoplasmic
ined in the Light microscope. H owever, Feu lgen-positive inner and outer
reticulum
nuclear membrane
material, nucleolus-associated chromatin, often rims th e The o uter nuclear membrane closely resembles the mem-
nucleolus. brane of the endoplasmic reticulum and in fact is contin- perinuclear space
ribosomes
nuclear
nuclear
pore
complex
a
DNA a
nucleus
nuclear lamina
FIGURE 2.58
Structure of the nuclear envelope and its relationship to the rER. a. b. This electron micrograph, prepared by the quick-freeze deep-etch FIGURE 2.59
This schematic drawing shows the organization of the nuclear wall. A technique, shows the nucleus, the large spherical object, surrounded Structure of the nuclear lamina. a. This schematic drawing shows the molecules between nucleus and cytoplasm. b. Electron micrograph of
double membrane envelope surro unds the nucleus. The outer mem- by the nuclear envelope. Note that the outer membrane possesses ri- structure of the nuclear lamina adj acent to the inner nuclear mem- a portion of the nuclear lamina from a Xenopus oocyte. It Is formed
brane is continuous with the membranes of rER; thus, tl1e perinuclea r bosomes and Is continuous with the rER. x 12,000. (Courtesy of Dr. brane. The cut window In the nuclear lamina shows the DNA within by intermediate filaments (lamins) that are arranged in a square lat-
space communicates with the rER lumen. The inner membrane is ad- John E. Heuser, Washington University School of Medicine.) the nucleus. Note that the nuclear envelope is pierced by nuclear tice. X43,000. (Adapted from Aebl U, et al. Nature 1986;323:
jacent to nuclear intermediate filaments that form the nuclear lamina. pore complexes, which allow for selective bidirectional transport of 560-564.)
66 CHAPTER 2 Tlu Cr/1 CHAPTER 2 The Ctll 67
The nuclear envelope possesses an array of openings called either ribosomes or other protein complexes (transporters) The NPC mediates bidirectional nucleocytoplasmic transport than the 70- to 80-nm measurement of the pore bound-
nuclear pores captured during their passage through the pore at the time ary. H owever, even the smaller nuclear protei ns that are
of fixatio n. Various experiments ha ve sh own that t he nuclear pore capa ble of diffusion are selectively transported, presum-
At numerous sites, the paired membranes of the nuclear With special techniques, such as negative staining and complex regulates the passage of proteins between the ably because the rate is faster than by simple diffusion.
envelope are punctuated by 70- to 80-nm "openings" high-voltage transmission electron m icroscopy, the nu- nucleus and the cytoplasm (Fig. 2.62). The significance of
through the envelope. T hese openings, or nuclear pores, are clear pore exhibits additio na l structura l detail. Eight mul- the NPC ca n be readily appreciated, as the nucleus does During cell division, the nuclear envelope is disassembled to
formed from the fusion of the inner and o uter membranes tidomain protein subunits arranged in an octagonal cen- not carry out protein synthesis. Ribosomal proteins are allow chromosome separation and is later reassembled as the
o f the nuclear envelope. With an ordinary TEM, a tral framework at the periphery of each pore form a partially assembled into ribosomal subunits in the nucle- daughter cells form
diaphragm-like structure appears to cross the pore opening cylinder-li ke structure known as the nuclear pore com- olus and are transported through nuclear pores to the cy-
(Fig. 2.60). Often, a small dense body is observed in the plex (NPC). The NPC, whose total mass is estimated at toplasm. Conversely, nuclear proteins, such as histones In early prophase of cell division, enzymes (kinases) a re
center of the opening. Such profiles a re thought to represent 125 X 106 Da, is composed of a bout 50 different nuclear and lamins, are produced in the cytoplasm a nd are trans- activated that ca use phosp horylation of the nuclear
pore complex proteins collectively referred to as nucleo- ported through nuclear pores into t he nucleus. Transport lamins and oth er lamina-associated proteins of the n u-
porins (Nup proteins) . T his centra l framework is inserted through the N PC largely depends on the s ize of t he mol- clear envelope. After phosphorylation, the proteins be-
between two cytoplasmic and nuclear rings (Fig. 2.61). ec ules: come soluble, and t he nuclear envelope disassembles. The
From the cytoplasmic ring, eight short protein fibrils pro- lipid compon ent of the nuclear membranes then disasso-
t rude into t he cytoplasm. The nucleoplasmic ring com- Large molecules (such as RNAs, large proteins, and ciates from the proteins and is retained in small cytoplas-
plex anch ors a basket (or nuclear "cage," wh ich r esem- macromolecu lar complexes) depend for p assage on the mic vesicles. Th e replicated chromosomes then attac h to
bles a fish trap ) assembled from eight thin 50-nm-long presence of a n attached signal sequence called the nuclear the microtubules of the mitotic spindle a nd undergo ac-
filaments joined distally by a 30- to 50-om-diameter ring. localization signal. La beled proteins destined for t he nu- tive movement.
The cylinder-shaped central fra mework encircles the cen- cleus then bind to a soluble cytosolic receptor called a nu- Reassembly of the nuclear envelope begins in late
tral pore of the NPC, which acts as a close-fitting di- clear import receptor that directs them from the cyto- anaphase, when phosphatases are acti vated to remove the
aphragm or gated channel. ln addition, each N PC con- plasm to an appropriate NPC. They are then actively phosphate residues from the nuclear lamins. During
tains one or more water-filled cha nnels for transport of transported through the pore by a GTP energy-dependent telophase, t he nuclear lamin s begin to repolymerize a nd
small molecules. mechanism. The NPC transports proteins as well as ribo- form the nuclear lamina material around each set of daugh -
soma l subunits in their full y folded configuration. ter chromosomes. At the same time, vesicles containing the
Io11s a nd smaller water-soluble molecules (less than 9 lip id components of the nuclea r membranes and structural
Da) may cross the water-filled channels of the NPC by membrane protein components fuse, and an envelope is
simple diffusion. This process is nonspecific and does formed on the surface of the already-reassembled nuclear
cytoplasmic ring subunit not require nuclear signal proteins. The effective size of lamina. By the end of teloph ase, forma tion of a nuclear en-
central framework the pore is about 9 nm for substances that diffuse, rather velope in each daughter cell is complete.
scaffold
...
y
-
. . ..
!
. . .. ~lrw
............ .
luminal
subunit outer and inner
nuclear membrane
nucleoplasmic
ring subunit
FIGURE 2.61 ..' . a.. I
b
Schematic drawing of the structure of the nuclear pore complex.
Each pore contains eight protein subunits arranged in an octagonal FIGURE2.62
central framework at the periphery of the pore. These subunits form Electron micrographs showing protein-coated gold particles pass- at the site of the nuclear pore complex. The particles are in a linear
a nuclear pore complex that Is Inserted between two cytoplasmic and Ing through nuclear pore complexes. a. Protein coated with gold par- array and appear to be in transit through the nuclear pore complex
FIGURE 2.60 nuclear rings. Eight short protein fibrils protrude from the cytoplasmic ticles was injected into the cytoplasm of an oocyte. Wlthin15 minutes from the cytoplasm to the nucleoplasm. The path of the particles II
Electron micrograph of the nuclear envelope. Note the visible nu ring into the cytoplasm. The nuclear ring anchors a basket assembled of injection, the coated gold particles are largely concentrated in the lustrates the pathway taken by proteins synthesized in the cytoplasm
clear pore complexes (arrows) and the two membranes that constitute from eight thin fi laments joined dista lly by a protein ring. The cylin- region of the nuclear pore complexes of the nuclear envelope (ar- as they are transported into the nucleus. x 200,000. (Courtesy of Dr.
the nuclear envelope. At the periphery of each pore, the outer and In drical central framework encircles the central pore, which acts as a row/1eads). x 60,000. b. A higher magnification of the area marked by Carl M. Feldilerr.)
ner membranes ofthe nuclear envelope appear continuous. x3 0,000. close-fitting diaphragm. tile double arrow11ead in a shows an elongate cluster of gold particles
68 CHAPTER 2 He Cell C H APTER 2
Nucleoplasm populations may actually slowly i_ncrease in size during first m eiotic division; see page 70), cells duplicate their
life, as do the smooth muscle cells of the gastrointestinal DNA. This phase of the cell cycle is called the S or synthe-
Nucleoplasm is the material enclosed by the nuclear envelope tract and the epithelial cells of the lens. sis phase. At the beginnmg of this phase, the chromosome
exclusive of the chromatin and the nucleolus Rapidly renewing populations include blood cells, ep- number is 2n, a nd the DNA content is 2n; at the end, the
itheLial cells and derma l fibroblasts of the skin, and the ep- chromosome number is 4n, and the D NA content is 4n (see
Although crystalline, viral, and other inclusions are ithelial cells and subepithelial fibroblasts of the mucosal page 70) .
sometimes found in the nucleoplasm, until recently, lining of t he alimentary tract.
morphologic techniques showed it to be amorphous. It Mitosis follows the S phase and is described in four phases
must be assumed, however, that many proteins and other
metabolites reside in or pass through the nucleus in rela- Q CELL CYCLE Mitosis consists of four phases:
tion to the synthetic and metabolic activity of the chro-
matin and nucleolus. New structmes have recently been Somatic cell division is a cyclic process divided into two phases: Prophase begins as the chromosomes condense and be-
identified within the nucleoplasm, including intranuclear mitosis and interphase come visible. As the c hromosomes continue to condense,
lamin-based arrays, the protein filame nts emanating in- each of the four chromosomes derived from each ho-
ward from the nuclear pore complexes, as well as the ac- For renewing cell populations an d growing cell popula- mologous pair ca n be seen to consist of two chromatids.
tive gene-tethered R NA transcription and processing ma- tions, including embryonic cells, cells rn tissue cultme, and The chrom atids a re held together by the centromere or
c hinery itself. It is li kely that improved TEM a nd even tumor cells, the cell cycle has two principal phases: mi- kinetochore. Other ch anges at this time include disap-
immunocytochemical methods will further elucidate the tosis (M phase) a nd interphase. Three other phases, gap, pearance of the nucleolus, replication of the centrioles,
nature of the nucleoplasm, but the possibility remains that (G,), synthesis phase (S), a nd gap 2 (G:z), further subdivide and disintegration of th e nuclear envelope.
chromatin is the main constituent of the nuclear structure. interphase (Fig. 2.63 ). Mitosis nearly always includes both Metaphase (Fig. 2.66) begins as the mitotic spindle, con-
karyokinesis (division of the nucleus into two daughter nu- sisting of three types of microtubules, becomes organized
clei) and cytokinesis (division of the cell into two daughter around the MTOCs located at opposite poles of the cell.
Q CELL RENEWAL cells) and lasts about 1 hour. It is usually followed by G ,, a The first type of astralmicrotubules are nucleated from
period in which no DNA synthesis occms. G 1 is usually a the y-tubulin rings in a star-like fashion around each
Somatic cells in the adult organism may be classified according period of cell growth and may last only a few hours in a rap- MTOC. The second type of polar microtubules also orig-
to their mitotic activity idly dividing cell or may last a lifetime in a nondividing cell. inates from the MTOC; however, these microtubules ex-
A cell that leaves the cycle in G , to begin "terminal" differ - tend away from the MTOC. T he third type of kineto-
The level of mitotic activity in a cell can be assessed by entiation enters the G 0 phase, "0" for "outside" the cycle. chore microtubules is formed by MTOC-independent
the number of mitotic metaphases visible in a single high- The S or DNA synthesis phase follows G 1 and usually mechanisms that involve kinetochores. These micro-
magnification light microscopic field or by autoradi- lasts about 7 ho urs. The DNA of the cell is doubled during s
DNA synthesis tubules and their associated microtubule motor proteins
ographic studies of the incorporation of tritiated thymi- the S phase, and new chromatids a re formed that will be- direct the movements of the chromosomes to the plane in
dine into the newly synth esized DNA prior to mitosis. come obvious at prophase or metaphase (see Figs. 2.64 FIGURE 2.63
the middle of the cell, the equatorial or metaphase plate.
Using these methods, cell populations may be classified ei- a nd 2 .65 ) of the next M p hase. The brevity of the S phase Cell cycle. This diagram illustrates the cell cycle of rapidly dividing
cells in relation to DNA synthesis. After mitosis, the cell is in inter- Anaphase (Fig . 2.66) begins as the c hroma tids separ ate
ther static, stable, or renewing: allows the use of tritiated thymidine to label only those and are pulled to opposite poles of the ceiJ by the mo-
cells engaged in DNA synthesis at the time the radioac- phase. G, represents the period during which a gap occurs in DNA
Static cell populations consist of cells that no longer di- synthesis. S represents the period during which DNA synthesis occurs. lecular motors (dyneins) sUding a long kinetochore mi-
ti vely labeled nucleotide is present. crotubules toward the MTOC.
vide (postmitotic cells), such as cells of the central nerv- During this phase, tritiated thymidine can be incorporated into the
The S phase is a lso followed by a period in which no DNA DNA to serve as an experimental tracer. G2 represents a second gap Telophase (Fig. 2.67) is marked by the reconstitution o f
ous system, or cells that divide only ra rely, such as skele-
synthesis occurs, a second gap or G2 phase. G2 may be as in DNA synthesis. Go represents the path of a cell that has stopped di- a nuclear envelope arou nd the chromosomes at each
tal and ca rdiac muscle cells.
short as 1 hour in rapidly dividing cells or of nearly indefi- viding; however, such a cell may reenter the cell cycle at the R point pole. The chromosomes uncoil and become indistinct
Stable cell populations consist of cells that divide episodi- nite duration in some polyploid cells and in cells, such as the after an appropriate stimulus. The cell residing In G0 may undergo ter- except at regio ns that rema in condensed in the inter-
cally and slowly to maintain normal tissue or organ struc-
pri_mary oocyte, that are arrested in G2 for extended periods. minal differentiation, Gro, and produce a population of permanent phase nucleus. The nucleoli reappear, and rhe cytoplasm
ture. These cells may be stimulated by inj u ry to become
Cells identified as reserve stem cells may be thought of nondividing cells (e.g., adult neurons). The average timi ng of each divides to form two daughter cells. Because the chromo-
more mjtoticaUy active. Periosteal a nd perichondrial cells, phase of the cell cycle is indicated on the diagram.
as G 0 cells that may be induced to reenter the cell cycle in somes in the daughter cells contain identical copies of
smooth muscle cells and endothelial cells of blood vessels,
response to injury of the cell populations within the tissues th e duplica ted DNA, the d a ug hter cells are genetically
and fibroblasts of the connective tissue may be included in
of the body. Activation of these cells may occur in normal identical and contain the same kind and number of
this category.
wou nd healing and in the repopulation of the seminiferous Mitosis is a cell division process that produces two daughter chromosomes. The daughter cells are 2n in DNA con-
Renewing cell populations may be slowly or rapidly r e-
epithelium after intense acute exposure of the testis to x-ir- cells with the same chromosome number and DNA content as tent and c hromosome number.
newing but display regular mitotic activity. Division of
radiation or during regeneration of an o rgan, such as t he the parent cell
such cells usually results in two daughter cells that dif-
liver, after remova l of a major portion. If the damage to the
feren tiate both morphologically and functionally o r two
tissues is too severe, even the reserve stem cells die, and The process of cell division usuall y incl udes division o f Meiosis
cells that remai n as stem cells. Daugh ter cells may di vide
there is n o potential for regeneration. both the nucleus (karyokinesis) a nd the cytoplasm (cytoki-
o ne or more times before their mature state is reached.
nesis). ln the strictest sense, the terms mitosis a nd meiosis Meiosis is a process consisting of two sequential cell divisions
The differentiated cell may ultimately be lost from the
Mitosis are used to describe the duplication and distribution of the that produces gametes containing half the number of
body.
c hromosomes. If cytokinesis does not follow karyokinesis, chromosomes and half the DNA found in somatic cells
Slowly renewing populations include smooth muscle Cell division is a crucial process that increases t he number a binuclea te cell is formed.
cells of most hollow organs, fibroblasts of the uterine wall, of cells, permits renewal of cell populations, and allows Cells that a re not in the process of dividing a re called The zygote and a ll the somatic cells derived from it are
and epithelia l cells of the lens of the eye. Slowly renewing wound repair. 1'esting or interphase cells. Prior to entering mi tosis (or t he diploid (211) i.n c hromosome number; the gametes, having
70 C H APTER 2 Tbe Cell
CHAPTER 2 Tile Cell 71
MEIOSIS
MITOSIS prophase I
____...~-@-@-@- (~
leptotene zygotene pachytene di plotene
FIGURE 2.67
metaphase I ~ . Mitotic spindle in telophase. In this phase, DNA is segregated and a
{~~- ~!
continuation of
meios is as seen nuclear envelope is reconstituted around the chromosomes at each
continuation of \ p_ole of the ~italic spindle. The cell divides into two during cytokine-
c0 meiosis as see n ( (~ ~ SIS. In the middle of the cell, actin, septins, myosins, microtubules, and
in spermatogenesis other proteins gather as the cell establishes a ring of proteins that will
'iii
~anaphase
- :; constrict, forming a bridge between the two sides of what was once
(/) --
- "C
(1) - on~ cell. The chro~osomes uncoil and become indistinct except at
0 ctl
-Q) c:
O
\........ I reg1ons that remam condensed in interphase. The cell types and
en preparation are the same as those in Figures 2.65 and 2.66. x 1,400.
:::J
"C
~ ~ FIGURE 2.65
Mitotic spindle in metaphase. Using indirect Immunofluorescence
(Courtesy of Dr. Thomas u. Mayer.)
~
techniques, the mitotic spindle in a Xenopus Xl-1 77 cell was labeled
lelophase I with an antibody against atubulin conjugated with fluorescein
(green). DNA was stained blue with fluorescent DAPI stain. In The cytoplasmic events associated with meiosis differ in the
~
metaphase, the nuclear membrane disassembles, DNA is condensed male and female
into chromosomes, and microtubules form a mitotic spindle. The ac
:======= ~ melaphase II
lion of microtubule-associated motor proteins on the microtubules of
.
, . , the mitotic spindle creates the metaphase plate along which the chro T he nuclear events of meiosis are the same in males and
telophase f~males, but t_he cytoplasmic events are markedly different.
mosomes align in the center of the cell. x 1,400. (Courtesy of Dr.
@ = :~ ~
Thomas U. Mayer.) Ftgure 2.64 Illustrates the key nuclear and cytop lasmic
events of meiosis as they occur in spermatogenesis and oo-
~ .: :.
.. I genesis. The events of meiosis through metaphase I are the
:~ ~
(l)'iJ
spermatids t fI \
same in both sexes. Therefore, the figure illustrates the dif-
daughter cells Q> O
ferences in the process as they diverge after metaphase I.
e~ r,J
0" In males~ the two meiotic divisions of a primary sper-
~ t t ovum
matocyt~ yteld four _structurally identical, although geneti-
s permatozoa ~ cally ~mque, haplotd spermatids. Each spermatid has the
f
*note: prophase II, anaphase II,
spermiogenesis ~apacJty to differentiate into a spermatozoon . In contrast,
11~ fema les, the t_wo meiotic divisions of a primary oocyte
and telophase II are not shown. yteld one haplotd ovum and three haploid polar bodies.
FIGURE 2.64 The ovum receives most of the cytoplasm and becomes the
Comparison of mitosis and meiosis in an idealized cell with two has only two chromosomes (n). In addition, during the chromosome functional gamete. T he polar bodies receive very little cy-
pairs of chromosomes (2n). The chromosomes of maternal and pa pairing in prophase I of meiosis, chromosome segments are ex toplasm and degenerate.
ternal origin are depicted in red and blue, respectively. The mitotic di changed, leading to further genetic diversity. It should be noted that
vision produces daughter cells tl1at are genetically identical to the in humans the first polar body does not divide. Division of the first The nuclear events of meiosis are similar in males and females
parental cell (2n). The meiotic division, which has two components, a polar body does occur In some species.
reductional division and an equatorial division, produces a cell that During the S phase that precedes meiosis, ch romosomes
are rep licated. The DNA con tent becomes 4n, and the chro-
FIGURE 2.66
mos~me nut~~e~ becomes 4n. The cells then undergo a re-
Mitotic spindle in anaphase. This immunofluorescent Image comes
ductional dwtsta1t (meiosis I) and an equatorial division
only one member of each chromosome pair, are described as by reduction in DNA content to the haploid (ln) amount in from Ill~ same cell type and identical preparation as in Figure 2.65.
Connections that hold the sister chromatids together break at this (meiosis II). During meiosis I, the materna l a nd paternal
haploid (1n). During gametogenesis, red uction in chromo- the second meiotic division. chromosomes pair and exchange segments. T hey then sepa-
some num ber to the haploid state (23 chromosomes in hu- D uri ng meiosis, the chromosomes pair and may ex- st~ge. The chroma_tids are then moved to opposite poles of the cell by
~rcrotubuleassoc1ated molecular motors (dyneins and kinesins) tJ1at rate from _one another. At the end of meiosis I, each daughter
ma ns) occurs th rough meiosis, a process that involves two change chr omosome segments, thus altering the genetic
slide along the kinetochore microtubules toward the centriole and are c~ll c?ntams one member of each pair of chromosomes (the
successive cell divisions, the second of which is not preceded composition of the chromosomes. This genetic exchange, dtplotd or 2n amount), and the amount o f DNA is reduced
also pushed by the polar microtubules (visible between the separated
by an S phase. This reduction is necessary to mainta in a con- called crossing-ove1; and the ra ndom assortment of each
chrom_os~mes~ away from each other, thus moving opposite poles of to 2n. In meiosis II, the chromatids separate from one an-
stant number o f chromosomes in the species. Redu ction in mem ber of the chromosome pairs into ha ploid gametes the 1TI1Iot1c spindle into the separate cells. x1,400. (Courtesy of or. other, establishing the haploid number (n) of chromosomes
ch romosome number in the fi rst meiotic division is followed give rise to infinite genetic diversity. Thomas U. Mayer.) and reducing the DNA content to the haploid amount (n) .
72 CHAPTER 2 The Ctll C H APTER 2 Tile Cell 73
Phases in the process of meiosis are similar to the phases of haploid DNA content (ln). U nlike the cells produced by CELL DIVISION CELL DEATH
mitosis mitosis, which are genetically identical to the parent cell,
~Jo)
th e cells produced by meiosis are genetically unique.
PROPHASE I
The prophase of meiosis I is an extended phase that is sub-
divided into five stages (see Fig. 2.64):
Q CELL DEATH 6
HOMEOSTASIS
Leptotene. The chromosomes become visible as thin In humans, as in all other multicellul ar organisms, the
strands. rates of cell pro liferation a nd cell death determine the
Zygotene. Homologous chromosomes of maternal and net cell production. An abnormality in any of these rates
paternal origin pair. This pairing involves the formation can ca use disorders of cell accumulation (e.g., hyper- CELL LOSS DISORDERS: CELL ACCUMULATION
of a synaptonemal complex, a tripartite structure that plasia, cancer, autoimmune diseases) or disorders of cell AIDS DISORDERS :
brings the chromosomes into physical association so loss (atrophy, degenerative diseases, AIDS, ischemic in- Alzheimer's disease cancer
Parkinson's disease lupus erythematosus
that crossing-ove r may occur. jury ). Therefore, the balance (homeostasis) between cell
aplastic anemia glomerulonephritis
Pachytene. As the chromosomes condense, the individ- production a nd cell death must be ca refully maintained myocardial infarction viral infections
ua l chrom atids become visible. Cr ossing-over occurs (Fig. 2.68).
FIGURE 2.68
early in this phase.
Schematic diagram showing the relationship between cell death ber will occur. Such conditions are categorized as cell loss disorders.
Diplotene. The chromosomes condense further, and chi- Cell death may occur as a result of acute cell injury
and cell division. Under normal physiologic conditions (homeostasis), When the situation is reversed and the rate of cell division Is higher
asmata or contacts between the chromatids appear. The or an internally encoded suicide program the rate of cell division and the rate of cell death are similar. If the rate than the rate of cell death, the net gain in cell number w ill be promi-
chiasmata indicate crossing-over may have occurred. of cell death is higher than that of cell divisions, a net loss of cell num nent, leading to a variety of disorders of cell accumulation.
Diakinesis. The chromosomes reach their maximum Cell death may result from accidental cell injury or
thickness, the nucleolus disappears, and the nuclear en- mechanisms that ca use cells to self-destruct. The two dif-
velope disintegrates. ferent mechanisms of cell death are
Necrosis, o r accidental cell death. Necrosis is a patho-
logic process. It occurs w hen cells are exposed to an un -
METAPHASE I favorable physical or chemical environ ment (e.g., hy-
Metaphase I is similar to the m etaphase of mitosis except pothermia, hypoxia, radiation, low pH, cell traum a) Necrosis begins with impairment of the cell's ability aggregates, and tbe nucleus may divide into several dis-
that the paired chromosomes are a ligned at the eq uatorial that ca uses acute cellular injury and damage to the to maintain homeostasis crete fragments bounded by the nuclear en velope.
p late w ith o ne member on either side. Anaphase I and plasma memb rane. U nder physio logic conditions, dam- Decrease in cell volume is achieved by shrinking of t he
telophase I are similar to the same phases in mitosis except age to the plasma membrane may also be initiated by As a result of cell injmy, damage to the cell membrane cytoplasm. The cytoskeletal elements become r e01gan-
t hat the cemromeres do not split an d the paired ch ro- viruses, substances such as complement, or proteins leads to an influx of wa ter and extracellular ions. Intracel- ized in bund les par allel to the cell surface. Ribosomes
matids, held by the centrom ere, remain together. A mater- called per forins. Rapid cell swelling an d lysis are two lular organelles, such as the mitochondria, rER, and nu- become clumped w ithin the cytoplasm, the rER forms a
na l or paternal member of each homo logous pair, now con- characteristic features of this process. cleus, undergo irr eversible changes tha t are caused by cell series of concentr ic w horls, and most of the en docytotic
taining exchanged segments, moves to each pole. Apoptosis [Gr., falling off, as petals from flowers}, also referred swelling and cell membr ane ru ptu re (cell lysis). As a resu lt vesicles fuse with the plasma membrane.
Segregation or random assortment occurs because the ma- to as programmed cell death. Apoptosis represents a of t he ultimate brea kdown of the plasma membrane, the Loss of mitochondrial function is caused by cl1anges in
ternal and paternal chromosomes of each pair are ran - physio logic process. During apoprosis, cells t hat are no cytoplasmic contents, including lysosomal enzymes, are re- the permeability of the mi tochondrial membr ane cha n-
domly a ligned on one side or the other of the metaphase longer need ed are eliminated fro m t he organism. T his leased into the extracellular space. Therefore, necrotic cell nels. The integrity of the mitochondrion is breached,
plate, thus contri buting to genetic diversity. At the comple- process may occur during norma l embryologic d evelop- death is often associated w ith extensive surro unding tissue the mitochondria l transmembrane potential drops, and
tion of meiosis I, o r the reductional division, the cytoplasm ment or other normal physiologic processes, such as fol- damage and an intense inflammatory response (Fig. 2.69) . the electron transport chain is disrupted. Proteins from
divides. Each resulting da ughter cell (a second ary sperma- licular auesia in the ova ries. Cells can initiate their own the mitochondria l intermembra ne space, such as cy-
tocyte or oocyte) is haploid in chromosome number (l n), death through activation o f an internally encod ed sui- Apoptosis is a mode of cell death that occurs under normal tochrome c, ar e released into the cytoplasm to activate
conta ining one member of each chro mosome pair, but is cide program. Apoptosis is characterized by controlled physiologic conditions a cascade of proteolytic enzymes called caspases that
still diploid in DNA content (2n). autodigeston, which maintai ns cell membrane integrity; are r esponsible fo r disma ntling the cell. The regulated
thus, the cell "dies w ith dignity" without spilling its con- ln apoptosis, the cell is an active participan t in its own release of cytochrome c suggests that mitochondria,
tents and damaging its neigh bors. dem ise ("cellular suicide"). This p rocess is activated by a under the influence of Bcl-2 proteins (see page 74), are
MEIOSIS II
va riety of extrinsic and intrinsic signa ls. Cells undergoing the decision make rs for initiating apoptosis. Thus
After meiosis I, without passing through an S phase, the In additio n, certain cells or thei r secretions fou nd in t he apoptosis show characteristic morphologic and biochemi- many researchers view mitochondria either as th e
cells quickly en ter meiosis II, the eq uatoria l division , w hich immw1e system are toxic to other cells (e.g., cytotoxic ca l features (see Fig. 2.69): " headquarters for the leader of a crack suicide sq uad"
is more like mitosis because the centromeres d ivide. The CD8+ T lymphocytes, NK cells); they in itiate processes or as a "high sec urity prison for the leader s of a mil i-
chromatids then separa te at anaphase II and move to op- that des troy designated cells (e.g., ca ncer-transformed or DNA fragmentation occu rs in t he nucleus and is a n ir- tary co up. "
posite poles of the cell. During meiosis II, t he cells pass virus-infected cells). ln contrast to necrosis and apoptosis, reversible event that com mits th e cell to die. DNA frag- Membrane blebbi1tg results fro m cell membrane alter-
through prophase II, metaphase II, a naphase II, and cytotoxic death does not in volve one specific mechanism. mentation is a result of Ca 2 +-dependen t and Mgl+- ations. One alteration is related to translocati on of cer-
telophase II. T hese stages are essentially the same as those For example, cell death mediated by cytotoxic CDS+ T d ependent activation of nuclear endon ucleases . These ta iJl molecu les (e.g., phosphatidylserine) from the cyto-
in mitosis except that they in vo lve a haploid set of chro- lymphocytes combines some aspects of both necros is and enzymes selectively cleave DNA, generating small plasmic surface to the o uter surface o f the plasma
mosomes and produce daughter cells that have only the apoptosis. oligonucleosomal fragments. N uclea r chr omatin then membr ane. T hese changes ca use the plasma membr a ne
74 CHAPTER 2 HeCd/
FIGURE2.69
Schematic diagram of changes occurring in necrosis and apoptosis.
This diagram shows the major steps In necrosis and apoptosis. In
fie
tense inflammatory response. In apoptosls (right column), the cell
shows characteristic morphologic and biochemical features such as
0 DNA fragmentation, decrease in cell volume, membrane blebbing
without loss of membrane Integrity, and formation of apoptotic bod-
ies, causing cell breakage. Apoptotic bodies are later removed by
o@j
o~
~"'>~.;::
. phagocytotic cells without inflammatory reactions.
A~
'D G
l injury at
cell membrane DNA fragmentation
to change its physical and chemical properties and lead
to blebbing without loss of membrane integrity (see Fig.
FIGURE 2.70
a
Electron micrograph of apoptotic cells. a. This electron micrograph nuclear fragmentation. Note the reorganization of the cytoplasm and
~
~@
2.69). shows an early stage of apoptosis in a lymphocyte. The nucleus is al- budding of the cytoplasm to produce apoptotic bodies. x 5,200.
Formation of apoptotic bodies, the final step of apop- ready fragmented, and the irreversible process of DNA fragmentation c. Apoptotic bodies contain ing fragments of the nucleus, organelles,
0 tosis, results in cell breakage (Fig. 2.70). These mem-
brane-bounded vesicles originate from the cytoplasmic
is turned on. Note the regions containing condensed heterochromatin
adjacent to the nuclear envelope. x 5,200. b. Further fragmentation of
and cytoplasm. These bodies will eventually be phagocytosed by cells
from the mononuclear phagocytotic system. x5,200. (Courtesy of Dr.
.~o bleb containing organelles and nuclear material. They DNA. The 11eterochromatin in one of the nuclear fragments {left) be- Scott H. Kaufmann, Mayo Clinic.)
~
. gins to bud outward through the envelope, Initiating a new round of
. are rapidly removed by phagocytotic cells. The removal
() ..._. of apoptotic bodies is so efficient that no inflammatory
response is elicited.
0 Apoptosis is regulated by external and internal stimuli
apoptotic body
ligands for
Apoptotic processes can be activated by a variety of phagocytic
external and internal stimuli. Some factors, such as tu- cell receptors
mor necrosis factor (TNF), acting on cell membrane re-
ceptors, trigger apoptosis by recruiting and acti vati ng
the caspase cascade. Consequently, the TNF receptor is
known as the "death receptor." Other externa l activa-
tors of apoptosis include transforming growth factor {3
(TGF-{3), certain neurotransmitters, free radicals, oxi-
da nts, and UV and ioning radiation. Internal activa tors
of apoptosis include oncogenes (e.g., myc and rei), tu-
mor suppressors such as p53, a nd nutrient deprivation
antimetabolites (Fig. 2.71).
Apoptosis can a lso be inhibited by signals from other
cells and the surrounding environment via so-called sur-
vival factors. These include growth factors, hormones
such as estrogen and androgens, neutral amino acids,
zinc, and interactions with extracell ular matrix proteins.
formation of However, the most importa nt regulatory function in
apoptotic bodies apoptosis is ascribed to intern al signals from the Bcl-2
DNA
family of proteins. Members of this family consist of an- fragments
tiapoptotic and proapoptotic members that determine the
life or death of a cell. These proteins interact with each
other to suppress or propagate their own activity by act- injury
radiation
ing on downstream activation of various executional death
toxins
steps of apoptosis. T hey a lso act independently on mito- ~ receptor FIGURE 2.71
free
chondria to regulate the release of cytochrome c, the most radicals Schematic drawing of mechanisms leading to apoptosis. Both exter-
potent apoptosis-inducing agent. nal and internal stimuli ca n trigger apoptosis by activating the enzy-
receptor-ligand matic caspase cascade. Many external activators act on the cell to ini-
withdrawal of interactions tiate signals lead ing to apoptosis; note that TNF and TGF-,8 act through
s urvival factors TNF a 'death receptor: Controlled release of cytochrome c from mitochon-
TGFB dria is an important interna l step in the activation of apoptosis.
76 CHAPTER 2 Thr Cell CHAPTER 2 Tlu Crll 77
TABLE 2.3.Review of Organelles and Cytoplasmic Inclusions: A Key to Light Microscopic TABLE 2 .4. Organelles and Cytoplasmic Inclusions: Functions and Pathologies
and Electron Microscopic Identification
Organelle
Organelle or
Examples
or Light Microscopic Electron Inclusion Function of Associated Pathologies
Inclusion Size (J.Lm ) Features Microscopic Features Nucleus Storage and use of genome Inherited genetic diseases; environmentally induced
Nucleus 3-10 Largest organelle within the cell w ith Surrounded by two membranes (nuclear enve- mutations
distinct boundary; often visible nucleoli lope) containing nuclear pore complexes and Nucleolus Synthesis of rRNA and partial assembly of riboso ?
and chromatin pattern regions perinuclear cisternal space; regions with con mal subunits
densed and diffuse chromatin pattern (hete- Plasma membrane Jon and nutrient transport; recognition of environ Cystic fibrosis
rochromatin and euchromatin)
mental signals; celltocell and cell-to-extracellular Intestinal malabsorption syndromes
Nucleolus 1-2 Roughly circular, ba sophilic region Dense, nonmembranous structure containing matrix adhesions Lactose Intolerance
within the nucleus; visible in living cells fibrillar and granular material rER Binds ribosomes engaged in translating mRNA for Pseudoachondroplasia
throughout interphase with interference
proteins destined for secretion or for membrane in- Calcium phosphate dihydrate crysta l deposition disease
microscopy
sertion ; also Involved in chemical modifications of
Plasma membrane 0.008-0.01 Not visible The external membrane and membranes sur- proteins and membrane lipid synthesis
rounding membranous organelles of the cell; sER Similar to the rER but lacks the ribosome-binding Hepatic endoplasmic reticular storage disease
two inner and outer electron-dense layers sepa
function; involved in lipid and steroid metabolism
rated by an intermediate electron-lucent layer
Golgl apparatus Chemical modification of proteins: sorting and lcell disease
rER Area -5-10 Often observed as a basophilic region Flattened sheets, sacs, and tubes of membranes
packaging of molecules for secretion or transport to Polycystic kidney disease
of cytoplasm referred as ergastoplasm with attached ribosomes other organelles
sER Throughout Not visible; cytoplasm in region of Flattened sheets, sacs, and tubes of membranes Secretory vesicles Transport and storage of secreted proteins to Lewy bodies of Parkinson 's disease
cytoplasm sER may exhibit distinct eosinophilia without attached ribosomes plasma membrane Prolnsulin diabetes
Golgl apparatus Area -5-10 Sometimes observed as negative- Stack of flattened membrane sheets, often adja- Mitochondria Aerobic energy supply (oxidative phosphorylation, Mitochondrial myopathies such as MERRF,A MELAS,"
staining region; appears as network in cent to one side of the nucleus
ATP); Initiation of apoptosls Kearns-Sayre syndromes, and Laber's hereditary opt ic
heavy-metal-stained preparations; visi-
ble in living cells with interference mi- atrophy
Endosomes Transport of endocytosed material; biogenesis of
croscopy M-6-P receptor deficiency
lysosomes
Secretory vesicles 0.050-1.0 Observed only when vesicles are very Many relatively small, membrane-bounded vesi-
Lysosomes Digestion of macromolecules
large (e.g., zymogen granules in pancreas) cles of uniform diameter; often polarized on Glycogen storage disease type II
one side of cell Tay-Sachs disease
Mitochondria 0.2-2 X 2-7 sometimes observed in favorable situa- Two-membrane system: outer membrane and Metachromatic leukodystrophy
Peroxisomes Oxidative digestion, e.g., fatty acids
tions (e.g., liver or nerve cells) as very inner membrane arranged in numerous folds Zellweger's syndrome
small, dark dots; visible in living cells (cristae); in steroid-producing cells inner mem Cytoskeletal element Various functions Including cell motility, intracellular lmmotile cilia syndrome, Alzheimer's disease, epidermolysis
stained with vital dyes, e.g., Janus green brane arranged in tubular cristae and extracellular transport; maintenance of cellular bullosa
Endosomes 0.02-0.5 Not visible Tuboloveslcular structures with subdivided lu skeleton
men containing electron-lucent material or Ribosomes Synthesize protein by translating protein-coding se Many antibiotics act selectively on bacterial ribosomes, e.g.,
other smaller vesicles quence from mRNA
tetracyclines, amlnoglycosides (gentamicin, streptomycin)
Lysosomes 0.2-0.5 VIsible only after special enzyme histo- Membrane-bounded vesicles, often electron Glycogen Short-term storage of glucose in the form of There are several known glycogen storage diseases, Includ-
chemical staining dense branched polymer; found In liver, skeletal muscle, ing major groups of hepatic-hypoglycemic and muscle-en-
Peroxisomes 0.2-0.5 Visible only after special enzyme histo Membrane-bounded vesicles, often with and adipose tissue ergy pathophysiologies
chemica l staining electron-dense crystalloid inclusions Lipid droplets Storage of esterified forms of fatty acids as high-en- Lipid storage diseases such as Gaucher's and NiemannPick
Cytoskeletal elements 0.006-0.025 Only observed when organized into Long, linear staining pattern with width and fea ergy storage molecules disease, liver cirrhosis
large structures (e.g., muscle fibrils) tures characteristic of each filament type
AMyoclonic epilepsy and ragged red fibers syndrome.
Ribosomes 0.025 Not visible Very small dark dots, often associated with 8
M itochondriai myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome.
the rER
Glycogen 0.010-0.040 Observed as a purple haze region of Nonmembranous, very dense grape-li ke inclu-
cytoplasm (metachromasia) with tolui sions
dine blue-sta ined specimen
Lipid droplets 0.2-5, up to 80 Readily visible when very large (e.g., in Nonmembranous inclusions; generally appear
adipocytes); appear as large empty as a void in the section
holes in section (lipid itself is usually re
moved by embedding solvents)
Mu scle tissue, which is made up of contractile cells and
is responsible for movement
9 EPITHELIUM
N erve tissue, which receives, transmits, and integrates Epithelium is characterized by close cell apposition and
informa tion from outside and inside the body to control presence at a free surface
the activities o f the bod y
Each o f these basic tissues is defined by a set of general Epithelial cells, whether arra nged in a single layer or in
FIGURE 3.4
Nerve tissue. a. A Mallory-stained section of a peripheral nerve. Nerve ons and ensheathes the bundle, thus forming a structural unit, the
tissue consists of a vast number of thread-like myelinated axons held nerve. X270. b. An Azan-stalned section of a nerve ganglion, show-
together by connective tissue. The axons have been cross-sectioned ing the large, spherical nerve cell bod ies and the nuclei of the small
and appear as small, red, dot-like structures. The clear space sur- satellite cells that surround the nerve cell bodies. The axons associ-
rounding the axons previously contained myelin that was dissolved ated with the nerve cell bodies are unmyelinated. They are seen as
and lost during preparation of the specimen. TI1e connective tissue is nerve fiber bundles (NFB) between clusters of the cell bodies. x 270.
stained blue. It forms a delicate network around the myelinated ax-
It is of clinical interest that, under certain conditions, abnormal dif- composed of less differentiated tissues that usually lead to malig-
ferentiation may occur. The result is formation of a tumor mass nancy. An example of a solid-mass ovarian teratoma containing
that contains a variety of mature tissues arranged in an unorgan- fully differentiated tissue is shown in the center micrograph of Fig-
ized fashion. Such masses are referred to as teratomas. Teratomas ure 3.5. The low power reveals the lack of organized structures but
almost always occur in the gonads. In the ovary, these tumors usu- does not allow identification of the specific tissues present. How-
ally develop into solid masses that contain characteristics of the ever, with higher magnification, as shown in the insets (a- f), mature
mature basic tissues. Although the tissues fail to form functional differentiated tissues are evident.
structures, frequently organ-like structures may be seen, i.e., teeth, The example given in Figure 3.5 shows that one can readily
hair, epidermis, bowel segments, etc. These tissues are thought to Identify tissue characteristics, even in an unorganized structure.
arise through parthenogenic oocyte development. Teratomas may Again, the Important point is the ability to recognize aggregates of
also develop In the testis, but they are rare. Moreover, ovarian ter- cells and to determine the special characteristics that they exhibit.
atomas are usually benign, whereas teratomas in the testis are
FIGURE3.5
Ovarian teratoma. In the center Is a H&E-stained section of an a. Simple columnar epithelium lining a cavity of a small cyst. Xl 70.
ovarian teratoma seen at low magnification. This mass is com- Inset. Higher magnification of the epithelium and the underlying
posed of various basic tissues that are well differentiated and easy connective tissue. x 320. b. Dense regular connective tissue form-
to identify at higher magnification. The abnormal feature is the ing a tendon-like structure. x 170. c. Area showing hyaline carti-
lack of organization of the tissues to form functional orga ns. The lage (C) and developing bone spicules (B). x 170. d. Brain tissue
tissues within the boxed areas are seen at higher magnification in with glial cells. x 170. e. Cardiac muscle fibers. x 220. Inset. Higher
micrographs a-f x lO. The higher magnification allows identifica- magnification showing intercalated disks (arrows). x 320. f. Skele-
tion of some of the basic tissues that are present within this tumor. tal muscle fibers cut in cross section. x 220.
84 CHAPTER 3 Tiss11es, ( ollcef>l a11d Classificatioll
layer, the dorsal ectoderm of the embryo . Some nervous first goal is to recognize aggrega tes of cells as tissues and
system cell s, such as ependymal cells and cells of the determine the special characteristics that they present. Are
choroid plexus in the CNS, retain the absorptive and sec- the cells present at a smface? Are they in contact with their
retary fu nctions characteristic of epith elial cells. neighbors, or are they separated by definable intervening
material? Do they belong to a group with special proper-
ties, such as muscle or nerve?
\/IDENTIFYING TISSUES The stru cture and the function of each fundamental tis-
sue are examined in subsequent chapters. In foc using on
Recognition of tissues is based on the presence of specific a single specific tissue we are, in a sense, artificially sepa-
components within cells and on specific cellular relationships rating the constituent tissues of organs. However, this
separation is necessary to und erstand and appreciate the
Keeping these few basic facts and concepts about the histology of the various organs of the body and the means
fundamental four tissues in mind can facilitate the task of by which they operate as functio na l units and integrated
exam ining and interpreting histologic slide material. The systems.
\ j OVERVIEW OF EPITHEliAL They exhibit functiona l as well morphologic polarity;
STRUCTURE AND FUNCTION i.e:, different fu nctions are associated with three distinct
morphologic surface domains: a free surface or apical
Epithelium covers body surfaces, lines body cavities, domain, a lateral domain, and a basal domain. (The
and constitutes glands
properties of each domain are determined by specific
mem bra ne p roteins.)
BOXES
BOX 4.1. Clinical Correlations: lmmotile Cilia Syndrome 95
BOX 4.2. Functional Considerations: Basement Membrane and Basal Lamina
Terminology 107
BOX 4.3 . Functional Considerations: Mucous and Serous Membranes 117
FIGURE 4.1
Diagram of small intestine absorptive epithelial cells. a. All three cel- cell membrane into the intercellular space, and, finally, across the
lular domains of a typical epithelial cell are indicated on the diagram. basement membrane to tile connective tissue. b. This photomicro-
The junctional complex provides adhesion between adjoining cells graph of a plastic-embedded, thin section of intestinal epithelium,
and separates the luminal space from the Intercellular space, limiting stained with toluidine blue, shows cells actively engaged in fluid
tile movement of fluid between the lumen and the underlying con- transport. Like the adjacent diagram, tile intercellular spaces are
nective tissue. The pathway of fluid movement during absorption (ar- prominent, reflecting fluid passing into this space before entering the
rows) is from the intestinal lumen into the cell, then across the lateral underlying connective tissue. x 1,250 .
87
88 CHAPTER 4 Epit/Jelinl Tissue TABLE 4 .1. Types of Epithelium
nuses are ro d-shaped and arranged like the staves of a enzymes (e.g., hyd rolases), ion c han nels, a nd carrier pro- its contractile ability, which could' have the effect of de-
barrel. tei ns (e.g., g lucose transporters). The structural surface creasing the diameter of the apex of the cell, causing the
modifications include microvilli, whose stiff actin cores are anchored into the
Diverse epithelial functions can be found in different organs termi nal web, to spread apart and increase the intermi-
of the body Microvilli, cytoplasmic processes th at extend fro m the crovillous space.
cell surface
A given epithelium may serve on e o r more functions, de- Stereocilia (stereovilli), m icr ovilli of unusual length Stereocilia are unusually long, immotile microvilli
pe nding on th e activity of the cell typ es that are present: Cilia, motile cytoplasmic processes
Stereocilia are not widely distributed among epithelia.
Secretion, as in the colu m nar e pi t heli um of th e sto mach Microvilli are finger-like cytoplasm ic projections on the apical They are, in fact, limited to the epididymis, to the proximal
a nd th e gastric gla nds surface of most epithelial cells part of the ductus deferens of the male reproductive system,
Abs01ption, as in t he columnar epitheliu m of the intes- and to t he sensory (hair) cells of the ear. They are included
tines and proximal convoluted tubu les in the kidney As observed with t he electron microscope (EM ), mi- in t h is section because this unusual surface modification is
Transport, as in tra nsport of m ateria ls or cells alo ng the crovilli var y widely in ap pearance. In some cell types, mi- traditionally treated as a sepa1ate structural entity.
su rface of a n epithelium by motile cilia or in transport crovilli are short, irregular, ble b-like projections. In other Stereocilia of the genital ducts are extremely long
of materials across an epithelium to a nd from the con- cell types, t hey are ta ll, closely packed, w1iform projections processes that extend from t he apical su rface of tl1e cell
n ective tissu e that gr eatly increase the free cell surface area. In general, and facilitate absorption. Unique featmes in clude an apical
Protection, as in the stratified squamous epithelium of the num ber and shape of t he m icrovilli of a given cell type cel l protrusion from which they arise and thick stem por-
the skin (epidermis) and the transitio nal e pithelium of correlate with its absorptive capacity. Thus, cells that prin- tions that are in terconnected by cytoplasm ic bridges. Be-
the urina ry bladder cipally transport flu id and absorb metabolites have m any cause electron microscopy reveals their internal structure
Receptor function, to receive an d t ra nsd uce external closely packed, ta ll m icrovilli. Cells in whic h t ransepi the- to be tha t of unusually long microvilli, some histologists
stim uli, as in the taste buds of the tongue, olfactory ep- lial transport is less active have sma ller, mor e irregularly now use the term stereovilli (Fig. 4.4a ). Seen in the light
ith elium of the nasal mucosa, and th e re tin a of the eye sh aped microvilli. microscope, these processes frequently resemble the ha irs
Among the fl ui d-tra nsporting epi thelia, e.g., those of the of a paint brush because of the way they aggrega te into
Epitheli a involved in secretion or absorptio n a re typica lly intestine a nd k id ney tubu le, a d isti nctive border of verti cal pointed bundles.
simple 01; in a few cases, pseudostratified. The height of the striatio ns at the a pica l surface of the cell, repr esenting the Like microvilli, stereocilia are suppo.rted by internal
cells o ften reflects the level of secretory or absorptive activ- close packed microvilli, is easily seen in t he light micro- actin fi lament bundles t hat are cross-linked by fimbrin. Un-
ity. Simple sq uamous epithelia are compatible w ith a high scope. In intestina l a bsorptive cells, this surface structure like microvilli, a plasma membra ne- associated molecule,
rate of transepithelial transp ort. Stra tification o f the epithe- was origina lly ca lled the striated border; in the k idney erzi1t, anchors the actin filaments to the plasma membrane
lium usually correlates w ith transepithel ial impermeability. tubule cells, it is called the b1'Ush border. Where there is no of stereocil ia. The stem portion of the stereocilium and the
Finally, in some pseudostratified epithelia, basal cells are the appa ren t surface modification based on light m icroscope apical cell protrusion contain the cross-bridge- forming
stem cells that give rise to the mature functional cells of the observations, microv illi, if present, are usua lly short and molecule a-actinin (Fig. 4.4b). A striking difference be-
epitheliu m, thus balancing cell tu rnover. nor numer ous; thus, they may escape detection in the light tween microv illi and stereocilia, other than size and the
mi croscope. presence of erzin, is the absence of villin from the tip of the
The varia tions seen in microvilli of va rious types of ep- stereocil ium.
Q CELL POLARITY ithelia are shown in Figure 4.2. The microvilli o f the intes- Stereocilia of the sensory epithelium of the ear are
tinal epi thelium (s triated borde r) are the most highl y or - uniform in d iameter and possess an internal structure
Epithelia l cells exhibit distin ct polarity. T hey have a n api- dered an d are even more un ifo rm in app earance than t hose similar to that of genital duct stereocilia. However, they
cal domain, a lateral domain, and a basal domain. Sp ecific that constitu te th e brush bor der of k idney cells. T hey also lack both erzin and a -actinin. T hese stereocilia serve as
biochemical ch aracteristics are associated with each cell conta in a conspicuous co re of actin filamen ts (micr o fi la- sensory receptors rather than absorptive structures.
surface. These c haracteristics and th e geometric arrange- ments). Actin fi la ments a re a nc hored to villin located in
ments o f the cells in the epith eliu m de termine t he func- the tip of the microvillus a nd extend down in to the ap ical Cilia al'e motile cytoplasmic structures capable of moving flu id
tio na l pola rity of a U three cell dom ains. cytoplasm. H ere, they interact w ith a horizontal network and particles along epithelial surfaces
The free or a pical doma in is alw ays d irected to wa rd the of actin filaments, the temtinal web, which lies just below
exterior surface or the lumen of a n en closed cavity or tube. the base o f the microvi lli (Fig . 4.3a). T he actin fi la ments in- Cilia possess an internal structure that provides for their
The latera l domain commu nicates with adj acent cells a nd side the microvill us a re c ross-linked at 10-nm inte rvals by movement. Tn most ciliated epithelia, such as the trachea,
is cha racterized by specialized attach ment a reas. The basal t he actin-bu ndling proteins fascin a nd fimbrin. This cross- bronchi, o r oviducts, cells may have as man y as several hun-
dom ain rests on the basa l lamina a nchoring the cell to un - linkage provides support and gives rigid ity to the m i- dred cilia, all arranged in orderly rows. In the tracheo-
derlying connective tissue. crovi ll i. In addition, the core of actin filaments is associ- bronchial tree, the cilia sweep mucus a nd trapped particulate
a ted w ith myosi1t I, a molecule t hat bi n ds the actin materia l toward the oropharynx where it is swallowed with
filaments to the p lasma membrane of t he microvill us . The saliva and thus eliminated from the body. In the oviducts,
Q THE APICAL DOMAIN AND ITS additi o n o f villi n to epithelial cells growing in cu ltu res in- cilia help transport ova and fluid toward the uterus.
MODIFICATIONS duces forma tion of mic rovilli o n th e free a pical surface. FIG URE4.2 In some epithelia, only a single cilium per cell may be
Th e te rmi nal web is composed of actin fila ments stabi- Electron micrographs showing variation in microvilli of different present, e.g., the epithelial cells of the rete testis in the male
lized by spectrin, which also anc hors the ter min al web to cell types. a. Epithelial cell of uterine gland; small projections.
In ma n y epithelial cells, the apica l doma in exhibits sp ecial reproductive tract and the vestibula r ha ir cells of the ear.
b. Syncytiotrophoblast of placenta; Irregular, branching microvilli.
structu ral surfa ce modifica tio ns to carry o ut specific fu nc- the apical ce ll membrane (Fi g. 4.3b) . The presence of In these instances, the single cili u m is tho ught to have a
c. Intestinal absorptive cell; uniform, numerous, a nd regularly
tions. In addition , the apica l doma in may conta in speci fic myosin II and tropomyosin in t he termina l web expla ins arranged microvilli. All figu res X20,000. sensory role.
92 CHAPTER 4 Epithelial Tissue
vi ii in
FH+I--+--1-+ actin
filament
actin filaments
~1-~l...-.f- myosin I
terminal
web
myosin II
b
b FIGURE4.4
Molecular structure of stereocilia. a. Electron micrograph of stereo- connected by cytoplasmic bridges. Note t11e distribution of actin fila-
FIGURE 4.3 cilia from the epididymis. Tl1e cytoplasmic projections are similar to ments within the core of the stereocilium and the actin-associated
Molecular structure of microvilli. a. High magnification of microvilli location of specific actin filament-bundling proteins. Note the distri- microvilli, but they are extremely long. x2o,ooo. b. Schematic dia- proteins: fimbrin and erzin in the elongated portion (enlarged box),
from Figure 4.2c. Note the presence of the actin filaments in the mi- bution of myosin I within the microvilli and myosin II within the ter- gram showing the molecular structure of stereocilia. They arise from and a-actinin in the terminal web and apical cell protrusion.
crovilli (arrows), wh ich extend into the apical cytoplasm. x BO,OOO. b. minal web. The spectrin molecules stabi lize the actin filaments within the apical cell protrusions, having thick stem portions that are inter-
Schematic diagram showing molecular structure of microvilli and the the terminal web and anchor them into the apical plasma membrane.
Cilia give a "crew-cut" appearance to the epithelial surface cross-sectional view reveals a characteristic configuration
of nine pairs or doub.lets of circularly ananged micro-
In the light microscope, cilia appear as short, fine, hair- tubules surrounding two central microtubules (Fig. 4.6b).
like structures emanating from the free surface of the cell The microtubules composing each doublet are con-
(Fig. 4.5). A thin , dark-staining band is usually seen ex- structed so that the wall of one microtubule, designated
tending across the cell at the base of the cilia. This dark- the B microtubule, is actually incomplete; it shares a portion
staining band represents structures known as basal bodies. of the wall of the other microtubule of the doublet, the A
These structures take up stain and appear as a continuous microtubule. The A microtubule is composed of 13 tubulin
band when viewed in the light microscope. When viewed dimers, arranged in side-by-side configuration, whereas the
with the EM, however, the basal body of each cilium ap- B microtubule is composed of 10 tubulin dimers. When seen
pears as a distinct individual structure. in cross section at high resolution, each doublet exhibits a
pair of "arms" that contain ciliary dynein, a microtubule- FIGURE 4.5
Cilia contain an organized core of microtubules arranged associated motor protein. This motor protein uses the en- Ciliated epithelium. Pllotomicrograpll of a H&E-stained specimen of
in a 9 + 2 pattern ergy of adenosine triphosphate (ATP) hydrolysis to move tracheal pseudostratified ciliated epithelium. The cilia (C) appear as !lair-
a long the surface of the adjacent microtubule (see Fig. 4.6b). like processes extending from the apica l surface of the cells. The dark
Electron microscopy of a cilium in longitudinal profile The dynein arms occur at 24-nm intervals along the length line immediately below the ciliary processes is produced by the basal
reveals an internal core of microtubules (Fig. 4.6a). A of the A microtubule and extend out to form temporary bodies {88} associated with th e cilia. x 750.
94 CH A PTER 4 Ef>itbclio l Tissue CHAPTER 4 Epitbclinl Tissue 95
cr oss-bridges with the B microtubule of the adj acent dou- that make up the basal body, a microtubule doublet grows
blet. A passive elastic component formed by nexin perma- upward, creating a pro jection of the apical membrane con-
nently links the A microtubule with the B microtubule of ad- taining the nine d oublets found in the mature cilium. Si-
central sheath central pair of jacent doublets at 86-nm intervals. The two central mu ltaneously, the two single central microtubul es form
projections microtubules
microtubules are separate but are partially enclosed by a within the ring of doublet microtubules, thus yielding the
central sheath projection at 14-nm intervals along the length characteristic 9 + 2 arrangement.
of the cilium. Radial spokes extend from each of the nine
doublets toward the two central microtubules at 29-nm in- Cilia beat in a synchronous pattern
tervals. The proteins forming the radial spokes and the
nex in connections between the o uter doublets make large- Cilia display a regular and synchronous undulating
amplitude oscillations of the cilia possible. move ment. A cilium remains rigid as it ex hibits a rapid
The 9 + 2 microtubule array courses from the tip of the forward movement called th e effective stroke; it becomes
cilium to its base, where the outer paired microtubules join flex ible and bends on the slower return movement, the
the basal body. The basal body is a modified centriole con- recovery stroke. The plane o f movement of a cilium is
sisting of nin e short microtubule triplets arranged in a ring. perpendicular to a line joining the central pair of m icro-
Each of the paired microtubules of the cilium is continuous tubul es. Cilia in successive rows start their beat so that
w ith two of t he triplet micro tubules of the basal body. The each row is slightl y more adva nced in its cycle than the
two central microtubules of the cilium end at the level o f following row, thus creating a w ave that sweeps acr oss
the top of the basal body. Therefore, a cross section o f the the epith elium. This metachronal rhythm is responsible
basal body wou ld revea l nine circularly arranged micro- for moving mucus over epithelial surfaces or facilitating
tubule triplets but not the two centra l single microtubules the flow of fluid and other substances through tubular
of the cilium. organs and ducts .
u..,..:...;~~c
Ciliary activity is based on the movement of the dou-
\ B
x..,...,._,..,...;u~ Cilia develop from procentrioles blet microtu buies in rei a tion to one anot her. Ciliary
A movement is initiated by the dynein arms (see Fig. 4.6b).
The process of ciliar y formation in differentiating cells The ciliary dynein located in the anns of the A micro-
involves the replication of the centriole to give rise to mul- tubule forms temporary cross-bridges with the B micro-
plasma
membrane microtubule
tiple procentrioles, one for each cilium. The procentrioles tubule of the adjacent doublet. Hydrolysis of ATP pro-
triplets grow and migrate to the apical surface of the cell, where duces a sliding movement of the bridge along the B
each becomes a basal body. From each of the nine triplets microtubule. The dyn ein molecules produce a continuous
b
Cilia play a significant role in the human body. The mucociliary
transport that occurs in the respiratory epithelium is one of the im-
portant mechanisms protecting the body against invading bacteria
FIGURE4.6 and other pathogens. Failure of the mucociliary transport system is
Molecular structure of cilia. a. Electron micrograph of longitudinally sectioned cilia from the caused by several hereditary disorders grouped under the general
oviduct. The internal structures within the ciliary process are microtubules. Most of the basal name of immotile cilia syndrome. Kartagener's syndrome, for in-
bodies appear "empty" because of the absence of the central pair of microtubules in this portion stance, is caused by a structural abnormality involving absence of
of the cilium. One basal body (secondfrom left) has been sectioned peripherally through the outer dynein arms (see electron micrograph at right). Young's syndrome
microtubule triplet. X20,000. b. Schematic diagram of cilium, showing its cross section (upper is characterized by malformation of the radial spokes and the
plane) with the pair of central microtubules and the nine surrounding microtubule doublets. The dynein arms. The most prominent symptom of immotile cilia syn-
dynein arms extend from the A microtubule and make temporary cross-bridges with the B mi- drome is chronic respiratory difficulty (including bronchitis and si-
crotubule of the adjacent doublet. Inset. Compare the diagram with the cross section in the elec- nusitis), although situs inversus of the viscera is also common. Res-
tron micrograph (c) and identify corresponding structures. x 180,000. The molecular structure of piratory problems are caused by severely impaired or absent ciliary
the microtubule doublet is shown adjacent to the cross section. Note t11at the A microtubule of motility that results in reduced or absent mucociliary transport in structure. Males with Kartagener's syndrome are sterile. The flagel-
the doublet is composed of 13 tubulin dimers arranged in a side-by-side configuration, w 11ereas the tracheobronchial tree. The transposition of the viscera may be lum of t11e sperm, which is similar in structure to the cilium, is im-
the B microtubule is composed of 10 tubulin dimers and shares the remaining dimers with those related to tile lack of ciliary activity during the developmental motile. In contrast, some females with tile syndrome may be fertile.
of the A microtubule. The cross section of tile basal body (lower plane) shows the arrangement process. Another possibility is that microtubules that designate a In such individuals, the ciliary movement may be sufficient, though
of nine microtubule triplets. These structures form a ring structure. Each microtubule doublet of form of polarity within cells may also indirectly influence the polar- impaired, to permit transport of the ovum through the oviduct.
the cilium is an extension of two inner microtubules of the corresponding triplet. ity of organ systems. It may also result from abnormal microtubular (Photomicrograph courtesy of Patrice Abeii-Aieff. x 180,000.)
96 CHAPTER 4 Epit!Jrlinf Ti ssue C HAPTER 4 EJ>it!Jelinf Tiss11r 97
shear force during this interdoublet sliding directed to- The terminal bar, however, does represent a significant
ward the ciliary tip. As a result of this ATP-dependent structural complex. Electron microscopy has shown it in-
phase of the effective stroke, the cilium bends. At the cludes a specialized site that joins epithelial cells (Fig. 4.8a).
] APICAL DOMAIN
same time, the passive elastic connections provided by It is also the site of a barrier to the passage (diffusion) of
nexin and the radial spokes accumulate the energy nec- substances across the epithelium. The specific structural
zonula
essary to bring the cilium back to the straight position, components that make up the barrier and the attachment occludens
thus producing the recovery stroke. device are readily identified with the EM and are collectively
However, if all dynein arms along the length of the Ami- referred to as a junctional complex (see Table 4.4). These
crotubules in all nine doublets attempted to form tempo- complexes are responsible for joining individual cells to-
rary cross-bridges simultaneously, no effective stroke of gether and contain three types of junctions (Fig. 4.8b):
the cilium would result. Thus, regulation of the active
Occluding junctions, as a result of their impermeable
shear force is required. Current evidence suggests that the
nature, allow epithelial cells to function as a barrier.
central pair of microtubules undergo rotation with respect
Also called tight junctions, occluding junctions form the
to the nine outer doublets. This rotation ma y be driven by z
intercellular diffusion barrier between adjacent cells; by
another motor protein, kinesin, which is associated with
limiting the movement of water and other molecules
ex
the central pair of microtubules. The central microtubule :ll:
through the intercellular space, they maintain physico- 0
pair can act as a "distributor" that regulates the sequence c
chemical separation of tissue compartments. Because ...J
of interactions of the dynein arms in a progressive manner <t
they are located at the most apical point between ad- a:
to produce the effective stroke. w
joining epithelial cells, occluding junctions prevent the
migration of specialized membrane proteins between the
t:i
...J
\1 THE LATERAL DOMAIN AND ITS apical and lateral surfaces, thus maintaining the in-
SPECIALIZATIONS IN CELL-TO-CELL tegrity of these two domains.
ADHESION Anchoring junctions provide mechanical stability to ep- b
ithelial cells by linking the cytoskeleton of one cell to the
The lateral domain of epithelial cells is in close contact cytoskeleton of an adjacent cell. These junctions are im-
with the opposed lateral domains of neighboring cells. portant in creating and maintaining the structural unity
maculae
Like the other domains, the lateral domain is characterized of the epithelium. Anchoring junctions interact with focal hemidesmosomes adherentes
by the presence of unique proteins, in this case the adhe- both actin and intermediate filaments and can be found adhesions (desmosomes)
sion molecules that are part of junctional specializations. not only on the lateral cell surface but also on the basal
domain of the epithelial cell. FIGURE4.8
The molecular composition of the lipids and proteins that Junctional complex. a. Electron micrograph of the apical portion of two adjoining epithelial cells
form the lateral cell membrane differ significantly from the Communicating junctions allow direct communication
of the gastric mucosa, showing tile junctional complex. It consists of the zonula occludens (ZO),
composition of those that form the apical cell membrane. between adjacent cells by diffusion of small (< 1000 Da)
zonula adllerens (ZA), and macula adherens (MA). x30,000. b. Diagram showing the distribution
In addition, the lateral cell surface membrane in some ep- of cell junctions in the three cellular domains of columnar epithelial cells. The apical domain with
ithelia may form folds and processes, invaginations and microvilli has been lifted to better illustrate spatial arrangements of junctional complexes within the
evaginations that create interdigitating and interleaving
v: y cell.
tongue-and-groove margins between neighboring cells .
Terminal bars represent epithelial cell attachment sites molecules (e.g., ions, ami no acids, second messengers, (Fig. 4 .9a). The high-resolution TEM similarly reveals that
metabolites). This type of intercellular communication the zonula occludens is not a continuous seal but rather a se-
Before the advent of electron microscopy, the close ap- permits the coordinated cellular activity that is impor- ries of focal fusions between the cells. These focal fusions
position of epithelia l cells was attributed to the presence of tant for maintaining organ homeostasis. are created by specific transmembrane proteins of adjoining
a viscous adhesive substance referred to as "intercellular cells that traverse the cell membrane and join in the inter-
cement." This cement stained deeply at the apicolateral cellular space. The transmembrane protein occludin has
Occluding Junctions
margin of most cuboidal and columnar epithelial cells. been identified as the sealing protein. The cytoplasmic por-
When viewed in a plane perpendicular to the epithelial sur- The zonula occludens (pl. , zonulae occludentes} repre- tion of occludin is associated with the zonula occludens
face, the stained material appears as a dot-like structure. sents the rnost apical component in the junctional comp lex proteins Z0-1, Z0-2, and Z0-3 (Fig. 4.9b,c) . Occludin in-
When the plane of section passes parallel to and includes between epithelial cells. teracts with the actin cytoskeleton through Z0-1. Regula-
the epithelial surface, however, the dot-like component is tory fu nctions during the formation of the zonula occludens
seen as a dense bar or line between the apposing cells (Fig. The zonula occludens is created by localized sealing of have been suggested for all ZO proteins. In addition, Z0-1
FIGURE4.7
4.7) . The bars, in fact, form a polygonal structure (or adjacent plasma membranes is a tumor suppressor, and Z0-2 is req uired in the epider-
Terminal bars in pseudostratified epithelium. Photomicrograph of
band) at the periphery of each cell. ma l growth factor-receptor signaling mechanism. The Z0-
a H&E-stained specimen, showing the terminal bars in a pseudo-
Because of its location in the terminal or apical portion of stratified epithelium. The bar appears as a dot (arrowheads) when Examination of the zonula occludens or tight junction 3 protein interacts with Z0-1 and the cytoplasmic domain
the cell and its bar-like configuration, the stainable material seen on its cut edge. When the bar is coursing parallel to the cut sur- with the transmission electron microscope (TEM) reveals a of occludirL Many pathogenic agents, such as cy-
visible in light microscopy was called the tenninal bar. It is face and lying within the thickness of tile section, it is seen as a lin narrow region in which the plasma membranes of adjoining tomegalovirus (CMV) and cholera toxins, act on Z0-1 and
now evident that intercellular cement as such does not exist. ear or bar-like profile (arrows). x sso. cells come in close contact to seal off the intercellular space Z0-2, causing the junction to become permeable.
98 CHAPTER 4 Epitbdia/ Tissuf CHAPTER 4 Epitlulia/ Tissur 99
adjacent cell membranes testinal and urinary bladde r epithelia, the intercellu lar re- ability to resist separation. Although the zonula occludens
gion is highly impermeable. involves a fusion of adjoining cell membranes, their resist-
ance to mechanical stress is limited. Reinforcement of this re-
The zonula occludens separates the luminal space from the gion depends on a strong bon ding site below the zonula oc-
intercellular space and connective tissue compartment cludens. Like the zonu la occludens, this lateral adhesion
device occurs in a continuous band or belt-like configmation
It is now evident t hat the zonula occludens plays an es-
around the cell; th us, the adheri ng junction is referred to as
sentia l role in t he selective passage of substa nces from o ne
a zonula adhereos. The zon ula adherens is composed of the
side of a n epithelium to t he other. Because the diffusion of
transmem brane adhesion molecule E-cadherin. On the cyto-
water a nd solutes between cells is restricted by the zonu la
plasmic side, the tail of E-cadherin is bound to catenin (Fig.
occludens, transport must occur by active means. Active
4 .11 a). The r esul ting cadherin-catenin complex binds to
tra nsport req uires specialized membrane transport pro-
vinculin a nd a-actinin and is required for the interaction of
teins tha t move selected substan ces across th e apical
cadherins with the actin filaments of cytoskeleton. The ex-
p lasma membra ne into the cytoplasm and t he n across the
tracellular components o f t he E-cadberin molecules from ad-
transmembrane lateral membra ne below the level of t he junction .
cytoplasmic jacent cells are linked by Ca2 + io ns or a n additional extracel-
domain of domain of lular lin k protein. Therefore, the morpho logic a nd func tional
occludin occludin C The zonula occludens establishes functional domains in the
in tegrity of the zonula adherens is calcium dependent. Re-
plasma membrane
mova l of Ca2+ leads to dissociation of E-cadherin molecules
FIGURE4.9
Zonula occludens. a. Electron micrograph of the zon ula occludens, occludin within the occluding junction. Compare the linear pattern of a nd disruption of the junction.
As a junction, the zonula occludens restricts not only the
showing the close approximation of the outer lamellae of adjoining grooves with the ridges detected in the freeze-fracture preparation in When examined with the TEM, th e zo n ula adherens is
passage of water, electrolytes, a nd other small molecules
plasma membranes. The extracellular domains of proteins Involved Figure 4.10. c. Diagram showing the occludin molecule and the major c ha racterized by a uniform 15- to 20-nm space between
across the epithelia l layer b ut also t he diffusion of mole-
In the formation of this junction (occludins) appear as a single associated proteins of the occluding junction. Note that one of the as the opposing cell m embranes (Fig. 4.1lb). The intercell u-
sociated proteins, Z0-1, interacts with the cell cytoskeleton binding cules with in the p lasma membrane itself. T hus, the cell is
electron-dense line (arrows). x 100,000. b. Diagram showing the or lar space is of low e lectron dens ity, appearing a lmost
ganlzatlon and pattern of distribution of the transmembrane protein actin filaments. able to segregate certain internal membrane proteins on
clear, but it is evid ently occupied by extracellular compo-
the apica l (free) surface an d restrict others to the lateral or
nents of adjacent E-cadherin molecules and Ca 2 ~ ions .
basal surfaces. In t he intestine, for instance, the enzym es
T he a rra ngement of the various ju nctional proteins in membra ne, w here t hey appear as ridge- like structures. The Within the confines of the zonul a adheren s, a moderately
for terminal digestion of pep tides a nd saccharid es (d ipep-
forming th e zo na occluden s seal is best visualized by the opposing surface of the fractured mem brane, the E-face, electron -dense materia l called fu zzy plaque is found
tidases a nd disaccharid ases) a re localized in the membrane
freeze fracture technique (Fig . 4. 10). When the plasma reveals complementar y grooves t hat r es ult from detach - along t he cytop las mi c side o f the membrane of each cell.
of the microvilli of th e ap ical surface. The Na +fl( +-ATPase
membrane is frac tu red a t the sire of the zon ul a occludens, ment of th e protein particles from the opposing surface. This material correspo nds to th e location of the cytoplas-
that drives salt a nd water transport, as well as a mino acid
t he junctional proteins are observed o n t he P-face of the The ridges and g rooves a re a rranged as a network of anas- mic component of the E-cadherin- catenin complex and
an d suga r transport, is restricted to t he latera l plasm a
tomosing strands, thus creating a functional seal with in t he the associated proteins (a-actinin a nd vinc ulin ) in to
mem brane below the zon ula occl udens.
intercell ular space. They correspond to the location of the which actin fi laments attach. Evidence also s uggests t hat
rows of transmembrane proteins. t he fuzzy plaque represen ts the st aina ble su bstance in
Observations of d ifferen t kinds of epithelia reveal that Anchoring Junctions light m ic roscopy, the terminal bar. Associa t ed with the
the complexity and n umber of strand s fo rming the zon ulae e lectron-dense materia l is a n array of 6-nm actin fi la-
occl udentes varies. In epithelia in which anastomosing Anchoring junction s provide lateral ad hesio ns between ep- m ents that stretch across the apica l cytoplasm of the ep-
strands or fusion sites are spa rse, such as certain kidney ithelial cells, using proteins th at link into t he cytoskeleton itheli al cell, the termi na l web.
tubules, the intercellular pathway is partially permeable to of the adjacent cells. Two types of a nchoring cell-to-ceil
water and so lutes. In contrast, in epithelia in w hic h the junctions can be identified on th e lateral cell surface: The fascia adherens is a sheet-like junction that stabilizes
stra nds are n u mero us and extensively intertwined , e.g., in- nonepithelial tissues
Z011ula adherens (pl., z onulae adhe1'entes), wh ic h inter-
acts w it h the network o f acti n fi laments inside the cell
Ph ys ical a ttach ments t hat occur between cells in tissues
Macula adhe1'e11s (p l., maculae adhe1'entes) or desmo-
other t han epith elia are usually n ot prominent, but t he re
FIGURE 4.10
some, w hich interacts with inte rmed ia te fi laments
is at least one n o tab le excepti on . Cardiac muscle cells are
Freeze fracture preparation of zonula occludens. The fract ure mem In addition, two other types of a nc horing junctions can arranged end to e nd , forming thread-like contracti le
brane surface shown here reveals an anastomosing network of be fo und w he re epithelial cells rest on th e connective tissue units. The cells are attached to each other by a combin a-
ridges (arrows) located near the apical surface of the cell (note mi- matrix. These focal adhesious (focal contacts) and t ion of t yp ica l desmoso rnes, or maculae ad her ences, a nd
crovilli (Mv) present at the cell surface). This is the Pface of the mem-
hemidesmosomes are d iscussed in t he section on t he basal broa d adh esion plates that morphologica ll y resemble the
brane. (The Eface of the fractured membrane would show a com
domain (see pages 1 09 to 111 ). zon ula ad herens o f ep ithelia l cells . Because the a ttach-
plementary pattern of grooves.) The ridges represent linear arrays of
transmembrane proteins (most likely occludins) involved in the for ment is not rin g-like but rather has a broad fa ce, it is
mation of the zonula occludens. TI1e membrane of the opposing cell The zonula adherens provides lateral adhesion between called t he fascia adherens (Fig. 4.12). At th e molecul a r
contains a similar network of proteins, which is in register with the epithelial cells level, th e structure of the fa scia a dherens is similar to that
first cell. The actual sites of protein interaction between the cells form of the zonul a adhe rens; it a lso contains the zon ula occlu-
the anastomosing network. X100,000. (From Hull BE, Staehelin LA. J The integrity of epithelial surfaces depends in large part on dens Z0-1 protein foun d in d1e tig ht junctions of epithe-
Ce//Bio/1976; 68:688-704.) the lateral a dJ1esion of the cells with one another and their lial cells.
I 00 CHAPTER 4 Epithelial Tiss11r C HA PTER 4 Epit/,e/inl Tissue 10 I
cell membrane
I
connexons
FIGURE 4.13
Molecular structure of the macula adherens (desmosome). a. Elec because of extraction of the plasma membrane to show components
tron micrograph of a macula adherens, showing the intermediate fil of this structure. x 40,000. (Courtesy of Dr. Ernst Kallenbach.)
aments (arrows) attaching into a dense intracellular attachment b. Schematic diagram showing the structure of a macula adherens. extracellular space
plaque located on the cytoplasmic side of the plasma membrane. Note the intracellular attachment plaque with anchored intermediate
The intercellular space is also occupied by electron-dense material filaments. The extracellular portions of desmocollins and des- FIGURE 4.14
(arrowheads) containing desmocollins and desmogleins. The intercel mogleins from opposing cells interact with each other in the localized Structure of a gap junction. a. Electron micrograph showing the called connexons, have a central opening of about 2-nm in diameter.
lular space above and below the macula adherens is not well defined area of tile desmosome, forming the cadherin "zipper: plasma membranes of two adjoining cells forming a gap junction. The channels formed by the registration of the adjacent complemen-
The unit membranes (arrows) approach one another, narrowing the tary pairs of connexons perm it the flow of small molecules through
intercellular space to produce a 2-nm-wide gap. X 76,000. b. Drawing the channel but not into the intercellular space. Conversely, sub-
of a gap junction, showing the membranes of adj oining cells and the stances in tile intercellular space can permeate the area of a gap
fluorescent dye is injected w ith a micropipette into one Gap junctions can be visualized in TEM sections and freeze structural components of the membrane that form channels or pas- junction by flowing around the connexon complexes, but they can-
cell of an epith elia l sheet. The readily visualized dye can fracture preparations sageways between the two cells. Each passageway is formed by a cir- not enter the channels. c. The diameter of the channel in an individ-
be seen to pass to the immediately adjacent cells. These cular array of six subun its, dumbbell-shaped transmembrane proteins ual connexon is regulated by reversible changes in the confirmation
experiments confirm that adjacent cells share communi- When viewed with the TEM, the gap junction appears as that span tile plasma membrane of each cell. These complexes, of tile individual connexins.
ca ting channels that allow sma ll molecules and ions to an area of contact between the plasma membranes of ad-
pass directly between cells without entering the extracel- jacent cells (Fig. 4.14a). When uranyl acetate is applied as
lular space. a "stain" before embedding the tissue (en bloc staining), a Morphologic Specializations of the Lateral Cell . mo tic gradient between the salt concentration in the in-
gap junction appears as two parallel, closely apposed Surface tercellular space and the concentration in the cytoplasm.
Gap junctions reduce resistance to passage of electric current plasma membranes separated by a gap of 2 nm. The intercellular space distends because of the accumu-
between adjacent cells Freeze fracture images of gap junctions revea l groups lateral cell surface folds (plicae) create interdigitating lating fluid moving across the epithelium , but it can dis-
of channels fo rmed by the appos ition of identical struc- cytoplasmic processes of adjoining cells tend o nly to a limited degree because of junctional at-
Electrical conductance studies of gap junctions involve tures in the facing membranes. Known as connexons, tachments in the apical and basal portions of the cell.
the introduction of microelectrodes into neighboring cells these structures consist of six integra l membrane proteins Th e latera l surfaces of certain epithelial cells show a Hydrostatic pressure gradually builds up in the intercel-
and the esta blishment of a voltage difference between the called connexins, configured in a circular arrangem ent tortuous boundary due to infoldings or plicae along the lular space and drives an essentiall y isotonic fluid from
electrodes. Current flow between the cells is then meas- (Fig. 4 .14b). Each cha nnel is composed of two conn ex- border of each cell with its neighbor (Fig. 4.15 ). These ill- the space into the underlying connective tissue. The oc-
ured . If no gap junctions are present between the neigh- ons, one belonging to the plasma membrane of each cell. fo ldings increase the lateral surface area of the cell and clud ing junction at the apical end of the intercellular
boring cells, the current flow is low, primaril y because of Channels in gap junctions can fluctuate rapid ly between are particularly prominent in epithelia that are engaged in space prevents fluid from moving in the opposite direc-
the high electri cal resistance of the plasma membranes. In an open 2-nm-diameter channel and a closed state fluid a nd electrolyte transport, such as the intestinal and tion. As the action of the sodium pump depletes the cy-
contrast, if neighboring cells are joined by gap junctions, thro ugh reversible changes in the confirmation of the in- gallbladder epithelium. In active fluid transport, sodium toplasm of sa lt and water, these are repla ced by diffusion
there is little electrical resistance between them, and cur- dividual connexins (Fig. 4.14c). The molecular m echa- ions are pumped out of the cytoplasm at the lateral across the apica l plasma membrane, whose surface area is
rent flow is high. The low resistance reflects the direct cy- nism of channel reg ulation is not yet full y understood . plasma membrane by Na+fJ<+-ATPase localized in that g reatly increased by the presence of microvilli, thus al-
toplasmic continuity between the two cells, resulting from Like many other cellular organelles whose electron mi- membrane. Anions then diffuse across the membrane to lowing the continuous movement of fluid from the lu men
the presence of the gap junctions. Therefore, gap junctions croscopic appearance suggests a static structure, gap maintain electri.cal neutrality, and water diffuses from the to the connective tiss ue as long as the Na +fiU -ATPase is
are also called low-resistance junctions. junctions are actuall y dynamic. cytoplasm into the intercellular space, driven by the os- acti ve.
I 04 C HA PTER 4 Epilhdinl Tissue C H APTER 4 Epil/,e/inl Tissue 10 5
cle cells (Fig. 4.18); this helps to delineate them from the The basal lamina is the structural attachment site for overlying
FIGURE 4.1 5 surroundi ng connective tiss ue in histologic sections. Con- cells and underlying connective tissue
Lateral interdigitations. Electron micrograph showing info/dings or nective tissue cells other than adipocytes do not show a
interdigitatlons at the lateral surfaces of two adj oin ing intestinal ab- similar PAS-positive or silver reaction. T hat most connec- Examinatio n of the site of epithelial basement mem-
sorptive cells. X25,000. ti ve tissue cells are not surrounded by basement membrane branes with the EM revea ls a discrete layer of electro n-
material is consistent with their lack of adhesion to the con- dense matrix material 40- to 60-nm thick between the ep-
necti ve tissue fi bers. In fact, they m ust migrate within the
Q THE BASAL DOMAIN AND ITS tissue under appropriate stimu li to functio n.
SPECIALIZATIONS IN CELL-TO-
EXTRACELLULAR MATRIX
ADHESION
FIGURE 4.18
The basa l domain of epithelial cells is cha racteri zed by sev- Photomicrograph of smooth muscle cells stained by the PAS
era l fea tu res: method. This photomicrograph is stained by the PAS method and
counterstained with hematoxylin (pale nuclei). The muscle cells have
Basement membrane, which is located next to the basa l been cut in cross section and appear as polygonal profiles because
surface of epithelial cells of the presence of PAS-positive basement membrane material sur-
FIGURE 4.16
Cell-to-extracellular matrix junctions, which anc ho r the Tracheal basement membrane. Photomicrograpl1 of a H&E- stained rounding each cell. As t11e plane of section passes through each
cell to the extracellular matrix section of the pseudostratlfled ciliated epithelium of the trachea. The smooth muscle cell, it may or may not pass through the portion of
Plasma membrane infoldings, which increase surface basement membrane appears as a thick homogeneous layer imme- the cell that includes the nucleus. Therefore, in some of the polygo-
ar ea a nd facilitate morphologic interactions between ad- diately below the epithelium. It is actua lly a pa rt of the connective tis- nal profiles, nuclei can be seen; in other profiles, no nuclei are seen.
jacent cells sue and is composed largely of densely packed collagen fibrils. x 450. The cytoplasm is not stained. xsso.
106 C HAPTER 4 EpitiJrlia l Tissur CHAPTER 4 EpitlJrlinl Tissr1r 10 7
FIGURE4.22
Demonstration of basement membrane
material in splenic vessels. a. Photomicro-
graph of a silver preparation revealing two
longitudinally sectioned venous sinuses In
tile spleen. Tilese blood vessels are sur-
munded by a modified basement mem-
brane, which takes tl1e form of a ring-like
structure, mucil like tile hoops of a barrel,
rather tilan a continuous layer or lamina.
Tile rings are blackened by tile silver a nd
appear as bands wilere the walls of the
vessel have been tangentially sectioned
(arrows). To the right, the cut has pene-
trated deeper into the vessel and shows
the lumen (L). Here. the cut edges of the
rings are seen on both sides of the vessel.
In the lower vessel, the cut rings have been
sectioned in a virtually perpendicular
plane, and the rings appear as a series of
dots. x 400. b. Electron micrograph of the
wa ll of a venous sinus, showing a longitu-
dinally sectioned endothelial cell (EnC). The
nucleus (N) of the cell is protruding into the
lumen. The basal lamina material (asterisks)
has t11e same homogeneous appearance
as seen by electron microscopy in otiler
FIGURE 4.21 sites except that it is aggregated into ri ng-
Basal lamina in the kidney glomerulus. Electron micrograph of a kidney minal) surface of the endothelial cell. x 12,000. Inset. Relationship at li ke structures rather than into a flat layer
glomerular capillary, showing the basal lamina (BL) Interposed between higher magnification. Note that the endothelial cells and epithelial cells or lamina. Moreover, its location and plane
the capillary endothelial cell (En) and the cytoplasmic processes (P) of ep- are separated by the shared basal lamina and that no collagen fibrils are of section correspond to the silver-
ithelial cells (podocytes). The epithelial cell is located on the outer {ablu- present. N, nucleus of epithelial cell; L. lumen of capillary. X40,000. reactive, dot-like material in the panel
above. x 25,000.
ria l a lso corresponds to a PAS-positive staining reactio n, as stan ce to m ove from one tissue to an o t her (e.g., from o ne
descri bed above (see Fig . 4.18). A lthough t he term " base- com pa rtment to another), it must cross such a la mina.
ment mem brane" is n ot o rdin arily app lied to the ext racel- Filtration. The movemen t o f substances to and from th e growing p rocesses of a cell use t he basa l lam ina that re- In additio n , tra nsmem brane proteins located in the basal
lu lar stai nab le m a teria l of these nonepithe lial cells in lig ht connective t iss ue is regul ated in part by th e ba sal lam ina, m ains a fter cell loss, thus helping to ma in tai n the origi- cell do m ain (m a in ly related to th e integrin fa mily o f ad he-
m icroscopy, t he terms " basa l la m in a" or "external la m- la rgely thro ugh io ni c charges and integral spaces. Filtra- nal t issue architectu re. For example, w hen nerves aie sion mo lecu les) interact w ith the basa l la mina.
ina" a re typically used at the EM level. tio n is well characterized in the ki d ney, w here t he damaged , n ew n eurom uscu la r ju ncti ons fro m a g rowi ng
p lasm a filtra te m ust cross th e com pound basal la mi nae axo n w ill be established o nly if th e exte rnal la mi na re- Focal adhesions create a dynamic link between the actin
Basal laminae have multiple functions o f capill a ri es a nd a dj acent epit helia l cells to reach the ma ins imact a fter injury. cytoskeleton and extracellular matrix proteins
urinar y space w it hi n a rena l corp uscle.
Vario us func tio ns are now attributed to the basal la mina: Polarity induction. Epit heli a l cells exhi bit functi onall y Focal ad hesions are responsibl e for a ttachi ng lo ng bun-
di ffe re nt mem brane p roperties as a resu lt of s urface ex- Cell-to-Extracellular Matrix Junctions d les of actin filaments (stress fi bers) into the basal lam ina.
Structural attachment. As n o ted, the basal la m ina serves
as a n intermediary str ucture in the attachment of cells to posure. Specific properties attributable to the basal T he organization of cells in epithel ium depends on the T hey play a promi nent role d ur ing dyna mi c cha nges t hat
t he ad jacent cmm ective t issue. m em bra ne su rface, as opposed to t he apical a nd la ter a l su pport provided by th e extrace llu lar matrix, o n wh ic h occur in epithelial cells, e.g., m igra tion of epith el ia l cells in
Compartmentalization. Structurally, basal a nd ext ernal m embra ne su rfaces, are ind uced by t he presence of the the basal su rface of each cell rests. Anchoring junctious wound repai r. These foca l adh esions form d ynam ic attach-
laminae separa te or isola te the con nective tissue from ep- basal la mina. For example, epit helial cells grown in o r- ma inta in the morphologic in tegrity of th e e p ithelium- m ents to the unde rlying connective tissue by linking acti n
ithel ia , nerve, and muscle tissues. Connecti ve tissue-in- dinary t issue cul t ure fla tten as t hey pro liferate a nd g row con nective t issue interface. T he two major a nchoring junc- fila ments to extracell ula r matri x proteins (Fig. 4 .23).
c lud ing al l of its specialized tissues, such as bone and car- in the c ul tu re . W hen grown on the surface of an artifi- tio ns are In genera l, focal adhesions consist of a cyto plasmic face
tilage (with the exception of adipose tissue, in tha t its ceUs cial basa l la mina in the culture medium, the same cells to w hich act in fi laments a re bound, a t ransmembran e con-
possess an externa l lam ina)--can be viewed as a single, d isplay their ch aracteri stic sha pe as well as norm al po- Focal adhesions, w h ic h anch or actin filamen ts of the cy- necting region, and a n extracell ular face that binds to t he
con tinuo us com partment. In contrast, epithelia, muscles, larity a nd functio n. toske leton into the basemen t mern brane proteins of the extracell ular matrix. T he main fam ily of
a nd nerves are sep a rated from adjacent con nective tissue Tissue scaffoldi ng. T he basal lam ina serves as a gu ide o r Hemidesmosomes, which a nc hor the intermed ia te fila - tra nsmembra ne proteins in volved in focal adhesio ns a re in-
by intervening basal or external la min ae. For a n y s ub- scaffold d uring regeneration. Newly fo rmed cells or ments of cytosk eleton into t he basem ent membr a ne tegrins, w hich are concentrated in clusters w ithin t he areas
I I0 CHAPTER 4 Epilhrlial Tissu e C H APTE R 4 Epillulial Tissue I I I
w here the junctions can be detected. lntegrins are cap able of reins capa ble of anchoring interme d iate fila ments of the cy- nent in pr oximal a nd di stal tubules o'f the kidney (Fig. 4.25)
t ransducing signals to the interior of the cell, w here they af- toske let o n. In contrast to the desmosome, whose trans- and in certain d ucts of the saliva1y glands. Mitoch ondria are
fect cell migra tion, differentiatio n, a nd growth. On the cy- membrane proteins belong to the cad heri n family of cal- typically concentrated at th is basal site to provide the energy
toplasmic face, in tegrins interact with actin-binding p roteins cium-dependent molecu les, the transmem brane proteins req uirem ents for active t ra nsport. The mitochondr ia are
(a-actinin, vinculin, talin, paxillin) as well as m an y regula- fo und in the hemid esmosome include the integrin class of usually oriented vertically w ithin t he folds. The orientat ion
tory protei ns, such as focal adhesi01~ kinase or tyrosine ki- cell matrix receptors. The extracellular p ortion s of these of the mitochondria, com bined with the basal mem bra ne in-
nase. On the extracellula r side, integrins bind to extracellu- integrins enter the basal lam ina and in teract w ith its pro- foldings, r esults in a striated a ppearance along the basal as-
lar matrix glycoproteins, u sua ll y lam ini n and fibronectin. tei ns, including laminin a nd type IV collagen. In addition , pect of the cell w hen observed in the lig ht microscop e. Be-
type XVII collagen, a transmembrane molecule, ca n be de- cause of this p henomenon, the sa livar y gland ducts tha t
Hemidesmosomes occur in epithelia that require strong, stable tected within the hemidesmoso me (Fig. 4. 2 4b). In certain possess these cells are referred to as striated ducts.
adhesion to the connective tissue skin diseases characterized cl inically by blister fo rm a tion,
suc h as bullous pemphigoid, hig h levels of antibodies di -
A varia nt o f t he anchoring junction simila r to the rected aga inst comp o n ents of the hemid esmosome, includ- \1 GLANDS
d esmosome is found in certa in epithelia su bject to abrasion ing a ntibodies against type XVII collagen , ca n be detected.
fibronectin
and mechanical shea ring for ces that would tend to sepa- T ypically, gla nds a re classified into two m ajor groups ac-
basement __t_ r ate t he epithelium fro m t he un derl ying connective tissue.
Morphologic Modifications of the Basal Cell
cording to how t he ir products a re released (Ta ble 4.2):
me mbrane L ....___ Typicall y, it occurs in th e cornea, the skin, a nd the muco sa Exocrine glands secrete t heir products onto a surface di -
-- - - - of the oral cavity, esop hagus, a nd vagi na. In these loca-
Surface
rectly or throug h epithelia l ducts or tubes tha t a re con-
FIGURE4.23 tions, o nly half the d esmosome is p resent, hence the na me Many cells t ha t t ransport fluid have infoldings at the basal nected to a su rface. Ducts may convey the secreted m a-
Molecular structure of focal adhesions. Diagra m showing the mo- hemidesmosome. H emides mosom es are fou n d on the basa l cell surface. These basal surface modi fications are promi- teria l in a n una ltered fo rm or may m odify the secretion
lecular organization of focal adhesions. On the cytoplasmic side, note cel l surface, w here th ey provide increased adhesion to the by concentratin g it o r a dding o r reabsorbing constitu ent
the arrangement of different actin-binding proteins. These proteins basal la mina (Fig. 4 .24a). When o bserved w ith the EM, the substa nces.
Interact with integrins, the transmem brane proteins, the extracellular h emidesmosome exhibits a n attachment plaque on the cy-
domains of which bind to fibronectin. Endocrine glm~ds lack a d uct system. They secrete the ir
toplasmic side of the basal p lasma membra ne. The protein products into t he connect ive tissue, w here th ey en ter t he
composition o f this structu re is similar to that of the bloo dstream to reac h their target cells. The products of
desmosomal plaque, as it contains desmoplakin-like pro- endocrine gla n ds are ca lled hormones.
In some epithelia, individ ua l cells secr ete a substa nce
tha t does not reach the bloodstream but ra ther affects
other cells w ithin the sa me epithelium. Such secretory ac-
tivity is referred to as paracrine. The secretory mater ia l
intermediate fila me nt
r eac hes the target cells by diffusion th rough the extracellu-
lar sp ace or immediately subj acent connective tissue.
intracellular
a ttachment plaque
Cells of exocrine glands exhibit different mechanisms
of secretion
Simple coiled tubular Skin: eccrine sweat gland Coiled tubular structure is composed of the se-
cretory portion located deep In the dermis
r; .~ ~=~
: . ~:l "C
c
"'
Ill Simple branched Stomach: mucus-secret- Branched tubular glands with wide secretory
i:3 tubular ing glands of the pylorus portions are formed by the secretory cells and
Cl.l
iS. produce a viscous mucous secretion
and cell debris are discharged into the lumen of the The simplest arrangement of a mul ticell ular gla nd is a E
iii
gland . This mechanism is found in sebaceous glands of cellular sheet in which each surface cell is a secretor y cell.
skin and the tarsal (Meibomian) glands of the eyelid. For example, the lining of the stomach a nd its gastric pits
is a sheet of mucus-secreting cells (Fig. 4.27) .
Exocrine glands are classified as either unicellular or multicellular Other multicellular glands typica lly form tubula r invagi- Simple Urethra: paraurethral Simple acinar glands develop as an outpouch-
nations from the surface. The end pieces of the gla nd acinar and periurethral glands ing of the transitional epithelium and are
Unicellular glands are the simplest in structure. In unicel- conta in the secretor y cells; the portion of the gland con- formed by a single layer of secretory cells
lular exocrine glands, the secretory component consists of necting the secretor y cells to the surface serves as a d uct. If
single cells distributed among other nonsecretory cells. A the duct is unbranched, the gland is ca lled simple; if the
typical example is the goblet cell, a mucus-secreting cell po- duct is branched, it is ca lled compou1td. If the secretory Branched Stomach: mucus-secret- Branched acinar glands with secretory por-
sitioned among other columna r cells (Fig. 4.26). Goblet cells portion is shaped like a tu be, the gland is tubulat'; if it is acinar ing glands of cardia tions are formed by mucus-secreting cells; the
are located in the surface lining and glands of the .i ntestines shaped like a flask, the gland is alveolar or acinar; if the short, single-duct portion opens directly into
and in certain passages of the respiratory tract. tube ends in a sac-like dilation, the gland is tubuloalveo- the lumen
Multicellular glands are composed of more than one lar. Tubular secretory portions may be straight, branched,
cell. They exhibit varyi ng degrees of complexity. Their or coiled; alveolar portions may be single or branched .
structural orga nization a llows subclassification according Various combinations of duct and secretory portion shapes Compound Duodenum: submucosal Compound tubular glands with coiled secre-
to the arrangement of the secretory ceJls (parenchyma) an d a re fou nd in the body. Classification and description of ex- tubular glands of Brunner tory portions are located deep in the submu-
the presence or absence of branching of the duct elements. ocrine glands may be fou nd in Tab le 4.3. cosa of the duodenum
"'c
"C
Compound
Ill Pancreas: excretory Compound acinar glands with alveolar-shaped
i:3 acinar portion secretory units are formed by pyramid-shaped
"C
c serous-secreting cells
::I
0
c.
E
8
Mucous and serous glands are so named because of the type Surface ectoderm gives rise to Components of the inner ear
of secretion produced Adenohypophysis (anteri or lo be of pituitary gland)
Epidermis and its derivatives (ha ir, nails, sweat glands,
The secretory cells of exocrine gla nds associated with sebaceous gla nds, and the parenchyma a nd ducts of the Neuroectoderm gives r ise to
the various bod y tubes, e.g., the alimentary canal, respira- manunary glands)
tory passages, and urogen ital system, are often described Cornea and lens epithelia of the eye Neural tube and its derivatives (the central nervous sys-
as being mucous, serous, or both. Enamel organ and enamel of the teeth tem, including ependyma, pineal body, and neurohy-
Mucous secretions are viscous and slimy, whereas serous
secretions are watery. Goblet cells, secretory cells of the
sublingual salivary glands, and surface cells of the stomach MESODERM
are exampl es of mucus-secreting cells. The mucous nature
of the secretio n r es ults from extensive glycosylation of the muscles of trunk and skeleton except skull urogenital system including gonads,
dermis of skin ducts, and accessory glands
connective tissue
FIGURE4.29
Serous-secreting compound gland. Photomicrograph of pancreatic connective tissue and muscle of viscera and limbs
serous membranes of pleura, pericardium,
acinus (A) (outlined by the dotted line) with its duct (D). The small
skull and peritoneum
round objects within the acinar cells represent the zymogen gran-
dentin blood and lymph cells
ules, the stored secretory precursor material. x 320. cardiovascular and lymphatic systems
spleen
constituent proteins with anio nic oligosaccharides. The
mucinogen granules, the secretory product wi thin the cell,
are therefore PAS positive (see Fig. 4.17a). However, they
are water soluble and lost during routine tissue prepara-
tion. For this reason, the cytoplasm of muco us cells ap- ECTODERM
pears to be empty in H &E-stained paraffin sections. An-
other char acteristic feature of a mucous cell is that its ENDODERM surface ectoderm
nucleus is usually flattened against the base of the cell by
accumulated secretory prod uct (Fig. 4 .28).
In contrast to mucus-secreting cells, serous cells produce
epithelium of:
trachea
.--1
~
l
epidermis, hair, nails, cutaneous
poorly glycosylated or nonglycosylated protein secretions. bronchi ' - - - - -- -- - ------1 and mammary glands
lungs trilaminar embryonic disk anterior pituitary gland
The nucleus is typically round or oval (Fig. 4.29). The apical enamel of teeth
cytoplasm is often intensely stained with eosin if its secretory epithelium of: internal ear
granules are well preserved. The perinuclear cytoplasm often Gl tract corneal epithelium and lens of eye
appears basophilic because of an extensive rough endoplas- liver
mic reticulum, a characteristic of protein-synthesizing cells. pancreas
Serous cell-containing acini (sing., acinus) are found in urachus neuroectoderm
the parotid gland and pancreas. Acini of some glands, such
as the submandibular gland, contain both mucous and epithelium of:
pharynx
epiblast
I \
I
serous cells. In ro uti ne tissue preparation, the sero us cells neural crest neural tube
thyroid gland
are more removed from the lumen of the acinus and are
shaped as crescents or demilunes (" ha lf-moons") (see page
455 for an explanation of demilune formation) at the pe-
tympanic cavity
pharyngotympanic tube
tonsils
t
cranial and sensory
parathyroid glands ganglia and nerves
riphery of the mucous acinus.
. adrenal medulla
FIGURE4.28
9 HISTOGENESIS OF EPITHELIUM
0'
inner cell mass
melanocytes
pharyngeal arch cartilages
head mesenchyme
Schwann cells
central nervous system
Mucus-secreting compound gland. Photomicrograph showing two
The three ger m layers in the developing embryo contribute retina
small lobes of a mucus-secreting gland associated with the larynx. pineal body
Each displays the beginning of a duct (D) into which mucin is secreted to the formation of the various epithelia .
posterior pituitary gland
(arrows). The individual secretory cells that form the acinus (A) are dif
ficult to define. Their nuclei (arrowl1eads) are flattened and located in Ectodermal Derivatives FIGURE4.30
the very basal portion of the cell, a feature typical of mucus-secreting
glands. The cytoplasm is filled with mucin that has been retained dur- The derivatives of the ectoderm may be divided into two Derivatives of the three germ layers. Schematic drawing illustrating mesoderm. (Based on Moore KL, Persaud TVN. The Developing Human,
ing preparation of the tissue and appears stained. x350. major classes: surface ectoderm and neuroectoderm. the derivatives of the three germ layers: ectoderm, endoderm, and Clinically Oriented Embryology. Philadelphia: WB Saunders, 1998.)
I 16 CHAPTER 4 Epi!/Jrlial Tiss11t
C H APTE R 4 Epi!belinl Tiss11e I I7
pophys is, and the sensory epitheliltnl of the eye, ear, and then lose their attachments from these sites of origina l a lo ng the villi to the surface of the intestinal lumen. The
outgrowth . As an epithelia l outgrowth of the pharyngeal BOX 4.3
nose) migra ti on of these new cells continues unti l they reach t he
Neural crest and its deriva tives (components of the pe- wall, the thymus grows into the med iastinum and also tips of the villi, where they und ergo apoptosis and slo ugh
ripheral nervo us system, including ga ng lia, nerves, and loses its original connection. Figure 4.30 (see page 115) off into the lu men.
glial cells; medullary cells of the adrena l gland; the summarizes the deri vatives of the three germ layers. Simila rly, the stratified squ amous epithelium of skin is
ami1te precursor uptake and decarboxylatiott (APUD) replaced in most sites over a period of approximately 28 In two general locations, surface epithelium and its underlying
cells of the diffuse neuroendocrine system; melanoblasts, days. Cells in the basal layer of the epidermis, appr opri- connective tissue are regarded as a functional unit called a
the precursors of melanocytes; and the mesenchyme of Q EPITHELIAL CELL RENEWAl ately named the stratum basale (germinativum), undergo membrane. The two types of membrane are mucous membrane
and serous membrane. The tenn membrane as used here
the head and its epithelial derivatives, such as cornea l mitosis to provide for cell renewa l. As these cells differen-
should not be confused with the biologic membranes of cells,
endothelium and vascu lar endothelium ) Most epithelial cells have a finite life span less than that of the tiate, they are pushed toward the surface by new cells in nor should the designations mucous and serous be confused
w hole organism the basal la yer. Ultima tely, the cells become keratinized with the nature of the gland secretion as discussed above.
and slough off. In both of the a bove examples, a stead y Mucous membrane, also called mucosa, lines those cavi-
Mesodermal Derivatives
Surface epithelia and epithelia of many simple glands state is mainta ined w ithin the epitheliu m, with new cells ties that conned with the o utside of the body, namely, the al-
Mesoderm gives rise to belong to the category of con tinuous ly renewing cell pop- norma ll y r eplacing exfoliated cells at the sam e rate. imentary canal, the respiratory tract, and the genitourinary
Endodermal Derivatives
Endoderm (o r entoderm) gives rise to
Respim t01)' system epithelium
A limentary canal epithelium (excluding the epithelium
of the ora l cavity and a nal region, which a re of ectoder-
ma l o rigin)
Extramuml digestive gland epithelium, e.g., the li ver,
pancreas, an d gallbladder
T hyroid, parathyroid, and thymus gland epithelia l com- FIGURE 4.31
Autoradiograph of intestinal gland (crypt). Autoradiograph of crypts
po nents
in the jejunum of a rabbit that had been injected w ith tritiated thymi-
Lining epithelium of the tympanic cavity and auditory dine 8 hours prior to death and fixation. Nearly all of the epithelial
(Eustachian) tubes cells in this replicative zone of the Intestinal mucosa are labeled, in
dicating that they were synthesizing DNA at the time the animal was
T hyroid and parath yro id glands develop as epithelia l injected. x 600. (From Parker FG, Barnes EN, Kaye Gl. Gastroenterology
outgrowths from the fl oor and walls of the pharynx; they 1974;67:607-621.)
1 18 CHAPTER 4 Epillulial Tissur
jJ
0
.:t~l '11:1..
~~:
Zonula adherens4 catenin catenin complex filaments vinculin cytoskeleton to
~ complex in adjacent cell the plasma
~. membrane at re-
- .J . : .. '7 /. gions of cell-cell
~ . 'I
adhesion
Macula adherens Cadherins (e.g., Desmogleins, In termediate Oesmoplakins, Couples the in-
(desmosome) desmoglelns, desmocollins in fi laments plakoglobins termediate fila-
desmocollins) adjacent cell ments to the
plasma mem-
brane at regions
of cell-cell adhe-
sion
"~~
matrix proteins filaments a-actinin actin cytoskele-
~l~
Ollf!l
.5 tl matrix protein filaments proteins, intermediate
~~ (e.g., laminin 5, collagen XVII filaments to the
V1
~~ ~~'!"'"~;
ill\~~
co llagen IV) extracellular
matrix
::::: I -
',';."\n~-'4 '"''
~
'C:~~
c Creates a con-
0 Gap junction Connexln Connexin in None Not known
tlc (nexus) adjacent cell duit between
two adjacent
....:I :::- cells for passage
~~
- I of small ions and
76.9
V I informational
"2 ~ micromolecules
::::1-lt..
E
E
8
CHAPTER 4 Et>ithclial Tiss11e 12 I
M
Figure 1, intestine, monkey, H&E x 640. aries are not evident and the nuclei are unevenly spaced. The
This shows the simple squamous epithelium (mesothe- uneven spacing is because the sectioning kn ife passes
lium) covering the outer stnface of the intestine. The epithe- through some cells witho ut incl uding the nucleus. This phe-
lium overlies a well-defined layer of connective tissue (CT) nomenon can be understood better and visualized more eas-
containing several small blood vessels (BV); deeper is a layer ily in a nonsectioned (whole mount), silver-impregnated
of smooth muscle (SM). The epithelial cells are very flat, as preparation of a piece of a very thin mesentery (the structure
judged by the shape of their nuclei (N). Note that cell bound- that holds the intestines in place), as in Figure 2.
M
Figure 2, mesentery, monkey, si lver X640. as revealed in tllis figure, it would be possible to envision
The mesentery is lying on the slide, and the microscope is why th e epithelial nuclei are unevenl y spaced in sectioned
focused on its upper Slllface to reveal the Slllface epithelial material ; the kni fe would pass tluough the cytoplasm of each
cells. Cell boundaries are revealed by a deposition of reduced cell but would not necessarily cut across the nucle us of each
sil ver along the intercellular spaces. The nuclei (N) appear cell. Some of the more ovoid nuclei in the preparation belong
oval or round when viewed from the stuface, as opposed to to fibroblasts (F) in the underlying connective ti ssue. Be-
flat or elongate when seen on edge, as in a section. If one cause of the thinness of the mesentery, they are in the same
were to draw a line representing a knife cut across the cells focal plane as the epithelial cells and are thus superimposed.
Fig ure 3, kidney, human, H&E X640. cells forming the pari etal layer appear as flattened bodies
This micrograph, another example of a simple squa- that s how the same uneven spacing as in Figure 1. The free
mous epithelium, reveals a sectioned renal corpuscle and surface of the epithelium faces Bowman's space (B). The
adj acent kidney tubules. The re nal corpu scle consists of a cross sections of tubules, marked with asterisks (lower left),
special capillary bed, the glo merulus, that is enclosed by provide a good example of a simple cuboidal epithelium.
Bowman's capsule, part of wh ic h (the visceral layer) is di- Although the cell boundaries are not evident, one can judge
rectly adjacent to the capill aries and part of which (the pari- that the heig ht of each cell approximates its width by the
etal layer) forms a thin-walled spherical structure com- spaci ng of the nucle i. Thus, it is a cuboidal epithelium.
posed of sim ple squamous epithelium . The nuclei (N) of the
Figure 4, ovary, monkey, H&E X640. epithe li al cells are approximately square or cuboidal in three
This example of a simple cuboidal epithelium ( Ep) shows dimensions. The free surfaces of these cells face the abdomi-
the cells that cover the Slllface of the ovary. T he epithelium nal cavity and are a modification of the simple squamous ep-
rests on a high ly cellular connective tissue (CT). The surface ithelium or mesothelium shown in Figures I and 2.
M
Figure 5, liver, human, H&E X400. adjoining cell possesses a mi rror-imaged grooved surface.
These cells also approximate a cube, but they are The opposi ng grooves form a small lumen or canaliculus
arranged in sheets separated by blood vessels (BV) called through which the bile produced by the cells reaches a b ile
si nusoids. T he epithe lium is unusual, in that several sur- duct. The canaliculi are not visible at thi s magnification but
faces of the ce ll possess a g roove that represents the free are located at the points of the anvws (see bile canaliculus,
surface. Where a grooved surface is present o n one cell , the Plate 62).
KEY
AV, arteri ole, vessel supplying glomerulus Ep, epithelium arrows, site o f bile canalicu lus
B, Bowman's space F, fibrob last nucleus asterisk, tubule possessing simple cuboidal
BV, blood vessel N, nucleus epithel ium
CT, connective tissue SM, smooth musc le
120
CHAPTER 4 EpitiJelinl Ti55u e I 23
Figure 1, exocrine pancreas, monkey, H&E x450. men) is greater than the width , the epith elium is simple
Tllis shows three epithelial forms. In the circle is a well- columnar. The second epithelial type is represented by a
oriented acinus, a functional group of secretory cells, each of small, longitudinally sectioned duct (anvws) extending
which is pyranlidal in shape. The secretory cells form a across the field. It is composed of flattened cells (note the nu-
spherical or tubul ar structure. The free surface of the cells clear shape), and on this basis, the epithelium is simple squa-
and the lumen are located in the center of the circle. T he lu- mous. Finally, there is a larger cross-sectioned duct (asterisk)
men is not evident here but is evident in a sinlilar ceil into which the smaller duct e nters. The nuclei of this larger
arrangement in Figure 4 (see circle). Because the height of duct tend to be round, and the cells tend to be square in pro-
the cells (the distance from the edge of the circle to the lu- file. Thus, these duct cells are a simple cuboidal epithelium.
Figure 2, kidney, human, H&E X450. the lateral celJ boundaries; note that cell width approximates
This section shows cross-sectioned tubules of several cell height. The cross-sectioned structures marked with aster-
types. Those that are labeled with the arrows provide another isks are another type of tubule; they are smaller in diameter
example of a simple cuboidal epithelium. The anvws point to but are also composed of a simple cuboidal epithelium.
Figure 3, colon, human, H&E x350. tory product. The epithelium lines the lumen of the colon and
The simple columnar lining epithelium of the colon shown extends down into the cotmective tissue to form the intestinal
here consists of a single layer of absorptive cells and mucus- glands (GL). Both cell types are tall with their nuclei located at
secreting cells (goblet cells). The latter can be recognized by the the base of the cell. The connective tissue (CT) contains numer-
light staining "goblet" (arrows) that contains the cell's secre- ous cells, many of which are Iymphocytes and plasma cells.
ffi
Figure 4, trachea, monkey, H&E x450. cause all of the cells rest on the basement me mbrane, they are
In addition to the tall columnar cells (CC) in this colurnnar regarded as a single layer, as opposed to two discrete layers,
epithelium, there is a definite layer of basal cells (BC). The one over the other. Because the epithelium appears to be strat-
columnar cells, which contain elongate nuclei and possess ified but is not, it is called pseudostratified columnar epithe-
cilia (C), extend from the smface to the basement membrane lium. The circle in the micrograph delineates a tracheal gland
(clearly visible in the trachea as a thick, acellular, homoge- simllar to the acinus in Figure 1 (circle). Note that the lumen
neous region that is part of the connective tissue (CT)). The of the gland is clearl y visible and the cell boundaries are also
basal cells are interspersed between the columnar cells. Be- evident. The gland epithelium is simple col umnar.
Figure 5, epididymis, human , H&E X450. e pithelium is pseudostratified. Note that where the epithe-
This is another example of pseudostratified columnar lium is verticall y oriented, on the right of the mic rograph,
epithelium. Again, two layers of nuclei are evident, those of there appear to be more nuclei, a nd the epithe lium is
basal cells (BC) and those of columnar cells (CC). As in the thicker. Th is is a result of a tangential plane of section. As
previous example, however, although not evide nt, the a rule, always examine the thinnest area of an epithelium to
columnar cells rest on the basement membrane; thus, the visualize its true organization.
Figure 6, vagina, human, H&E x 225. appear closely packed. As the cells become larger, they 'tend
This is the stratified squamous epithelium of the vagi- to fl atten out, forming di sk-li ke sq uames. Because the sur-
nal wall. The deeper cells, particularly those of the basal face cells retain this shape, the epithelium is called strati-
layer, are small , with little cytoplasm, a nd thus th e nuclei fied squamous.
KEY
BC, basal cell GL, intestinal gland boundaries of cuboidal tubule cells; Fig. 3,
C, cilia ar rows: Fig. I , tubule composed of simple mucus cups of goblet cells
CC, columnar cell squamous epi thelium; Fig. 2, lateral asterisk, duct or tubule of simple cuboidal
CT, connective tissue epithelium
122
CHAPTER 4 Epithelial Tiss11r I '2 5
Figure 2, skin, human, H&E X450. ithelium (SC) in two layers; the cells of the inner layer (the I
This shows a portion of the duct of a sweat gland just be- surface cells) appear more or less square. Because the epi-
fore the duct enters the stratified squamous epithelium (SS) dermal surface cells are not included in the field, the desig-
of the skin. The dashed line traces the duct withi n the epi- nation stratified squamous cannot be derived from the in-
dermis. This duct also consists of a stratified cuboidal ep- formation offered by the micrograph.
Figure 3, anorectal junction, human, H&E X300. and the underlying layers of cells. The simple columnar ep-
T he area shown here is the termina l part of the intesti ne. ithelium on the left is part of an intesti nal gland that is con-
The luminal epithelium on the left is typical simple colum- tinuous with the simple columnar epithelium at the intes-
nar (SCol) epithelium of the colon. This epithelium under- tinal luminal surface. The con nective tissue (CT) at thi s site
goes an abrupt transition (arrowhead) to a stratified is heavily infiltrated with lymphocytes, giving it an appear-
c uboidal e pithelium (StCu) at the anal cana l. Note the gen- ance unlike the connective tissue of other specimens on this
eral c uboidal shape of most of the surface cells (arrows) page.
Figure 4, urinary bladder, monkey, H&E x 400. are the sma llest, and their nucle i appear more crowded.
The epithelium of the urinary bladder is called transi- When the bladder is distended, the superfic ial cells are
tional epithelium, a stratifi ed e pithe lium that changes in stretched into squa mous cells, and the e pithelium is re-
appearance according to the degree of diste nsion of the duced in thickness to about three cells deep. The bladder
bladder. In the nondistended state, as here, it is about four wall usually contracts when it is removed, unless special
or fi ve cells deep. The surface cells are large and dome steps are take n to preserve it in a di stended state. T hus, its
shaped (asterisks). The cells immediately under the surface appearance is usually like that in Figure 4.
cells are pear shaped and slightly smaller. T he deepest cells
Figure 6, endocrine pancreas, human, H&E x 450. developed from the same epithelial smface, are made up of
Cells of the endoc1ine islet (of Langerhans) (En) of the cells with a free surface onto which the secretory product is
pancreas also have an e pithelioid arrangement. T he cells are discharged. Capillaries (C) are prominent in endocline tis-
in contact but lack a free surface, although they have devel- sues. Similar examples of epithelioid tissue are seen in the ad-
oped fro m an epithelia l surface by invagination. In contrast, renal and the parathyroid and pituitary glands, aU of which are
the surrounding alveoli of the exocrine pancreas (Ex), which endocrine glands.
KEY
C, capillary SC, stratified cuboidal epithelium arrowhead, transition site of simple strati-
CT, connective tissue SCol, stratified columnar epithe li um fied epithe lium to stratified cuboidal
En, e ndocrine cells SS, strati fied squamous epithelium arrows, surface cuboidal cells
Ex, exocrine cells StC u, stratified cuboidal epithelium asterisks, dome-shaped cells
JC, interstitial (Leydig) cells
124
plasma cells
Connective Tissue
GENERAL STRUCTURE AND FUNCTION OF CONNECTIVE TISSUE 126
EMBRYONIC CONNECTIVE TISSUE 128
CONNECTIVE TISSUE PROPER 128
CONNECTIVE TISSUE FIBERS 131
Collagen Fibers and Fibrils 131
eosinophil adipose cell lymphocytes
Reticular Fibers 134
Elastic Fibers 137 FIGURE 5.1
Loose connective tissue. a. Photomicrograph of a mesentery spread are presumed to be those of fibroblasts. Nuclei of other cell types, i.e.,
GROUND SUBSTANCE 139 stained with Verhoeff's hematoxylin to show nuclei and elastic fibers, lymphocytes, plasma cells, and macrophages, are also present but
EXTRACELLULAR MATRIX 139 counterstained with safranin for identification of mast cell granules are not identifiable. Mast cells are identified by the bright reddish
and with orange G for identification of other proteins (mainly colla- granules within their cytoplasm. Note the presence of the small blood
CONNECTIVE TISSUE CELLS 141 gen fibers). The elastic fibers appear as blue-black, thin, long, and vessel filled with red blood cells. X l50. b. Schematic diagram illus-
Fibroblasts and Myofibroblasts 141 branching threads without discernable beginnings or endings. Colla- trating the components of loose connective tissue. Note the associa-
Macrophages 142 gen fibers appear as orange-stained, long, straight profiles and are tion of different cell types with the surrounding extracellular matrix,
Mast Cells and Basophils 144 considerably thicker than the elastic fibers. Most of the visible nuclei which contains blood vessels and different types of fibers.
Adipose Cells 146
Undifferentiated Mesenchymal Cells and Pericytes 146
Lymphocytes, Plasma Cells, and Other Cells of the Immune System 147
phocytes, plasma cells, macrophages, and eosinophils, are TABLE 5.1. Classification of Connective Tissue
BOXES associated with the body's defense system; they fu nction
within the ground substance of the tissue. In contrast, bone Embryonic connective tissue
BOX 5.1. Clinical Correlations: Collagenopathies 136
tissue, another form of connective tissue, contains only a Mesenchyme
BOX 5.2. Functional Considerations: The Mononuclear Phagocytotic single celt type, the osteocyte. This ceU produces the fibers Mucous connective tissue
System 144
that make up the bulk of bone tissue. A uniq ue feature 'o f Connective t issue proper
bone is that its fibers are organized in a specific pattern and Loose connective tissue
become calcified to create the hardness associated with this Dense connective tissue
tissue. Similarly, in tendons and ligaments, fibers are the Irregular
prominent feature of the tissue. These fibers are arranged Regular
in parallel array and are densely packed to impart maxi- Specialized connective tissueA
Q GENERAL STRUCTURE AND m um strength. Adipose tissue (Chapter 6)
FUNCTION OF CONNECTIVE TISSUE Different types of connective tissue are responsible for a Blood (Chapter 9)
variety of functions Classification of connective tissue is based on the composition Bone (Chapter 8)
Connective t issue comprises a diverse group of cells embedded Cartilage (Chapter 7)
and organization of its cellular and extracellular components
Hemopoietic tissue (Chapter 9)
in a tissue-specific extracellular matrix The functions of the various connective tissues are re- and on its functions Lymphatic tissue (Chapter 13)
flected in the types of cells and fibers present within the tis-
' In the past, the designations elastic tissue and reticular tissue have been listed
In general, connective tissue consists of cells and an ex- sue and the character of the ground substance in the ex- The term connective tissue includes a va riety of tissues as separate categories of specialized connective tissue. The tissues usually
tracellular matrix that includes fibers, ground substance, tracellular matrix. For exarnple, in loose con nective tissue, with differing functiona l properties but with certain com- cited as examples of elastic tissue are certain ligam ents associated w ith the
and tissue fluid. It forms a vast and continuous compart- ma ny different cell types are present (Fig. 5.1 ). One type, mon characteristics that allow them to be grouped to- spinal column and the tunica media of elastic arteries. TI1e identifying fea-
ture of reticular tissue is the presence of reticular fibers and reticular cells to-
ment throughout the body, bounded by basal laminae of the fibrobla~, ~uces the e~ that serve a gether. For convenience they are classified in a maru1er that gether forming a t11reedimensional stroma. Reticular tissue serves as the
the various epithelia and by the basal or external lamina of structural role in the tissue. They also produce and main- reflects these features. Table 5.1 provides a classification stroma for hemopoietic tissue (specifically the red bone marrow) and lym
muscle cells and nerve supporting cells. tain the ground substance. Other cell rypes,S'Uch as lym- including subtypes of the principal connective tissues. phatic tissue organs (lymph nodes and spleen, but not the thymus).
~
126 127
I 28 CHAPTER 5 Co1111ecti11r Tisstte CHAPTER 5 Co1111 ective Tisstt e I29
------
Loose connective tissue, also sometimes called areolar ~oose connective tissue is a cellular connective tissue siderably more abundant and is composed of very thick fibers. the tendon is subdivided into fascicles by endo-
tissue withtliin-;;1d relativefy sparse ~fibers (Fig. 5.3) - XlOO. tendineum, a connective tissue extension of the epi-
I 30 CHAPTER 5 CoHHeclille Tissue C H APTER 5 Co>111ective Tissue I3I
ray is also fo und in th e cornea of the eye and is believed fibers typica ll y appea r as wavy structures of varia ble
to be responsible for its tra nsparen cy. width and indeterminate length. They stain read il y wi t h
eosin and other ac idic d yes. They can also be colored
w ith th e d ye an iline blue, used in Mallory's connective
Q CONNECTIVE TISSUE FIBERS tiss ue stain, or w ith the dye light green, used in Masson's
stai n.
Connective tissue fibers are of three principal types When examined w ith th e transmission electron micro-
scope (TEM), collagen fibers appear as bundles of fine,
Connective tissue fibers are p resent in varying amo unts, thread-like subumrs:-'fnese su.Qynits._ are ~ol{fgen fibrils
d epending on the structural needs or functio n of the con- (Fig. 5 .5). Within an individual fiber, the co agen fibrils
necti ve tiss ue. Ea~h type of fiber is pro du ced by fi bro blas ~ are r elatively uniform in diameter. In different locations
and is composed of proteir1consistmg orlong peptide and at different stages of development, however, the fibrils
chains. The types of connective tissue fibers are differ in size. In developing or immature tissues, the fibr ils
may be as sma ll as 15 o r 2 0 nm in diameter. In d ense reg-
Collagen fibers
ular connective tissue of tendons or other tiss ues that are
Reticular fibers subject to considerable stress, t hey may measure up to 300
Elastic fibers
nm in dia meter.
Collagen Fibers and Fibrils Collagen fibrils have a 68-nm banding pattern
Collagen fibers are the most abundant type of connective When collagen fibrils sta ined w ith osmium or other
tissue fiber heavy metals are exa mined w ith the TEM, they exh ibit a
seq uence of closely spaced t ransverse ba nds that repeat
Collagen fibers a re fkxi ble and have a rema rkably every 68 nm along t he length of the fib ril (Fig. 5.5, inset).
high te nsile strength. In the lig h t microscope, collagen T his banding pattern re flects the fibril's subunit stru cture,
FIGURE 5.4
Dense regular connective tissue-tendon. a. Electron micrograph of gen fibrils. The arrows Indicate processes of tendinocytes. x 9,500. In-
a tendon at low magnification, showing tendinocytes (fibroblasts) set. Photomicrograph of a tendon. Note the orderly and regular align-
and their thin processes (arrows) lying between the collagen bundles. ment of the bundles of collagen fibers. Tendinocytes are aligned in
x l ,600. b. A tendinocyte with prominent profiles of rough endoplas- rows between th e collagen fibers. x 200. (Electron micrographs mod-
mic reticulum (rER) is shown at higher magnification . The collagen ified from Rhodin J. Histology. New York: Oxford University Press,
fibers (C) can be resolved as consisti ng of very tightly packed colla- 1974.)
tendineum. It co ntains t he small blood vesse ls and menta flava) co ntain many elastic fibe rs and fewe r colla-
nerves of the tendon. gen fibers. T hese ligaments are ca lled elastic ligaments.
Ligaments, like tendons, consist o f fi bers and fibroblasts Aponeuroses resemble br oad, flattened tendons. Instead
~dl:i'l pa ralle}.The fibers of liga ments, however, are o f fi bers lying in parallel a rrays, t he fibers o f aponeu-
less re~a rly arr~ than those of tendons. Ligaments roses are arranged in multi ple layers. The bundles of col- FIGURE 5.5
)oii1 bone !~' w hich in some locations, such as in the lagen fibers in o ne layer tend to be arranged at a 90 an- Collagen fibrils in dense irregular connective tissue. Electron micro- fibrils are more dispersed. x 9,5 00. Inset. A longitudinal array of col-
spu1al cofu mn, requires some elasticity. A lthough collagen gle to those in the neighboring layers. The fibers w ithin graph of dense irregular connective tissue from the capsule of the lagen fibrils from the same specimen seen at higher magnification.
is the ma jor extracellular fiber of most ligaments, some of each o f th e layers are arranged in regular arrays; thus it testis of a young male. The thread-like collagen fibrils are aggregated Note the banding pattern. The spacing of the arrows indicates the 68-
the liga ments associated w ith the spinal column (e.g., liga- is a d ense regular conn ective t iss ue. This orthogonal ar- in some areas (X) to form relatively thick bundles; In other areas, the nm repeat pattern. X75,000.
I 31 CHAPTER 5 Couuective Tissue C HAPTER 5 Conuective Tissue I33
specifically, the size and shape of the collagen molecule Each collagen molecule is a triple helix com~ree
TABLE 5.2. Types of Collagen, Composition, location, and FunctionA
and the arrangement of the molecules that form the fibril iljtertw~~
(Fig. 5.6). The collagen molecule, also called tropocolla- Type Composition8 Location Functions
gen, measures about 300 nm long by 1.5 nm thick, with A single collagen molecule consists of three polypeptides
[1!1 (I)Jln:Z(I) Connective tissue of skin, bone. tendon, lig Provides resistance to force, tension. and stretch
a head and a tail. In forming a fibril, the collagen mole- known as a chains. The a chains intertwine, forming a aments, den tin, sclera, fascia, and organ
cules a lign head to tail in overlapping rows with a gap be- right-handed triple helix (Fig. 5 .6d) . Every third amino capsules (accounts for 90% of body colla-
tween the molecules within each row and a one-quarter- acid in the chain is a glycine molecule, except at the ends gen)
molecule stagger between adjacent rows. The strength of of the a chains. A hydroxyproline or hydroxylysine fre- II lnl (II)], Cartilage (hyaline and elastic). notochord, Provides resistance to 1ntennittent p1 essure
the fibril is due to covalent bonds between the collagen quently precedes each glycine in the chain, and a proline and intervertebral disc
molecules of adjacent rows, not to the head-to-tail at- frequently follows each glycine in the chain. Along with Ill ltd (Ill)! , Connective tissue of organs (uterus, liver, Provides structural support and elasticity
tachment of the molecules in a row. The banding pattern proline and hydroxyproline, the glycine is essential for the spleen, kidney, lung, etc.); smoot11 muscle:
observed with the TEM is caused large ly by osmium de- triple-helix conformation (Fig. 5.6e). Associated with the endoneurium. blood vessels, and fetal skin
position in the space between the heads and tails of the helix are sugar groups that are joined to hydroxylysyl IV lal (IV)],a2(1V) Basal laminae of epithelia, kidney Provides support and filtration barrier
glomeruli, and lens capsule
molecules in each row. residues. Because of these suga r groups, collagen is prop-
W described as a gly;:gPwtein.__
v I"1 (V)[,u2(V) or Distributed unifotmly throughout connec Localized at lhe surface of type I collagen fibrils along
o 1(V)n2(V)o3(V) live tissue stromu; may be relatecl to reticu witll type XII and XIV collagen to modulate blomechani
The a chains that constitute the helix are not all alike. la1 network cal properties of t11e fibril
a. Fibril They vary in size from 600 to 3,000 amino acids. To date, VI [al (VI)J,a2(VI) Forms part of the cartilage matrix lmmedi- Attaches the chondrocyte to the matrix
at least 27 types of a chains encoded by different genes ately surrounding the chondrocytes
have been identified. As many as 19 different types of col- VII [al (VII)[, Present in anchoring fibrils Secures basal lamina to connective tissue fibers
lagens have been categorized on the basis of the combina- VIII [al (VIII)],a2(VIII) Product of endothelial cells Facilitates movement of endothelial cells during angio-
tions of a chains they contain. These various collagens are genesis
classified by Roman numerals I to XIX according to the IX al (IX)a2(1X)a3(1X) Found in cartilage associated with type II Stabilizes network of cartilage type II collagen fibers by
chronology of their discovery. collagen fibrils interaction with proteoglycan molecules at their Inter-
For example, type I collagen is found in loose and dense sections
connective tissue. Two of the a chains (al ) are identical, and X lal (X)[, Produced by chondrocytes in the zone of Contributes to the bone mineralization process by form-
one (a2) is different and identified as an a2 chain. Thus, in hypertrophy of normal growth plate ing hexagonal lattices necessary to arrange types II, IX,
collagen nomenclature it is designated [al(I )ha2(1) (Ta ble and XI collagen within cartilage.
5.2). Type II collagen is present in hyaline and elastic carti- XI I" I(XI)i,u2(XI) Produced by chondtocytes; associated will1 Regulates size of type II collagen fibrils; it is essential tot
lage, where it occurs as very fin e fibrils. The collagen mole- type II collagen fibrils cohesive properties of cartilage matrix
cules of type II collagen are composed of three identical a XII [al (XII)I, Isolated from skin and placenta; abundant Localized at the surface of type I collagen fibrils along
-------d.----
in tissues where mechanical strain is high with type V and XIV collagen to modulate biomechani-
Triple helix chains. Because these a chains differ from those of other col-
1 cal properties of the fibril
r 10.4 nm (0. 15 0)------------'-'~ lagens, type II collagen is designated [al (II))3 XIII [al(XIII)I, An unusual transmembrane collagen de- Associated with the basal lamina along with type VII
Not only do the polypeptides of the various collagens tected in bone, cartilage, intestine, skin, collagen
differ, but the organization and arrangement of the mole- placenta, and striated muscles
cules within the fibrils also differ. For example, the mole- XIV lal (XIV)b Isolated from placenta; also detected in the Localized at the surface of type I collagen fibrils along with
cules of coll agen types I, II, III, V, and XI aggregate to form bone marrow type Vand XII collagen to modulate biomechanical prop-
68-nm-banded fibrils (as diagramed in Fig. 5.6a). In con- erties of the fibril; has a strong cell-cell binding property
I
e. Typical sequencEf trast, type N collagen forms a nonfibrillar network that XV lal(XV)b Present in tissues derived from mesenchyme Involved in adhesion of basal lamina to t11e underlying
of a 1 and a 2 -.'E - - - - provides structural cohesion to the basal lamina. Similarly, connective tissue
chains another nonfibrillar collagen, type IX collagen, binds and XVI lal(XVI)b Localized in close association with fibro- Contributes to structural integrity of connective tissue
interacts with type II collagen of cartilage at the intersec- blasts and arterial smooth muscle cells, but
not associated with type I collagen fibrils
tions of the fibrils. It serves to stabilize tlus tissue. Table
XVII [al (XVII)b Another unusual transmembrane collagen Interacts with integrins to stabilize hemidesmosome
5.2 lists the collagens that have been characterized to date,
found in epithelial cell membranes structure
including th eir structural variations and some of the roles
proline XVIII lal (XVIII)], Found in epithelial and vascular basement Represents a basement membrane heparan sulfate pro-
presently ascribed to them.
membrane teoglycan thought to inhibit endothelial cell proliferation
FIGURE 5.6 and angiogenesis
Collagen fiber formation involves events that occur both within XIX [a1 (XIX)],
Diagram showing the molecular character of a type 1 collagen fibril Discovered from the sequence of rhabdo- The pronounced vascular and stromal interaction sug-
and outside the fibroblast myosarcoma eDNA gests involvement in angiogenesis
in increasing order of structure. a. A collagen fibril displays periodic
banding with a distance (D) of 68 nm between repeating bands. "Fibrillar collagens are indicated by blue type. Nonfibrlllar collagens are indicated by black type.
b. Each fibril is composed of staggered collagen molecules. c. Each The production of fibrillar collagen (I, II, III, V, and XI) "Eacll collagen molecule is composed of three polypeptide a chains intertwined in a helical configuration . Tile Roman numerals in tile parentheses in tile Compo
molecule is about 300 nm long and 1.5 nm in diameter. d. The col- invo lves a series of events withi n the fibroblast that leads to sition column indicate tllat tile a chains llave a distinctive structure tllat differs from tile cllalns witll different numerals. Thus, collagen type I l1as two identical
lagen molecule is a triple helix. e. The triple helix consists of three a production of procollagen, the precursor of the collagen a l c11ains and one a2 chain; collagen type II has three identical crl chains.
chains. Every third amino acid of the a chain is a glycine. The X po- molecule. These events take place in m embrane-bounded
sition following glycine is frequently a proline, and the Y position pre- organelles within the cell. Production of the actual fibril oc-
ceding the glycine is frequently a l1ydroxyproline. curs outside the cell and involves enzymatic activity at the
1 34 CHAPTER 5 Co~r~rec tive Tissue C HAPTER 5 Co~r ~rective Tissue I 35
plasma membrane to produce the collagen molecule, fol- sim ultaneously creates a "cove" or indentation at its
INTRACELLULAR EVENTS
lowed by assembly of the molecules into fibrils in the ex- surface to allow molecules to concentrate where assem-
1 Uptake of amino acids (proline, lysine, etc.)
tracellular matrix under guidance by the cell (Fig. 5.7). bly will occur (see Fig. 5.7). Within the cove, the colla- by endocytosis
gen fibril self-assembles: The collagen molecules align in
Collagen synthesis involves a number of intracellular events rows and then cross-link by covalent bonds that form 2 formation of mRNA
between the lysine and hydroxylysine aldehyde gr oups. ~
PolypefJtide chains are produced by polyribosomes of
the rough endoplasmic reticulum (rE R). This synthesis --, ...
_,,-, ... _, -- '~~
-,...
(translation) is directed by information provided by Reticular Fibers 3 Synthesis of a chains with registration
messenger RNA (mRNA), and newly synthesized peptides by ribosomes
Reticular fibers provide a supporting framework for the
~
polypeptides are simultaneously discharged into the cis-
ternae of the rER. cellular constituents of various tissues and organs
Within the cisternae of the rER and the Golgi apparatus, 4 Hydroxylation of proline and lysine residues
a number of posttranslational modifications of the Reticular fibers and collagen fibers share a prominent (vitamin C required) and cleavage of signal
polypeptide chains occur. These include feature: They both consist of collagen fibrils. Unlike colla- sequence of rER
gen fibers, however, reticular fibers are composed of type
1. Cleavage of the signal peptide
2. Hydroxylation of proline and lysi ne residues while the
Ill collagen. The individual fibrils that constitute the r etic-
ular fiber exhibit a 68-nm banding pattern (the same as the
~ OH
5 Glycosylation of specific hydroxylysyl
polypeptides are still in the nonhelical conformation fibrils of type I collagen) . The fibrils have a narrow diam- residues in rER
3. Addition of 0-linked sugar groups to some hydroxy- eter (about 20 nm) and typically do not bundle to form
lysine residues (glycosylation) and N-linked sugars to
the two terminal positions
thick fibers.
In routinely stained H&E preparations, reticular fibers
cannot be identified positively. When vis ualized in the light
~ OH Gai-G\u
4. Formation of a triple helix by three polypeptide
chains, e..xcept at the terminals where the polypeptide microscope w ith special techniques, the reticular fibers 6 Formation of procollagen triple helix
chains remain uncoiled have a thread-like appearance. Because they contain a molecules in rER and movement into transfer
greater relative content of sugar groups than collagen vesicle
5. Formation of intrachain and interchain hydrogen
bonds that influence the shape of the molecule and fibers, reticular fibers are readily displayed by means of the
stabilize the interactions of the polypeptides. periodic acid-Schiff (PAS) reaction. They are also revealed
with special silver-staining procedures, such as the Gomori 7 Packaging of procollagen by Golgi into
secretory vesicles
The resultant molecule is procollagen . Note that ascor- and Wilder methods . After silver treatment, the fibers ap-
bate (vitamin C) is required for the function of pro lyl- pear black; thus, they are said to be argyrophilic (Fig. 5.9). 8 Movement of vesicles to plasma membrane,
hydroxylase and lysy lhydroxylase; w ithout posttransla- The thicker collagen fibers in such preparations are col- assisted by microfilaments and microtubules
tional hydroxylation of proline and lysine, the hydrogen ored brown.
9 Exocytosis of procollagen
bonds essential to the final structure of the collagen mol-
ecule cannot form. This explains w hy wounds fail to Reticular fibers are named for their arrangement in a vesicles
undergoing EXTRACELLULAR EVENTS
heal and bone formation is impaired in vitamin C defi- mesh-like pattern or network
ciency (scurvy). exocytosis 10 Cleavage of registered, nonhelical ends
of procollagen to form tropocollagen
The procollagen moves to the exterior of the cell by In loose connective tissue, networks of reticular fibers
means of exocytosis of secretory vesicles. Microtubules
are involved in the movement of the secretory vesicles
are found at the boundary of connective tissue and ep-
ithelium, as well as surro undi ng adipocytes, small blood
secretory
vesicles ~
from the region of the Golgi apparatus to the cell sur-
face. If the microtubules are disrupted w ith agents such
as colchicine or vinblastine, the secretory vesicles accu-
vessels, nerves, and muscle cells. Reticular fibers also
function as a supporting stroma in hemopoietic and lym-
phatic tissues (but not in the thynws). In these tissues,
() procotgen
peptidase
j t
procollagen
peptidase
mul ate in the Golgi region. the collagen of the reticular fiber is produced by a spe-
cia l cell type, the reticular cell. This cell maintains a -~-
-
INN WM
IJN.
Collagen synthesis also involves extracellular events unique relationship to the fiber; it surrounds the fiber tropocollagen
with its cytoplasm , t hus isolating the fiber from other tis- 11 Polymerization of tropocollagen into collagen
As procollagen is secreted from the cell, it is converted sue components. fibril (in coves initially)
to a collagen molecule by procollagen peptidase associ- In most other locations, the reticular fiber is produced
ated with the cell membrane, which cleaves the uncoiled by fibroblasts. Important exceptions to this general rule in- FIGURE 5.7
ends of the molecule (Fig. 5.8) . clude the endoneurium of peripheral nerves, where Collagen synthesis. Schematic representation of the biosynthetic bers within tile cell diagram correspond to the events numbered in
The aggregated collagen molecules then align to form Schwann cells secrete reticular fibers, and the reticular and events and organelles pa rti cipating in collagen synt11esis. Bold num- collagen production listed on the right.
the final collagen fibrils. The cell controls the orderly ar- other collagen fibers secreted by smooth muscle cells of the I I
ray of the newly formed fibrils by directing the secretory tunica media of blood vessels and the muscularis of the al-
vesicles to a localized surface site fo r discharge. The cell imentary canal.
C HAPTER 5 Colllltcl ive Tissru 13 7
The important role of collagens in the body can be illustrated by chains in the various collagens. In the future, gene therapy could
collagenopathies (collagen diseases), which are caused by a deficit potentially be used either to control deposition of faulty collagen or
or abnormality In the production of specific collagens. Most col- to reverse the disease process caused by the mutated genes. Table
lagenopathles are attributed to mutations In genes encoding the a 5.3 lists the most common collagenopathles occurring in humans.
FIGURE 5.9
Reticular fibers in the lymph node. Photomicrograph of a ly mph
TABLE 5.3. The Most Common Collagenopathies Occurring in Humans node silver preparation showing the connective tissue capsule at the
Type of Collagen Disease symptoms top and a trabecula extending from It at the left. The reticular fibers
(arrows) form an irregular anastomosing network. x 650.
I Osteogenesis imperfecta Repeated fractures after minor trauma, brittle bones, ab-
normal teeth, thin skin, weak tendons, bl ue sclerae, pro-
gressive hearing loss
II Kniest dysplasia Short stature, restricted j oint mobility, ocular changes Elastic Fibers
lead ing to blindness, wide metaphyses and joint abnor-
mality seen in radiographs
Elastic fibers allow tissues to respond to stretch and distensio~
Ill Ehlers-Danlos type IV Hypermobility of j oints of digits, pale thin skin, severe
bruisability, ea rly morbidity and mortality resulting from
rupture of vessels and Internal organs Elastic (ibe1s a re typically thi nner th an co llagen fibers
IV Alport's syndrome Hematuria resulting from structural changes in tl1e and are arranged in abra nch ing pattern to forn;-; thr ee-
glomerular basement membrane of the kidney, progres- dimensio nal network. The fibers are interwoven with colla::-
sive hearing loss, and ocular lesions gen fib~ distensibility of the tissue and to pre-
VII Kindler's syndrome Severe blistering and scarring of the skin after minor vent tearing from excessive stretching.
trauma, resulting from absence of anchoring fibrils Elastic fibers stain with eosin, but not well ; therefore,
IX Multiple epiphyseal dysplasia (MED) Skeletal deformations resulting from impaired endochon- they ca nnot a lways be d istinguished fro m co llagen fibers in
dral ossification and premature degenerative joint disease
ro utine H & E preparations. Beca use elastic fibers become
X Schmid metaphyseal chondrodysplasia Skeletal deformations characterized by modifications of somewha t refractile w ith certain fixatives, they may be d is-
the vertebral bodies and metaphyses of the long bone
tinguished from collagen fibers in specimens stained with
XI Stickler's syndrome type II Craniofacial and skeletal deformations, severe myopia,
H & E when they d ispla y this characteristic. Elastic fibers
retinal detachment, progressive hearing loss FIGURE 5.10
ca n also be selectively stained with specia l d yes such as or-
XVII Generalized atrophic benign epidermolysis Blistering skin disease with mechanically induced dermal- Collagen and elastic fibers. Photomicrograph of a mesentery spread
bullosa (GABEB)
cein or resorcin-fuchsin, as shown in Figure 5.10.
epidermal separation, resulting from faulty hemidesmo- stained with resorci n-fuchsin. The mesentery is very thin, and the mi-
somes, skin atrophy, nail dystrophy, and alopecia Elastic fibers are produced by m ost of the sa me cells that croscope can be focused through the entire thickness of the tissue.
prod uce collagen and reticular fibers, particula rl y fibr o- The delicate thread-like branching strands are the elastic fibers ().
blasts and smooth muscle cells. In contrast to co llagen Collagen fibers (C) are also evident. They are much thicker, and al-
fiber s, however, elastic fibers are composed of two struc- though they cross o ne another, they do not branch. x 200.
136
I 38 CHAPTER 5 Couuecli11e Tiss11r C HAPTER 5 Couurclivr Tiss11r I 39
The elastic property of the elastin molecule is due to its between layers of smooth muscle cells. Li ke the collagen Proteoglycans and GAGs are responsible for the physical
unusual polypeptide backbone that causes random coiling fi bers in the tunica media of blood vessel walls, the elastic properties of ground substance
ma terial of a rteries is produced by smooth muscle cells,
The random coiling of the elastin molecule a llows the not by fibroblasts. In contrast to elastic fibers, microfibrils GAGs are highly negatively charged because of the sul-
elastic fiber to be stretched and then to recoil to its origi- are not found in the lamellae. O nl y the amorphous elastin fate and carboxyl groups located on many of th e suga rs,
nal state. Elastin also contains desm osine and isodesmo- component is seen in electron micrographs. hence their propensity for staining with basic d yes. The
sine, two large amino acids that are responsible for the co- high density of negative charges also attracts water, form-
valent bonding of the elastin molecules to one another Elastin is synthesized by the same pathway as collagen ing a hydrated gel. The gel-like co~he grou nd
(Fig. 5.11). With the TEM, elastin appears as an amor- substance permits rap ia diffuS.On of water-soluble mo le-
pho us structure of low electron density. In contrast, the fi- As noted, elastic fibers are produced by fib roblasts. t ules15ut inmDifs movement of ~~e--nlolecuiesaiicrbacte
brillin microfibrils are electron dense and are read il y ap- Elastin synthesis parallels collagen production; in fac t, both fia,_ln - adoltion-;-proteogi~~ntaiflbin"dffig sites for
parent even within the elastin matrix (Fig. 5.12). In mature processes can occur simultaneo usly in a cell. The orderly ma ny growth factor s, such as transforming growth factor
fibers, the fibrillin microfibrils are located within the elas- modification and assembly of procollagen and proelastin, as {3 (TGF-{3). The binding of growth facto rs to proteoglyca ns
tic fiber and at its periphery. The presence of microfibrils well as the synthesis of other connective tissue components, may cause either their local aggrega tion or dispersion,
with in the fiber is associated with th e growth process; thus, a re controlled by signal peptides that are built into the be- w hich in turn either inh ibits or enhances the movement of
as the fiber is formed and thickens, the microfibrils become ginning of the polypeptide cha ins of each of the molecules. migrating macromo lecules, microorganisms, or metastatic
entrapped within the newly deposited elastin. Signal peptides can be compared to the airline tags o n cancer cells in the extracellula r environment.
In M arfa n's syndrome, a complex, autosomal dominant, luggage. Just as the tags ensure that baggage moves cor- Based o n differences in specific suga r r esidues, the na-
connective tissue disordet~ expression of the fibrilli n gene rectly from one aircraft to a nother at airpo rts, so signal ture of their linkages, and th e degree of sulfatio n, a fami ly
(FBN1) is abnorma l. Inmmnofluorescence of a skin biopsy peptides ensure that the components of procollagen and of seven distinct GAGs is recognized. They are listed and
specimen from a person with Madan's syndrome will show proelastin remain separate and properl y identified as they partially characteri zed in Ta ble 5.4. Several of these pro-
an absence of elastin-associated fib rillin microfibrils. One of pass throug h the organelles of the cell. During this transit, teoglycans are mod ified by connective tissue cells after
the consequences of the disease is abnormal elastic tissue. a series of synthetic events and posttr anslatio nal modifica- their sy nthesis. For examp le, heparin is formed by enzy-
tions occur before the polypeptides ultimately arrive at matic cleavage of heparan sulfate; dermatan sulfate is sim-
their proper destination. ilarly modified from chondroitin sulfate.
The GAG ,hya~{c ac~(HA) deserves special note be-
cause it differs .b:Qt:l1 t1e ot er GAGs in sever al respects. It
elastin 'I GROUND SUBSTANCE is an exceedingl.:y.J.Qpg, rigid molecule composed of a car-
molecules bohydrate cha in of thousands of sugar s, ra ther than th e
Ground substance occupies the space between the cells several hundred or fewer sugars found in other GAGs.
a and fibers Also, HA is !_1-~_QQIJ!lilto_~l:llUl_Q9-
teoglyc"!!b By means of special !:EJk_proteins,_ha_wever;-pro-
Ground substance is a viscous, clea r substance w ith a t~glycans iEJdirectly bin~o H~ forming'gianr macromol-
slipper y feel~igh wa~t and has li ttle m or- ecules, as in the gro und substance of cartilage (Fig. 5.13 ).
pho logic structure. In the lig ht microscope, ground sub- The swelling pressure, or turgor, that occurs in these giant
relaxed stance appears amorpho us in sections of tissue preserved h ydro philic m acromol ecules accounts for the ability of car-
FIGURE 5.12
Electron micrograph of an elastic fiber. The elastin (E) of the fiber has
by freeze dry ing or in frozen sections stained with basic
dyes or by the PAS m ethod. In ro utine H &E preparations,
g ro und substa nce is a lways lost because of its extraction
------
tilage to resist compression withou t inhibiting flexi bili ty.
cytes. Monocytes m i ra te from the bloodstream into the kidney-shaped nucleus. Lysosomes a're abundant in the cy-
~ uve n ssue, "where t ey 1 ~ o- toplasm and can be revealed by staining for acid phos-
~es. ~ phatase activity (both in the light microscope and with the
In tlie light microscope and with conventional stains, tis- TEM); a positive reaction is a further aid in identificatio n
sue macrophages are difficult to identify unless they dis- of the macrophage. With the TEM, the surface of the
play obvious evidence of phagocytotic activity, i.e., visible macrophage exhi bits numerous folds and finger-like pro-
ingested material within their cytoplas m. Another feature jections (Fig. 5.1 7a). The surface folds eng ulf the sub-
that assists in identifying macrophages is an indented or stances to be phagocytosed.
The macrophage contains a large Golgi apparatus, rER and A ltho ugh the m a in functio n of t he macrophage is p hago- ca lly because they contain heparin, 'a highl y su lfate d pro-
sER. mitochondria, secretory vesicles, and lysosomes cytosis, either as a defen se activ ity (e.g., phagocytosis of teoglycan (Fig. 5.19).
bacteria) or as a cleanup operat ion (e.g., p hagocyto sis of cell
The lysosomes of the macr o phage, along w ith the s ur- debris), it also plays an im portant r o le in immune resp onse Several vasoactive and immunoreactive substances are
face cyt oplasmic p r ojections, are t h e structu res m ost in- reactio ns. Macrophages have specific proteins on their sm - contained in mast cell granules
d ica ti ve of the specia li zed phagocytotic capability of t he face known as major histocompatibility complex II (MHC
cell (Fig. 5.17b ). The m acr oph age m ay a lso con tain en- II) molecules that allow them to interact w ith helper CD4+ .Mast cells release t heir gra n ules ro riately
docytotic ves icles, p hago lysosom es, a nd other eviden ce T lymphocytes. When macrophages engulf a foreign cell, 1)!i~ 1 an mdividua IS ex p ose .~en
o f p h agocytos is (i.e., r es id ua l bodies). T he rER an d a ntigen s- short po lypeptides, 7 to 10 amino acids lo ng, to w hich he or sh e has a lrea d y been sens itized. Sensitiza-
G_Q~i appara tus support the synt~p rote in s in~ from the fo reign cell- ar e displayed on the s urface o f MHC t ion develops after t he initia l encounter w ith a n a ntigen.
l(o~d'_in th~~d d igestive . fu n ctio ns, as II molec ules. If a CD4 + T lymphocyte recognizes the dis- During t his first enco u n te r, the immune system r ecognizes
we llasii1tlie cell 's secr et o r y f unct iO ns . I he s~ry played antigen, it becomes activa ted, triggering an immune the a ntigen as "nonse lf." Im m une syst em cells that express
prodi:ietslnve-rl1e"Cet1 by both the co nstit u t ive and r eg- respo nse (see C hapter 13). Because m acrophages " p resent" antibod y m o lecules o n their surface sp ecific for t he antigen
ulated exocytoftc p a tnways. R egula te d secretion ca n be antigen to helper CD4 + T lym p hocytes, they are ca lled anti- (cognate antibodies) pro lifera te an d d ifferen tiate into sp e-
activa te d- by p hagocytOSis, immu n e com p lexes, comple- gen-presenting cells (APCs). c ia lized a n tibody-secreting cells, p lasm a ce lls. T hese cells
ment, and signals fr om ly mphocytes (including t he r e- W h en m acrophages encou nter large fore ig n bodjes, they then produce antibodies aga inst t he antigen . Sever a l major
lease of lymphok ines, biologically active molecules that m ay fuse to for m a la rge cell w ith up to 1 00 nuclei that en- classes of a nti bod ies, ca lled immunoglobulins, ar e pro-
influence the acti vity of other cells). The secr e to r y prod- g u lfs the foreign body. These m ul tin ucleated cells a re d uced . Immunoglobul ins of the IgE class a re released by
ucts released by t he macropha ge include a wi de variety ca lled foreign body giant cells (La nghans cells). the p lasma cells and bind to Fe receptors loca ted o n th e
o f subst a nces related to th e immu ne response, a na ph y- plasma mem b rane of t he m ast cells. O n su bseq uent expo-
laxis, and infl am m ation. The release of n eutra l proteases
Mast Cells and Basophils sure to t he same ant igen, an a n tigen-antibody react ion oc-
an d GAGases (en zymes th a t b reak d own GAGs) facili -
curs at the mast cell su1face tha t causes the d isch arge of
tates th e m igratio n of the m acr oph ages t h rough the con - Mast cells ar e large, ovoid, con nect ive tissue cells (20 to m ast cell granu les.
nective t iss ue. 3 0 14m in dia m eter) w ith a spherica l n ucleus and cyt oplasm
The secretions of mast cell granules can result in immediate
FIGURE 5.18 hypersensitivity reactions, allergy, and anaphylaxis
Electron micrograph of a mast cell. The cytoplasm is virtually filled
BOX 5.2
with gra nules. Note a small lymphocyte present in the upper left of Several pr imar y s u bstances foun d ins ide m ast cell gran-
the figure. x 6,0 00. ules ar e
H istamine and slow-reacting substance of anaphylaxis
The cells that are included in the mononuclear phagocytotic sys- The main fu nctions of MPS cells a re phagocytosis, secretion (lym- (SRS-A), which increase the permeability of s m a ll blood
tem (MPS) are derived from monocytes and denote a population phokines), antigen processing, and a ntigen presentation to other filled w it h large, inten sely basophilic gran ules (Fig. 5 .18 ). vessels, ca using edema in the surround ing tissue.h1 add i-
of antigen-presenting cells Involved in the processing of foreign cells of the immune system. Some functionally important phago- The mast cell is related to, bu t not identica l w ith, the ba- tion, both substa nces increase mucus prod uctio n in the
substances. These cells are able to phagocytose avidly vital dyes cytotic cells are not derived from monocytes. For example, mi- sophi l, a blood cell th at con ta ins simil a r g ran u les (Ta ble bronchia l t ree and trigger contr action of smooth muscles
such as trypan blue and India ink, which makes them visible a nd croglia are small, stellate cells located pri marily along capillaries of
5 .6). The cell s urface ex h j bits n umero us m icrovi lli an d in the p ul mona r y air ways, causing bronch ospasm .
easy to identify in the light microscope. The common origin of the centra l nervous system, which fu nction as phagocytotic cells.
fol d s. The cytoplasm d isplays small amou n ts of rER , m i- Eosinophil chemotactic factor (ECF) and neutrophil
MPS cells from monocytes serves as the major distinguish ing fea- They are generally thought to arise from the mesectoderm of the
toch ond ria, a n d a Golgi apparatus. chemotactic factor (NCF), w hich attract eosinoph ils an d
ture of the system as it is currently perceived and is the basis for neural crest and not from monocytes; nevertheless, they are in-
the system's name. In addition, cells of the MPS display receptors cluded in the MPS. Similarly, fibroblasts of the subepithelial sheath Mast cells a re not easi ly identified in hu m an tiss ue sec~ neutrophils to the site of in fla m mat ion. The secr etions of
for complement and F, fragments of immu noglobulins. The vari- of the lamina propria of the intestine and uterine endometrium tions unl ess specia l fixatives are used to p reserve the eosinophi ls co unteract the effects of the h istam in e and
ous cells of the MPS are listed in Table 5.5. have been shown to differentiate into cells with morphologic, en- gra nules . After g lutara ldeh yde fixation, mast ce ll gra n - SR:S-A.
Most cells of the MPS become fixed in specific tissues and may zymatic, and functiona l characteristics of connective tissue ules can be dis played w it h basic dyes, s uc h as to lu id ine Heparin, a s ul fated g lycosa minoglycan, w hic h is an an -
adopt a va riety of morphologic appeara nces as they differentiate. macrophages. blue. It s ta ins t he gra nules inte nsely a nd metachroma ti- ticoagu lant. W hen it u nites w ith a ntithro mbin III, it can
Name of Cell Location TABLE 5.6. Comparison of Features Characteristic of Mast Cells and Basophils
Like that of mast cells, the ba sophil cell membrane ex- the tu nica adventitia of venules and small veins are the
hibits specific receptors for the Fe fragment of IgE im- primary source of new cells in heali ng wounds. In ad di-
mu noglobulin, which is produced in r esponse to aller- tion, fibroblasts, pericytes, and endothelial cells in portions
gens. In a llergi c reactio ns, IgE immunoglobulins beco me of the connective tissue adjacent to the wound divide and
bound to the s urface Fe receptor of the basophil. T his give rise to additiona l cells that form new connective tissue
binding triggers the rapid exocytosis of the basophil se- and blood vessels.
cretory granules. T he release of histamine, hepa ran sul-
fa te, ECF, NCF, and peroxidase contained in the granu les
enhances the vascular response in derma l hypersensitivity Lymphocytes, Plasma Cells, and Other Cells
reaction s, such as those that follow insect bites and of the Immune System
stings. In highly sensiti ve indiv iduals, the anti gen injected
by an insect can trigger a massive di scharge of basophil
lymphocytes ar e principally involved in immune responses
granules. This often-explosive, life- threatening reaction,
known as anaphylactic shock, is characterized by a de-
creased volum e of ci rculating blood (leaky vessels) and Connecti ve tiss ue lymphocytes are the smallest of the
constriction of smooth muscle cells in blood vessels and free cells in the connective tiss ue (see Fig. 5.18). They have
in the bronchial tree. The individua l has difficulty brea th- a thin rim of cytoplasm surrounding a deep ly staining, het-
FIGURE 5.19 erochromatic nucleus. Often, the cytoplasm of connective
Photomicrograph of a mast cell stained with H8E. The granules
ing and may exhibit a ras h as well as na usea and vomit-
ing. Symptoms of anaphylactic shock usually develop tissue lymp hocytes may not be visible. Normally, small
stain intensely and, because of their numbers, tend to appear as a
within 1 to 3 minutes, and they require immediate treat- numbers of lymphocytes are fou nd in the connective tissue
solid mass In some areas. The nucleus of the cell is represented by
ment w ith vasoconstrictors such as epinephrine. throughout the body. The number increases dramatically,
the pale-staining area. x 1,250.
however, at sites of tiss ue inflammatio n caused by patho-
Adipose Cells genic agents. Lymphocytes are most n umerous in the lam-
lila- propria of the respira tory and gastrointestinal tracts,
block numero us coagulation fac tors. Based on its anti- where they are involved in immunosurveilla nce against
coagu lant pr operries;11ij)aiTrl is useful ~treatm~nt _gf The adipose cell is a connective tissue cell specialized to store
pathogens and foreign su bstances that enter the body by
neutral fat
thrombosis.
--. .------ crossing the epithelial lining of these systems.
ln ad dition, several secondary media to rs, namely, Adipose cells differ entiate from undifferentiated m es-
leukotrienes a nd prostaglandin D, are r eleased durin g enchyma l cells and grad ua ll y accum ulate~yto FIGURE 5.20 lymphocytes are a heterogeneous population of at least three
mast cell activation. These mediators are no t stored in p_la.s.m.. They are located thro ugho ut lo~ connective tissue Electron micrograph of a small blood vessel. The nucleus at the up-
functional cell types: T cells, B cells, and NK cells
gr an ules but are synthesized by the cell and released im- as individua l cells and gr o ups of cells. W hen they accumu- per left belongs to the endothelial cell that forms the wall of tile ves-
mediately into the extracellular matrix. late in large numbers, they are ca lled adipose tiss ue. Th is sel. At the right is anotller ceil, a pericyte, that is in intimate relation At the molecular level, lym phocytes are characterized by
specialized connective tissue is discussed in Chapter 6. to the endotllelium. Note that the basal lamina (BL) covering the en- the express ion of specific molecules on the plasma mem-
Mast cells are especially numerous in connective tissues of skin dothelial ceil divides (arrows) to surround the pericyte. Xll.OOO. brane known as cluster of differentiation (CD) proteins.
and mucous membranes but are not present in the brain and Undifferentiated Mesenchymal Cells CD proteins recogn ize specific ligands on target cells. Be-
spinal cord ca use some CD proteins are present o nl y o n specific types
and Pericytes
of lymphocytes, they are considered speci.fic marker pro-
Many research ers have postulated the ex istence of cells in TEM studies have shown that pericytes surrou nding the
Mast cells are distributed chiefl y in the vicinity o f small teins. O n the basis of these specific m arkers, lymphocytes
loose connecti ve tiss ue of the adult that retain the multiple smallest venules have cytoplasmic cha racteristics almost
blood vessels, a ta rget of histamine and SRS-A. Mast cells can be class ified into three functional cell types:
identica l with those of the endothelial cells of the same ves-
are also present in the ca psules of orga ns a nd the connec- po tentials of embryonic mesenchyma l cells. These cells,
called undifferentiated mesenchymal cells, a re th o ught to sel. Pericytes associated with larger venu les have charac-
tive tissue that surrounds the blood vessels of organs. A T lymphocytes are characterized by the presence of the
give rise to differentiated cells that function in repair and teristics of smooth muscle cells of the tunica media of small
notable exception is the central nervous system . Although CD2, CDJ, an d CD7 marker proteins and the T cell re-
veins. In fortuitous secti ons cut para llel to the lo ng axis of
th e m eni nges (s heets of connecti ve tissue that surrou nd the fo rmation of new tiss ue, as in wou nd healing, and devel- ceptors (TCRs). T hese cells have a long life span and are
opment of new blood vessels (neovascularization). venules, the distal portions and proxima l portio ns of the
brain and spinal cord ) conta in mast cells, the connective effectors in cell-mediated immunity.
same pericyte ha ve characteristics of endothelia l cells and
tissue around the sma ll blood vessels within the brain and B lymphocytes are characterized by the presence of
smooth muscle cells, respectively. These studies sugges t
spina l cord is devoid of mast cells. The absence of rnast The pericyte may serve as one type of undifferentiated CD9, CD19, CD20, and CD24 proteins and a ttached
that during the development of new vessels, cells w ith
cells protects the brain and spinal cord fro m the potentially mesenchymal cell immunoglobulins IgM and IgD. These cells recogn ize
character istics of per icytes may differentiate into the
disrupti ng effects of the edema character istic of a llergic re- antigen, have a varia ble li fe span, and are effectors in
smooth muscle of the vessel wall.
~ns_:.. Mast cells are afSon~rl're-ttiymtls and, Pericytes, also ca lled adventitial cells o r perivascular antibody-mediated (humoral) immunity.
to alesser degree, in other lymphatic orga ns, but they are cells, are fo und around capillaries and venules (Fig. 5 .20). Natural killer (NK) lymphocytes are no n-T, non-B lym-
T hey a re surro unded by basal lamina material that is con- The fibroblasts and blood vessels within healing wounds p hocytes that express the CD16, CD56, and CD94 pro-
not present in the spleen.
tinuous with the basal lamina of the capi llary endothelium; develop from undifferentiated mesenchymal cells associated teins, no t fou nd on other lymphocytes. These cells do
thus, they are not truly located in the connecti ve tissue w ith the tunica adventitia of venules not produce immunoglobulins, nor do they express T CR
In certain immune reactions, basophils leave the circulation
and function in the connective tissue co mpartment. The pericyte is typically wrapped, at least on their surface. T hus, NK lymphocytes ar e not antigen
partially, aro und the capill ar y, and its nucleus takes o n a Autoradiographic studies of wound hea ling using para- specific. Simil ar in action to T lymphocytes, however,
Basophils are a lso characterized by the presence of in- shape simila r to that of endothelia l cells, i.e., fl attened but biotic (crossed-circulation ) pairs of anima ls have estab- th ey destroy virus-infected cells and some tumor cells by
tense ly basophilic secr etory gr anules in the cytoplasm. curved to confo rm to the tu bular shape of the vessel. lished that undiffer entiated mesenchymal cells located in a cytotoxic mechan ism.
148 CHAPTER 5 Couuecli11e Tissue
Figure 1, mammary gland, human, H&E x 160. its numerous thi ck fibers, is in contrast to the loose con-
tf
Figure 3, vagina, human, H&E x 250. the myriad nuclear profi les. T he area immed iately to the
T hi s exampl e of loose connecti ve tissue is fro m the wall right of the upper marked blood vessel (BV) is s hown at
of the vagina jus t be low the epithe lia l s urface. Aga in, note hig h magni ficatio n in Figure 4.
Figure 4, vagina, human, H&E x 480. matin pattern, and typically elongated nucleus make those
nuclei wi thout visible surro unding cytoplasm belong to lym- cleoli, typical of active fibroblasts. Usuall y, the thi n cytoplas- . . . .-?
.,
t
phocytes (L). Some of the round nuclei exh ibit a surro unding mic processes of the fi broblasts are obscured by blending in
but eccentti c mass of cytoplasm. T hese are plasma cells (PC). with the collagen. Some of the nuclei seen here may represent , I
The cytoplasm of some cells is obscured pattially by the nu-
cleus, making identity less certain (?). T he size, density, chro-
macrophages or mast cells, but these cells cannot be defini-
tively identi fied. ,
KEY
AT, adipose tissue E p, epithelium LCT, loose connective tissue
BV, blood vessel F, fibrob last nucleus PC, plasma cell ,
DCT, dense connective tissue L, lymphocyte anow, elongate nucleus
- .., 4
150
CHAPTER 5 Connective Tissue I 53
Figure 1, tendon, longitudinal section, human, merge with a neighboring fascicle. This is due to an
Ea H&E x 100.
T his spec imen incl udes the surroundi ng dense irregular
c onnective tissue of the tendon, the epitendi neum (Ept).
T he tendon fascic les (TF) that make up the te ndo n are sur-
obliqueness in the plane of section rather than an actual
mergi ng of fascicles. The collagen that makes up the bulk
of the tendon fascicle has a homoge neous a ppearance as a
result of the o rderly packi ng of the individual collagen fi -
rounded by a less dense connecti ve tissue than that associ- brils. The nucle i of the tendon cells appear as elongate pro-
ated with the epitendineum. In longi tudinal sections s uch as
this, the connective tiss ue that surro unds the individual fas-
fi les arranged in lineru rows. T he cytoplasm of these cells
blends in with the coll agen, leav ing o nly the nuclei as the
- -
cicles, the e ndotend ineum (Ent), seems to disappear at cer- representative feature of the cell.
tain poi nts, w ith the result that one fascicle appears to {. Epf
8
.. .,... #
Figure 2, tendon, longitudinal section, human, guish able fiom the collagen, as is typical in H&E paraffi n 4
I
Ea H&E x400.
Th is hig her magni fication micrograph shows the or-
de red single-file array of the tendon cell nuclei (TC) along
specimens. The variatio n in nuclear appeara nce is due to
the plane of section and the pos ition of the nucle i within the
thickness of the section. A small blood vessel (BV) cours- .. ... .
with the intervening coll agen. The latter has a homoge-
neous appearance. T he cytoplasm of the cells is indistin-
ing within the endotend ineum is a lso present in the speci-
men.
.. ... .
\ .
Figure 3, tendon, cross section, human, H&E form pattern in the lon gitudina l plane. T his is explained by
\ )
Ea
1
x 400. exami ni ng the dashed line in Fig ure 2, which is meant to
T his specime n is well preserved, and the de nsely packed represent an arbitrary cross-sectiona l cut of the tendo n. .
.
collagenous fibers appear as a ho mogeneous fi eld , even
though the fi bers are viewed on their cut e nds. The nuclei
Note the irregular spacing of the nuclei that are in d1e plane , r .-. .
... ..
of the cut. Lastl y, several small blood vessels (BV) are pres-
appear irreg ulruJy scattered, as opposed to their mo re uni- ent within the endotendine um (E11t) withi n a fascicle.
,
.;
, .. .
-- '...
, r
I
~
, . ; .
KEY .
..
BV, blood vessel
Ent, endotendineum
Ept, epitendineum
152
TC, tendon cell nuclei
TF, fascicle of tendon
dashed line, arbitrary cross-sectional cut of
tendon
' .., Ent
. . 3
-
CHAPTER 5 (Ollllecliur Tissue 1 55
Figure 3, artery, monkey, Weigert's x 80. spaces between elastic layers contai n collagen fibers and
KEY
BV, blood vessel 0, duct of sweat g land E, elastic fibers
C, collagen fibers
154
6 different parts of the body account, in p art, for the differ-
ences in body conto ur between females and males. In both
sexes, the breast is a preferential site for accumu lation o f
a dipose tissue; the n o nlactating female breast is composed
prima rily of this tiss ue.
/~
~mesenchymal cell
~ ~
Adipose Tissue Intemally, adipose tissue is preferentially located in the
great er omentum, mesentery, a nd re troperiton eal space
a nd is usu a lly ab undant around the kidneys. lt is also
fo und in bone marrow and between other tissues, w here it
fills in spaces . In the p a lms of the hands and the soles of
the feet, beneath the viscera l peri ca rd iu m (around the out-
OVERVIEW OF ADIPOSE TISSUE 156 side of the heart ), and in the orbits around the eyeballs,
WHITE ADIPOSE TISSUE 156 a dipose tissue functions as a cushion. It re tains this struc-
tura l function even during reduced caloric intake; w hen
Function of Wl1ite Adipose Tissue 156
Histogenesis of Fat Cells 157 a dipose tissue elsewhere becomes depleted of lipid, this t midstage
~ lipoblast
Structure of Adipocytes and Adipose Tissue 158 structural adipose tissue remains undiminished.
brown
~
Regulation of Adipose Tissue 158 a dipocytes
White adipose tissue produces the hormone leptin
BROWN ADIPOSE TISSUE 160
BOX
BOX 4.1. Clinical Correlations: Adipose Tissue Tumors 162
Adipose tissue is exclusively respon sible for the synthesis
a nd secretion of leptin {Gr. leptos, thin}, a 16-kDa p eptide hor-
mone in volved in the regulatio n of energy homeostasis.
V.e
l llpobla~
Generally accepted biologic effects of leptin ar e inhibition of
food intake, loss of body weight, and stimulation of the
metabolic rate. T hus, leptin fulfills the criteria for a circu-
lating satiety factor that controls food intake w hen the
body's store o f energy is sufficient. Leptin most likely p ar-
ticipates in an endocrine signa ling p athway that communi-
ca tes the energy sta te of a dip ose tissue to centers th at regu- mature lipoblast
The two types of ad ipose tissue, white adipose tissue
9 OVERVIEW OF ADIPOSE TISSUE
and brown adipose tissue, are so named because o f their
late energy uptak e. It acts on the central nervous system by (white adipocyte}
binding to specific receptors, m ainly in the hypothala mus. In FIGURE 6.1
color in the living sta te.
Adipose tissue is a specialized connective tissue consisting of addition, leptin communicates the fuel state of adipocytes Diagram of the development of adipose tissue cells. Like all con-
fat-storing cells (adipocytes) associated with a rich blood supply from fat storage sites to other m eta bo lically active tissues nective tissue cells, adipocytes are derived from mesenchymal cells (ei-
White a dipose t iss ue is the pred ominant type in adult ther mesodermally derived mesenchyme or ectomesenchyme derived
(i.e., fro m adipose tissue to muscle at a different sit e} .
humans. from the neural crest). Mesenchymal cells give rise to fibroblasts and
Indi vidua l fat-storing cells, or adipocytes, and groups of
Brown adipose tiss ue is present in humans during fetal fibroblast-li ke cells that are committed to becoming lipoblasts
a dip ocytes are fo und throu ghout loose connective tiss ue.
Tissues in w hich a dipocytes are the primary cell type are
life but diminishes dur ing the first d ecade after bir th. Histogenesis of Fat Cells (preadipocytes). Lipoblasts develop an external (basal) lamina and be-
gin to accumulate numerous lipid droplets in their cytoplasm. In white
designated adipose tissue. Adipocytes functi on as fat- Early histologists debated w heth er adipose tiss ue was a adipose tissue, these droplets fuse to form a single large lipid droplet
sto rage conta iners. The bod y has a limited capacity to
store carbohydra te and protein; th erefore, the fat con -
9 WHITE ADIPOSE TISSUE specific tissue, distinct from conn ective ti ss ue, or w hether
it was ordina ry connective tissue in which fib roblast s
that ultimately fills the mature cell, compressing the nucleus, cyto-
plasm, and cytoplasmic organelles into a thin rim around the droplet.
taine d w ithin adipocytes represents the storage of excess stored fat glo bules . The c urrent con sensus is that In brown adipose tissue, the individual lipid droplets remain separate.
Function of White Adipose Tissue
nutritional calories that are not immedia tely used in m e- adipocytes ar e a specific cell type and th at they are d erived (Modified from Henrikson RC, Kaye Gl, Mazurkiewicz JE. NMS Histology.
tabolism or other activity. Fat is an e fficient fo rm o f calo- Functions of white adipose tissue include energy storage, fro m undifferentia ted mesenchymal cells associated with Baltimore: Williams & Wilkins, 1997.)
rie storage because it h as a bo ut tw ice the calorie d ensity o f insulation, and cushioning of vital organs the adventitia of sma ll venu les (Fig. 6 .1 ). Therefo re,
carb oh ydra te a nd p rotein. The m etabolism of fat can a lso a dipocytes origina te from the same stem ce ll popu lation as
be an essentia l source of water and energy for the bod y in Unilocul a r adipose tissue forms a layer called th e pan- fibroblasts a nd myofibroblasts in hea ling w ounds. Even White adipose tissue begins to form midway through fetal
the even t of food deprivation. For example, the hump of a niculus adiposus or hypodermis in the connective tiss ue w ith the traasmission electron mi croscope (TEM), it is still development
ca mel consists large ly of fa t a nd is a source of both energy under the skin. This subcutaneous layer of connective tis- nea rl y impossible to d istingui sh early lipoblasts or
and wa ter for this d ese.rt a nim a l. sue has a significa nt insulating function. Concentrations o f preadipocytes from fibro blasts. Thus, many in ves tiga t or s The lipoblasts tha t initia lly develop along the small blood
a dipose tiss ue are found in the connective tiss ue under the describe the early lipoblast as a cell that is committed to vessels in the fet us are free of fat. Nevertheless, these cells are
There are two types of adipose tissue: white (unilocular) and skin of the abdomen, buttocks, axi lla, and t hi gh. Sex di f- differ entia t e into an adipocyt e but is m orphologicall y in- committed to becoming fa t cells a t this early stage; collec-
brown (multilocular) ferences in the thickness of this fatty layer in the skin of distinguish able fro m a fibro blast. tions of such cells are sometimes called primitive fat organs.
156 157
I 58 CHAPTER 6 ArliJ>o se Tissue CHAPTER 6 Adipose Tissue I 59
They are characterized by proliferating early lipoblasts and meshwork that separates adjacent adipocytes represents
proliferating capillaries. Lipid accumulation in lipoblasts the cytoplasm of both cells and the extracell ular matrix.
produces the typical morphology of the adipocytes. The strand is usually so thin, howeveJ; that it is not possi-
ble to resolve its component parts in the light microscope.
Early lipoblasts look like fibroblasts but develop small lipid Adipose tissue is richly supplied with blood vessels, and capillary
inclusions and a thin external lamina capi llaries are found at the angles of the meshwork where ~
adjacent adipocytes meet. Silver stains show that
TEM studies reveal that ea rl y lipoblasts have an elon- adipocytes are surrounded by reticular fibers (type III col-
gated configuration, multiple cytoplasmic processes, and
abundant endoplasmic reticulum and Golgi membranes.
lagen), which are secreted by the adipocytes. Special stains
also reveal the presence of unmyelinated nerve fibers and
\
As lipoblastic differentiation begins, smooth-surfaced vesi- numerous mast cells.
cles increase in numbe1~ with a corresponding decrease in nucleus
rough endoplasmic reticulum (rER) . Small lipid inclusions The lipid mass in the adipocyte is not membrane bounded
appear at one pole of the cytoplasm. P inocytotic vesicles
and an external lamina also appear. Transmission electron microscopy reveals that the inter-
face between the contained lipid and surrounding cyto-
Midstage lipoblasts become ovoid as lipid accumulation plasm of the adipocyte is composed of a 5-nm-thick con-
changes the cell dimensions densed layer of lipid reinforced by parallel vimentin
filaments measuring 5 to 10 nm in diameter. This layer sep-
With further development, the cells assume an oval con- arates the hydrophobic contents of the lipid droplet from
figuration. The most characteristic feature at this stage is the hydrophilic cytoplasmic matrix.
the extensive concentration of smooth vesicles and small The perinuclear cytoplasm of the adipocyte contains a
lipid droplets around the nucleus and extending toward small Golgi apparatus, free ribosomes, short profiles of
both pole.s of the cell. Glycogen particles appear at the pe- rER, microfilaments, and intermediate filaments. Filamen-
riphery of the lipid droplets, and pinocytotic vesicles and tous mitochondria and multiple profiles of sER are also
basal lamina become more apparent. These cells are desig- found in the thin rim of cytoplasm surrounding the lipid
nated midstage lipoblasts. droplet (Fig. 6.3).
b
The mature adipocyte is characterized by a single, large lipid
inclusion surrounded by a thin rim of cytoplasm Regulation of Adipose Tissue FIGURE6.2
White adipose tissue. a. Photom icrograph of white adipose t issue, cells is recognizable in some areas, and part of the nucleus of one of
In the late stage of differentiation, the cells increase in showing its characteristic meshwork in a H&E-stained paraffin prepa- the cells is included in the plane of section. A second nucleus (arrow),
The amount of adipose tissue in an individual is determined by
ration. Each space represents a single large drop of lipid before its which appears intimately related to one of the adipose cells, may ac-
size and become more spherical. Small lipid droplets coa- expression of the leptin (ob) gene
dissolution from the cell during tissue preparation. The surrounding tually belong to a fibroblast; it is difficult to tell w ith assurance. Be-
lesce to form large lipid vacuoles that occupy the central
eosin-stained material represents the cytoplasm of the adjoining cells cause of the large size of adipose cells, the nucleus is infrequently ob-
portion of the cytoplasm. Smooth endoplasmic reticulum The recent discovery of the leptin (ob) gene, which en- and some intervening connective tissue. X 320. b. High-power pho- served in a given cell. A capillary and a sma ll venule are also evident
(sER) is abundant, whereas rER is less prominent. These codes a fat-specific mRNA and leptin, has given some in- tomicrograph of a glutaraldehyde-preserved, plastic-embedded spec- in the photomicrograph. x 950.
cells are designated late lipoblasts. Eventually, the lipid sight into the mechanism of energy homeostasis. Hw11an imen of white adipose tissue. Tile cytoplasm of the individual adipose
mass compresses the nucleus to an eccentric position, pro- leptin gene expression occurs in mature aclipocytes and is
ducing a signet-ring appearance in hematoxylin and eosin highly regulated. Stud ies of obese individuals show that
(H&E) preparations. These cells are designated adipocytes levels of leptin mRNA in adipose tissue as well as serum
or mature lipocytes. levels of leptin are elevated in all types of obesity, regard- Deposition and mobilization of lipid are influenced by neural in a denervated fat pad continue to deposit fat. Adipose
less of whether it is caused by genetic factors, hypothala- and hormonal factors cells in the intact contra lateral fat pad mobilize fa t. It is
Structure of Adipocytes and Adipose Tissue mic lesions, or increased efficiency of food uti lization . now known that norepinephrine (which is liberated by the
Studies of individuals who have lost weight and those with One of the major metabolic functions of adipose tissue in- endings of nerve cells of the sympathetic nervous system)
Unilocular adipocytes are large cells, sometimes 100 (Lm or anorexia 1tervosa show that leptin mRNA levels in their volves the uptake of fatty acids from the blood and their initiates a series of metabolic steps that lead to the activa-
more in diameter ad ipose tissue and serum levels of leptin are significantly conversion to triglyceride within the adipocyte. Triglyceride tion of lipase. This enzyme spli ts triglycerides (neutral
reduced. In experimental anima l models, the addition of is then stored within the cell's lipid droplet. When adipose fats ), which constitute over 90% of the lipid in the fat of
When isolated, adipocytes are spherical, but they may recom binant leptin to obese, leptin-deficient oblob mice tissue is stimulated by neural or hormonal mechanisms, the adipocyte. The enzymatic activity is an early step in the
appea r polyhedral or oval when crowded together in adi- causes them to reduce their food intake and lose about triglycerides are broken down into glycerol and fatty acids, mobilization of the lipid.
pose tissue. Their large size is due to the accum ulated lipid 30% of their tota l body weight after 2 weeks of treatment. a process called mobilization. The fatty acids pass through An unusua l form of obesity is due to injury of the hypo-
in the cell. The nucleus is flattened and displaced to one Genetic obesity is most li kely related to the expression the ad ipocyte cell membrane to enter a capillary. H ere, they thalamus, the portion of the base of the brain where neu-
side of the lipid mass; the cytoplasm forms a thin rim of defective leptin (ob) or leptin receptor genes. This may are bound to the carrier protein albumin and transported to rosecretions that control pituitary function are synthe-
around the lipid. In routine histologic sections, the lipid is explain why identical twins usually have the same or close other cells, which use fatty acids as metabolic fuel. sized . Although the clinical manifestation of hypothalamic
lost through extraction by organic solvents such as xylene; to the same amount of body fat. Even when the amou nt of Neural mobilization is particularly important during pe- obesity is associated with increased food consumption, ex-
consequently, adipose tissue appears as a delicate mesh- body fa t in identical twins varies, however, the patterns of riods of fasting and exposure to severe cold. During early periments with laboratory a nimals with hypothalamic in-
work of polygonal profiles (Fig. 6.2). T he th in strand of distri.bution are a lways the same. stages of experimental starvation in rodents, adipose cells jury show that caloric intake is not the only factor leading
160 C HAPTER 6 Adipose 7i'ssue CHAPTER 6 Adipose Tissue I6I
When oxidized, it produces heat to warm the blood flow- locular adipocytes when they are stimulated by the sym-
ing through the brown fat on arousal from hibernation. pathetic nervous system.
This type of heat production is known as nonshivering
thermogenesis. Thermogenic activity of brown adipose tissue is regulated by
Brown adipose tissue is also present in nonhibernating the unique uncoupling protein found in mitochondria
animals and again serves as a source of heat. In humans,
multilocular adipose tissue is present in large amounts in The mitochondria found in the cytoplasm of brown adi-
the newborn, which helps offset the extensive heat loss pose tissue cells contain a unique uncoupling protein
that results from the newborn's high surface-to-mass ra- (UCP-1), which uncouples the oxidation of fatty acids from
tio. The amount of brown adipose tissue gradually de- the production of ATP. At the molecular level, UCP-1 facil-
creases as the body grows, but it remains widely distrib- itates proton transport across the inner mitochondrial
uted throughout the first decade of life. It then disappears membrane. The movement of protons from the inner mi-
from most sites except for regions around the kidney, ad- tochondrial compartment dissipates the mitochondrial
renal glands, aorta, and regions in the neck and medi- proton gradient, thus uncoupling respiration from ATP
astinum. As in the mobilization of lipid in white adipose synthesis . The energy produced by the mitochondria is
tissue, lipid is mobilized and heat is generated by multi- then used as heat. In experimental animals, UCP-1 activity
has been shown to increase during cold stress.
FIGURE 6.3
Electron micrograph showing portions of
two adjacent adipose cells. The cytoplasm
of the adipose cells reveals mitochondria
(M) and glycogen (the latter appears as the
very dark particles). x 15,000. Upper inset.
Attenuated cytoplasm (Cy) of two adjoining
adipose cells. Each cell is separated by a
narrow space containing external (basal)
lamina and an extremely attenuated
process of a fibroblast. x 65,000. Lower in-
set. The external (basal) lamina (BL) of the
adipose cells appears as a discrete layer
where the cells are adequately separated
from one another. F, fibroblast processes.
X3 0,000.
to obesity. Lesioned rats deposit more body fat than con- In routine H&E-stained sections, the cytoplasm of the
trol animals fed the same amounts of food. multilocular adipocyte consists largely of empty vacuoles
Hormonal mobilization involves insulin, a hormone because the lipid that ordinarily occupies the vacuolated
that inhibits the action of hormone-sensitive lipase and spaces is lost during preparation (Fig. 6.4) . Multilocular
thus blocks the release of fatty acids. It also enhances the adipocytes depleted of their lipid bear a closer resemblance
conversion of glucose into the tr.iglycerides of the lipid to epithelial cells than to connective tissue cells. The mul-
droplet by the adipocyte. In addition, other hormones tilocular adipocyte contains numerous mitochondria, a
modify various steps in the metabolism of adipose tissue, small Golgi apparatus, and only small amounts of rER and
including thyroid hormone, glucocorticoids, prosta- sER. The mitochondria contain large amounts of cy-
glandins, and hormones of the pituitary gland. tochrome oxidase, which imparts the brown color to the
cells.
Brown adipose tissue is subdivided into lobules by par-
9 BROWN ADIPOSE TISSUE titions of connective tissue, but the connective tissue
stroma between individual cells within the lobules is
Adipocytes of brown, multilocular adipose tissue contain sparse. The tissue has a rich supply of capillaries that en-
numerous fat droplets hance its color. Numerous unmyelinated nerve fibers are
present among the fat cells.
FIGURE 6.4
The cells of brown adipose tissue are smaller than those Brown adipose tissue. a. Photomicrograph of brown adipose tissue !rally located nuclei. Most of the cells are polygonal and are closely
of white adipose tissue. The nucleus of a mature multiloc- Metabolism of lipid in brown adipose tissue generates heat from a newborn in a H&E-stained paraffin preparation. The cells con- packed, with numerous lipid droplets. In some cells, large lipid
ular adipocyte is typica lly in an eccentric position within tain fat droplets of varying size. Note the large blood vessels within droplets displace nuclei toward the cell periphery. A network of col-
the cell, but it is not flattened, as is the nucleus of a uniloc- Hibernating animals have large amounts of brown adi- the tissue. x 150. b. This photomicrograph obtained at a higher mag- lagen fibers and capillaries surrounds the brown adipose cells. X320.
ular adipocyte. pose tissue. The tissue serves as a ready source of lipid. nification shows the brown adipose cells with round and often cen-
16'2 C HA PTER 6 Adi pose Tissttf
found in subcutaneous tissues in middle-aged and elderly individ- early lipoblast / '
uals. Although Figure 6.5 relates primarily to white adipose tissue
tumors, tumors of brown adipose tissue are also found. Not sur-
prisingly, these are called hibernomas.
t
midstage lipoblast
FIGURE 6.5
Adipocyte differentiation in relation to tumor cell develop-
myxoid t
liposarcoma ~- ------ late lipoblast
kature~pocyte~
ment. Diagram summarizing the relationships between differ-
entiation of normal adipose cells (midcolumn) and several types
of adipose tissue tumors {lateral columns). Each type of adipose
tissue tumor exhibits a predominant cell type that resembles
one of the stages of differentiation of normal adipose cells.
Solid-line arrows indicate the most frequently occurring cell type
in each kind of tumor. Dotted-line arrows indicate the less fre
quently occurring cell type in that tumor. (Modified from Fu YS,
well-differeotiated /
liposarcoma
t -'T
lipoma
~- lipid-depleted
et al. Patho/ Annu 1980;15(Part 1):85, with permission of the lipocyte
McGraw-Hill Companies.)
z Type II collagen constitutes the b ul k o f the fi bril; type XI
collagen regula tes tl1e fib r il size; a nd type IX collagen fa-
cilita tes fibril interacti on w ith the matri x proteoglycan
mo lecules. Type X collagen organizes the collagen fibrils
into a three-dimensional hexago na l la ttice. Because
joined to a co1e protein to form a proteoglycan
monomer (Fig. 7.1 ). Each linea r h yaluronic acid m ole-
cu le is associa ted w ith a pproximately 80 proteoglycan
mono me rs, w hic h a re bound to the hyaluro nic acid by
link pro teins to fo rm large hyaluronate proteoglycan
collagen type II
Cartilage is a n avascular tissue that consists of chondro- The ma trix o f hyaline cartilage ap pears g lassy in the li v-
cytes a nd a n extensive extracellular ma trix. PrQ._d uced a nd ing sta te, h ence the na me h ya line /Gr. hyalos, glassy].
m a i nta ined~ondrocyres, .the cartilage ma trix is solid Throughout the cartilage ma trix a re spaces call ed lacunae.
an:G-n~t also somewhat plia ble, w hich accounts for its Located w ithin these lacunae are t he chondrocytes. H ya-
res ilience. The la rge ra tio o f glycosam inoglycans to type II line ca rtilage is no t a simp le, iner t, homogeneous sub-
coll agen in the cartilage matri x ~b sta nce, but a complex li ving tissue. It provides a low fric-
sta nces between blo eJ. t urro unding connec- tion surface, participates in lu bricati on in synovia l joints,
ui? tis ue :illJd the chond oocyteS.._Jhe reby main taining the an d distribu tes ap plied fo rces tO the und erl ying bon e. Al-
viability o f the tissue. Also, the prese nce o f la rge a mounts thou gh its capacity for rep a ir is limited, unde r normal cir-
of hyaluro ni c acid in cartila e matrix ma ke ~ c umstances it shows no evide nce of abrasive wea r o ver a
~oea r weight, esp ecially a t points o movement, as in sy- lifetime. Th e macromol ecul es of hya li ne cartilage matrix
novia l jo ints.-Beca use it ma intains this pro perty even w hile co nsist of collagen (pred o mi na n tly type II fibrils), proteo -
growing, cartilage is a key tissue in most growing bon es . glyca ns, no ncollageno us proteins, a nd glycoproteins tha t
T hree diffe rent kinds of cartil age are ~n give it its mechanica l a nd bio logic properties.
the basis of characteri stics of the ma trix:
Hyaline cartilage matrix is produced by chondrocytes and
Hyaline cm'tilage, character ized by ma trix conta mmg contains three major classes of molecules
type 11 collagen fi bers, proteoglycans, a nd hya lu ronic ac id
Elastic cm'tilage, characterized by elastic fibers a nd elas- Three classes of mo lec ules are present in hya line carti-
FIGURE 7.1
tic lame llae in addition to the matr ix ma ter ia l of hya line lage ma tri x :
Molecular structure of the ground substance of hyaline cartilage. is interwoven with a network of collagen fibrils. Proteoglycan
ca rtil age This schematic diagram sl1ows the relationship of hyaluronate pro mo nomers are linked electrostatically to the collagen fibrils as well as
Fibrocm'tilage, cha racterized by a bunda nt type l colla- Collagen molecules. Collagen is the majo r ma trix pro- teoglycan aggregates to type II collagen fi brils and chondrocytes in by cross-linking glycoproteins. Chondrocytes, the principal cells of
ge n fibe rs in addition to the ma trix ma teri a l o f hya line tein . Fo ur coll agen types pa rticipa te in the forma tion o f tile ground substance of hyaline cartilage. A hyaluronic acid mole- hyaline cartilage, appear in isogenous groups.
ca rtilage relatively thin (20-nm -dia meter), short matrix fibrils. cule forming a linea r aggregate with many proteoglycan monomers
164 165
(66 CHA PTE R 7 Cnrlilnge C H APTER 7 C11rlilngr 167
Hyaline cartilage matrix is highly hydrated to permit diffusion chond rocytes produce matrix materia l, w hich surrou nd s cosaminoglycans and proteoglycans. ln older, less active ossification (Fig . 7.5). Initially, most 'long bones are repre-
of small metabolites and resilience them, they become dispersed . cells, the Golgi apparatus is smaller; clear areas of cyto- sented by cartilage models that resemble the shape of the
The cytoplasm of chondrocytes va ries in appea ra nce rela- plasm, when evident, usually indicate sites of extracted lipid adult bone. During t he developmental process when much
Like other connective tissue matrices, ca rtilage ma tri x is ti ve to their activity. Chondrocytes t hat are active in m a trix droplets a nd glycogen stores. In such specimens, chondro- of the carti lage is replaced by bo ne, the remaining cartilage
h igh ly hydrated . Sixty to eighty p ercent of t he net weigh t productio n display a reas of cytoplasmic basoph ilia, indicat- cytes a lso display considerable distortion because of shrink- ser ves as a g rowth site called the epiphyseal growth plate
of hya li ne cartilage is water. Much of this water is bound ing protein synthesis, and clea r areas, reflecting the large age after the glycogen a nd lipid are lost during the prepara- (epiphyseal disc). This cartilage remains functional as long
tightly to the hyal uronate proteoglycan aggregates, w hich Golgi apparatus (Fig . 7.3). C hondrocytes secrete not only tion of t he tissue. W ith the transm ission elect ron m icroscope as the bone grows in length (Fig. 7.6). In the adult, the car-
imparts resilience to the cartilage. Some o f the water is the collagen present in t he matrix but also a ll o f the gly- (TEM), the active cho nd rocyte displays numerous profiles tilage that remains from the developing skeleton is found on
bound loosely eno ugh, however, to a ll ow diff usion of of rough endoplasmic reticulum (rER ), a large Golgi appa- the articu lar surfaces of jo ints (articular cartilage), as seen in
sma ll m etabolites to a nd from the ch ondrocytes. ratus, secretory granules, vesicles, intermediate filaments, Figure 7 .7, and w it hin th e r ib cage (costal cartilages). H ya-
In articular ca rtilage, both transient a nd regional microtubules, and acti n microfilaments (Fig. 7.4). In old car- line cartilage is a lso present in the adult as the skeletal unit
c hanges occur in water conte nt d uring joint movement and t ilage cells, intermediate fila ments are numerous. in the trachea, b ronch i, larynx, a nd nose.
when the joint is subjected to press u re. The hig h degree of
hydration a nd the movement of wa ter in the matrix a llow Hyaline cartilage provides a model for the developing skeleton
the cartilage matrix to respond to varying pressure loads of the fetus
and contribute to cartilage's weigh t-bearing ca paci ty.
T hroughout life, cartilage und ergoes continuous internal In early fetal develo pment, hya line cartilage is the precur-
remod eling as the cells repl ace m atrix mol ecules lost sor of bones that develop by the process of endochond1al
through degradation. New evidence ind icates that normal
matrix turnover depends on the a bility of the chondrocytes
to detect cha nges in matri x composition . The chondrocyte
then responds by synthes izing appropriate types of new
molecules. In ad dit ion, the matr ix acts as a signal trans-
ducer for th e embedded chondrocytes. T h us, pressure
loads applied to the cartilage, as in synovial joints, create
mec ha nica l, electrica l, and ch emical signa ls that help direct
the synth etic activ ity of the chondrocyt e. As the body ages,
the composition of the matrix changes, and the c ho ndro-
cytes lose the ir a bi lity to respon d to these stim ul i.
A firmly attached connective tissue, the perichondrium, to that fo und around most hya line ca-r tilage. Unlike )lyaline
surrounds hyaline cartilage ca rtilage, which calcifies with aging, th e matrix o f elastic
cartiTage-does-norra leify- dunng t 1e agmg I>!:QCess.
The perichondrium is a dense connective tissue com-
posed o f cells that are indistinguisha ble from fibroblasts.
ln many respects, the perichondrium resem bles the cap- 9 FIBROCARTILAGE
sule that surro unds glands and man y organs. It a lso
serves as the so urce of new cartilage cells. When actively Fibrocartilage consists of chondrocytes and their matrix
growing, the perichondrium appears divided into an in- material i n combination within dense connective tissue
ne1' cellular layer, w hich gives rise to new ca rtil age cells,
a nd an outer fibrous layer. This division is not always ev- Fibrocartilage is a combination of d ense regular connec-
ident, es pecia ll y in perichondrium that is not ac tively pro- tive tiss ue and h yaline cartilage. The chondrocytes are dis-
persed among t he coll agen fibers, singly, in rows, and in
isogenous groups (Fig. 7.9). They are similar in appea rance
to the chondrocytes of hya line cartilage, but there is con-
siderably less matrix material associated with them, and
there is nos urro und ing perichondrium ...as in h ya line and
elastic cartilage. L1 a section containing fibrocartilage, a
pop ulation of cells w ith roun ded nuclei and a small
amount of su rroun d ing amorph o us matrix material is t yp-
ically seen. These nuclei belong to the cho ndrocytes.
Within the fibrou s areas are nuclei that are flattened or
elongated. These are fibroblast nuclei.
Fibrocartilage is typica lly present in intervertebral discs,
the symphysis pubis, a rticular discs of the sternoclavicular
a nd temporomandibular joints, menisci of the k nee joint,
FIGURE 7.7
Photomicrograph of the epiphysis of a long bone. The smooth artic-
FIGURE 7.6
ular surface is composed of hyaline cartilage and does not possess a
Photomicrograph of the proximal end of a growing long bone. A
perichondrium. The irregularly shaped boundary between the articu-
disc of hyaline cartilage-the epiphyseal plate-separates the more
lar cartilage and the underlying bone is clearly visible. x 480.
proximally located epiphysis from the funnel-shaped diaphysis lo-
cated distal to the plate. The articular cartilage on the surface of the
epiphysis contributes to the synovial joint and is also composed of
hyaline cartilage. Whereas the cartilage of the epiphyseal plate dis-
appears when lengthwise growth of the bone is completed, the ar-
9 ELASTIC CARTILAGE
ticular cartilage remains throughout life. The spaces within the bone
are occupied by marrow. x 85. Elastic cartilage is distinguished by the presence of elastin
in the cartilage matrix
neural crest cel ls. Known as a blastema of precartilage nor injuries. This lack of response to injury is due to carti- from perivascular or bone marrow stem cells. Prechondro-
(protochondral tissue), an aggregate of mesenchyma l or lage's avascularity, the immobility of the chondrocytes, clasts r esemble fibroblasts when seen with the TEM. Most
ectomesenchymal cells mar ks the site of hya line cartilage and the limited ability of m ature cho ndrocytes to prolifer- studies of cho ndroclast structure and function have been
formation. T he blastema cells begin to secrete cartilage ate. Some repair can occur, but only if the defect invo lves carried o ut o n the developing mandi ble, in which tru e en-
matrix and at this p oint are called chondroblasts. They the perichondrium. In these injuries, repair results fro m ac- d ochondral ossification d oes not take place. It is still un-
progressively move apart as they deposit matrix. When tivity of the plur ipotential progenitor cells located in the clear w hether chond roclasts are cells found w here bone is
they are completely surrou nded by matrix material, the perichondrium. Even in this case, however, few cartilage replacing cartilage or w hether they are limited to cartilages
cells are called chondrocytes. The mesenchymal tissue im- cells, if any, a re produced. Repair mostl y involves the pro- and bones that a re derived from the ectomesenchyme that
mediately surrounding the chondrogenic blastema gives duction of dense connective tissue. originates from ne ural crest cells.
rise to the perichondrium. At the molecular level, cartilage repair is a tenta ti ve bal-
ance between deposition of type I collagen in the for m of
Cartilage is capable of two kinds of growth, appositional scar tissue and repair by expression of the cartilage-speci.fic
and interstitial
collagens . However, in adu lts, new blood vessels com-
mon ly develop at the site of th e hea ling wound, w hich
W ith the onset of matrix secretion, cartilage gr owth con- stimu late the growth of bone rather tha n actua l cartilage
ti n ues by a combination of two processes: repair. The limited ability of cartilage to repair itself can
ca use significa nt problems in cardiothoracic surgery, such
A ppositional growth, the process that forms new carti- as coronary artery bypass surgery, w hen costal cartilage
lage at the surface of an existing cartilage must be cut to enter the chest cavity. A va riety of treat-
Interstitial growth, the process that for ms new cartilage ments may improve the healing of articula r cartilage, in-
within an existing cartilage cluding perichondral grafts, cell transplantation, insertion
of artificial matrices, and application of growth factors.
New cartilage cells produced during appositional
growth ar e derived from the inner portion of the sur- When hyaline cartilage calcifies, it is replaced by bone
rounding perichondrium. The cells resemble fibroblasts in
form and function, producing the collagen component of H ya line cartilage is prone to ca lcification, a process in
the perichondrium (type l collagen). When cartilage w hich ca lcium phosphate crys tals become embedded in the
growth is initiated, however, the cells undergo a change: cartilage matrix . The matrix of hya line carti lage undergoes
FIGURE 7.9
Photomicrograph of fibrocartilage from an intervertebral disc. The
the cytoplasmic processes disa ppear, the nucleus becomes calcificatio n as a regular occurrence in three well-defined
collagen fibers are stained green in this Gomorl trichrome prepara- rounded, and the cytoplasm increases in amoun t and be- situati o ns:
tion. The tissue has a fibrous appearance and contains a relatively comes more prominent. These cha nges resu lt in the cell be-
small number of fibroblasts with elongated nuclei (arrows) as well as coming a chond ro blast. Cho ndroblasts fltnction in carti- T he portio n of ar ticular cartilage that is in contact with
more numerous chondrocytes with dark round nuclei. The chondro- lage matrix production incl udi ng secretion of type II bone tissue in growing and adult bones, but not the sur-
cytes exhibit close spatial groupings and are arranged either in rows collagen. The new matrix increases the cartilage mass; at face portion, is calcified.
among the collagen fibers or in isogenous groups. x 160. Inset. High the same time, new fibroblasts are produced to mai ntain Ca lcification always occurs in carti lage that is about to
magnification of an isogenous group. Chondrocytes are contained the cell population of the perichond rium. be replaced by bone (endochondral ossifica tion) d uring
within lacunae. Typically, there is little cartilage matrix surrounding New cartilage cells produced d uring inte1stitial growth the growth period of an individual.
the chondrocytes. x 700. arise from the d ivision o f cho nd rocytes within their lacu- H yal ine cartilage in the adult calcifies with time as part
nae (see Fig. 7.2). This is possible only because the chon- of the aging process.
and certa in places where tendons attach to bones. The drocytes retain the ability to divide and the surrounding
presence of fibrocartilage in these sites indicates that re- matrix is distensible, thus permitting furt her secretory ac- ln most of these situations, give n suffic ient time, carti-
sistance to both compression and shearin g fo rces is re- tivity. Initiall y, th e daughter cells of the 'div idin g chondro- lage that calcifies will be replaced by bone. For example, in
q ui red of the tissue. T he cartilage acts much like a shock cytes occupy the same lac un a. As new matrix is secreted, a o lder indi vidu als, it is n ot uncommon to .fi nd portions of
absorber. The degree to wh ich such fo rces occur is reflected partition is for med between the da ughter cells; at this point the ca rtilage rings in the trachea rep laced by bone tissue
in the amount of cartilage matrix materia l present. each cell occupies its own lacun a. Wi th continued secre- (Fig. 7.10). Chondrocytes norma ll y derive al l of their nu-
tion of matrix, th e cells move even further apart. The over- trients and dispose of wastes by diffusion of ma teri als
all growth of ca rtilage thus results fro m both the intersti- th ro ugh the m atrix . W hen the matrix becomes heavi ly cal-
9 HISTOGENESIS, GROWTH, AND tial secretion of new matrix material by chondrocytes and cified, diffus ion is impeded and th e chond rocytes swell and
REPAIR OF HYALINE CARTILAGE the appositional secretion of matrix material by newly d if- die. The ultimate consequence of this event is removal of
FIGURE 7.10
fe rentiated chondro blasts. the calcified matrix and its replacement by bone.
Photomicrograph of a tracheal ring from an elderly individual,
Sollle investigators have described a cel l type, the chon-
Most cartilage arises from m esenchyme stained with HaE. The darker, somewhat basophilic areas on the left
Cartilage has limited ability for repair d1oclast, that resem bles an osteoclast (page 190) in both side of the micrograph represent normal cartilage matrix (C). The
T he process of cartilage development begins w hen mes- morpho logy and function. T his cell is thought to play a ro le lighter and more eosinophilic areas represent bone tissue (B) that has
ench yma l cells aggregate and form a mass of rounded, Cartilage can to lerate considera ble amounts of intense in the digestion of ca lcified cartilage that is to be replaced replaced the original cartilage matrix. A large marrow cavity has
closely apposed cells. In the head, most of the cartilage and r epetitive str ess. However, w hen damaged, cartilage by bone. T hese cells appea r to enter the carti lage along with formed w ithin t11e cartilage structu re and is visible in the center of the
arises from aggregates of ectomesenchyme derived from manifests a striking inab ility to heal, even in the most m i- new ly spro uting blood vessels and may, in fact, be derived micrograph. x 75.
CHAP TER 7 Cnrlilngt I73
5J
Figure 2, hyaline cartilage, human, H&E x1 60. cytes. T he capsule represents the site where the s ulfated
T he hyaline cartilage in thi s mic rograph is from a s pec-
ime n o btained shortly after death and kept cool during fi x-
glycosami noglycans are most concentrated . In co ntrast to
the basophilia of the cartilage matrix, the perichondrium
Ch ~
:.---
atio n. T he procedure red uces the loss of its negati vely (P) is stained w ith eosin. The lig htly stained regio n be-
charged s ulfate groups; thus, th e matri x is stained mo re tween the perichondrium a nd the deeply stained matrix is
heavily w ith he matoxylin. Also, note the very d istinct and matri x that has not yet matured. It has fewer sulfate g roups.
deepl y stained caps ules (a rrows) s urro und ing the cho nd ro-
_![\_
stained basophil ic area reveals imma ture cho ndrocytes (a r- nuclei are compared with the formative chondroblast nuclei
rows) within the pericho nd ri um (P). Closest to the cartilage of the in ner peric ho ndrial layer.
matrix, within the pe richo ndrium ( P), are several chondro-
KEY
Cap, capsule L, lacuna asterisk, capsule o f a lacuna, but with la-
C h, chondrocytes P, pericho ndrium cuna and contai ned chondrocyte not in-
FCh, formative chondrocytes a rrows, immatu re cho ndrocytes cluded within the thickness of the section
F ib, fi bro blasts
172
CHA PTER 7 Cartilage l 75
B
Figure 2, fetal finger, human, thionine-picric acid marrow cavity constitutes the metaphysis. With this staining
x30. method, the calcified cartilage appears dark brown. The
This figure shows a developing long bone of the finger newly formed metaphyseal bone, which is admixed with
and its articulation with the di stal and proximal bones. Be- this degenerating calcified cartilage and is difficult to de fine
fore the stage shown here, each bone consisted entirely of a at this low magnification, has the same yellow-brown color
hyaline cartilaginous structure similar to the cartilages seen as the diaphyseal bone. By the continued proliferation of
in Figure 1 but shaped like the long bones into which they cartilage, the bone grows in length. Later, the cartilage be-
would develop. Here, only the ends, or epiphyses, of the comes calcified; bone is the n produced and occupies the site
bone remain as cartilage, the epiphyseal cmtil age (C). The of the resorbed cartilage. With the cessation of cartilage pro-
shaft, or diaphysis, has become a cylinder of bone tissue (B) liferation and its replacement by bone, growth of the bone
surrounding the marrow cavity (MC). The dark region at the stops, and only the cartilage at the articular surface remains.
ends of the manow cavity is calcified cartilage (ar rowhead) The details of this process are explained under endochon-
that is b eing replaced by bone. The bone at the ends of the dral bone forma tion (Plates 13 and 14).
~ .
-- JC
/
KEY
B, bone JC, joint cavity MC, marrow cavity
C, cartilage L, ligament ari"Owhead, calcified cartilage
CT, connective tissue
174
i
CHAPTER 7 Cartilage J 77
B
Figure 1, epiglottis, human, H&E and orcein fibrous character is just barely visible in this figure. Also
stains xao. note the adipose tissue (AT) within the boundaries of the
This sectio n of the epiglottis contains e lasti c cartilage e lastic cartilage.
( EC) as the centrally located structure. The essential com- Both above and below the elastic cartilage is con nective
ponents of the cartilage, namely, the matrix that stains deep tissue, and each surface of the epig lottis is formed by strat-
blue and the light, unstai ned lacunae sunounded by matri x, ified squamous epithelium (SE). Mucous glands (MG) are
are evident in this low- magnification micrograph. The in the connecti ve ti ssue in the bottom of this figure.
perimeter of the cartilage is covered by perichondrium; its
Figure 2, epiglottis, human, H&E and orcein Most chondrocytes shown in this figure occupy only part of
KEY
AT, adipose tissue E C, elastic cartilage SE, stratified squamous epitheli um
E, elastic fiber MG, mucous gland
176
CH APTER 7 Cnrlilnge 1 79
PLATE 10. FIBROCARTILAGE
Fibrocartilage is a co mbinati o n of dense connective tissue and cartilage. It has a matrix with large bundl es of type I colla-
gen in addition to type ll coll agen. T he a mount of cartilage vari es, but in most locatio ns the cartilage cells and their matrix oc-
cupy a lesser portion of the tissue mass. Fibrocartilage is fo und at the intervertebral di scs, the symphysis pubis, the knee j oin t,
the mandibular j oint, the sternoclavicular joint, a nd the sho ulder j oi nt. It may also be present along the g rooves or insertio ns
for tendons and ligaments. Its presence is associated with sites where resilience is req uired in dense connective tissue to he lp
absorb sudden physical impact, i.e., where resistance to both compress ive a nd shearing fo rces is required in the tissue. Histo-
logicall y, fi brocartilage appears as small fields of cartilage blendi ng a lmost imperceptibly with regions of dense fibrous con-
nective tissue. It is usually identified by the presence of aggregates of rounded cartil age cells (isogenous groups) among bun-
dles of collagen fibers and by the basophili c sta ining of the caps ular matri x material and territoria l matrix secreted by these
cells. No peri chondrium is present.
B
Figure 1, intervertebral disc, human , Mallory's cells (C) are mo re numerous and exhibit c lose spatial
trichrome x 160. groupings, i.e., isogenous groups. Some of the carti lage
T his is a low-magnificatio n view of fi brocartilage. T he cells appear as elongate cl usters of cells, whereas others ap-
Mallory method stains coll agen light blue. T he tiss ue has a pear in single-file rows. T he matrix material immed iately
fibrous appearance, and at this low magnification the nuclei sutTotmding the cartilage cells has a homogeneous appear-
of the fibroblasts (F) appear as small, elongate or spindle- ance and is, thereby, distinguishable fro m the fibro us con-
shaped bodies. T here are re latively few fi broblasts prese nt, nective tissue.
as is characteristic of dense con nective ti ssue. The cartilage
B
Figure 2, intervertebral disc, human, Mallory's group of cartil age cells at the left of this figure a nd the n ob-
trichrome x 700. serving this same area in Figure I . Note the light ho moge-
This fig ure shows the area circumscri bed by the rectan- neous area around the cell nest in the lower-power view.
gle in Figure 1 at hi gher mag ni ficati o n. The cartilage cells T his is the regio n of cartilage matrix. At the greater magni -
are co ntained within lacunae ( anvws), and their cytoplasm fi cation of Figure 2, it is possible to see that some of the
stains deeply. The surrounding cartilage matrix material is collagen fibers are incorporated in the matrix, whe re they
scant and ble nds into the dense connective tissue. Cartil age appear as w ispy bundles.
matrix material can be detected best by observing the la rger
KEY
C, cartilage F, fibroblast arrow, lacuna
178
ondary role in the homeostatic regulation of blood cal- blood vessels, and nerves. If the bone form s a freely mov-
ci u m levels. able (synovial) joint, hya line cartilage is present. The a bil-
ity of the bone to perform its skeletal functio n is due to the
Bone matrix contains collagen type I and some collagen type bone tissue and, w here present, the hyal ine or articular
V, along with glycosaminoglycans, glycoproteins, carti.lage.
and sialoproteins
Bone tissue is classified as either compact (dense) or spongy
181
r
I 8'2 CHA PTER 8 Bour CHAPTER 8 Bouf I 83
iosteum th at covers an actively growing bone consists of the cavity is referred to as endosteum. The endostewn is
an o uter fibrou s layer that resembles other dense connec- often o nly one cell layer thick a nd consists of cells that can
articular cartilage
epiphysis on articular surface tive tiss ues a nd an inner, m ore cellular layer th at contains differentia te into osteoblasts in response to appropriate
the osteoprogenitor cells. If active bone formation is not stimuli. These osteoprogenitor cells, called endosteal cells,
metaphysis in progress on the bone s urface, the fibrou s la yer is the are flattened cells that r esemble fibro blas ts.
ma in compo nent of the peri osteum, a nd the inner layer is
no t well defin ed. The relatively few cells that ar e present, The marrow cavity and the spaces in spongy bone contain
the periosteal cells, are, however, ca pable of undergoing bone marrow
divisio n and becoming osteoblasts under a ppro priate
stimulu s. Red bone marrow co nsists of developing blood cells in
In general, the collagen fibers of the periosteum are differ ent stages of develo pment (see page 232) a nd a net-
arranged parallel to the surface of the bone in the fo rm of wo rk of reticula r cells and fibers that serve as a support-
a capsule. The character of the periosteum is different ing fra mewo rk fo r the developing blood cells a nd vessels.
diaphysis w here liga ments and tendons attach to the bone. Collagen As an indi vidual grows, the amount of red ma rrow does
fibers fro m these structures extend directly, but at an a ngle, not increase in proportion to bone g row th. In la ter stages
into the bone tissue, where they are continuo us with the of gr owth and in the ad ult, when the ra te of blood cell
collagen fibers of the extracellular matrix of the bone tis- for mat ion has diminished, the tissue in the marro w cav-
sue. These fibers are called Sharpey's fibers . ity consists mostly of fa t cells; it is then ca ll ed yellow
marrow. In r esponse to a ppropri ate stimuli, such as ex-
Bones that articulate with neighboring bones possess movable treme bl ood loss, yellow marrow can revert to red m ar -
(synovial) joints r o w. In the ad ult, red marrow is no rma ll y restricted to the
spaces of spongy bone in a few locat ions such as the ster-
Where a bone articulates with a neighboring bone, as in n um and the iliac crest. Diagnostic bone ma rrow samples
synovial joints, the contact areas of the two bones are re- and m arrow for transplanta tion are obtained fro m these
metaphysis ferred to as articular surfaces. The articular surfaces are sites.
covered by hyaline cartilage, also ca lled articular cartilage
beca use of its locatio n and function; articular cartilage is
epiphysis Mature Bone
exposed to the jo int cavity. This cartilage is no t covered
rticular cartilage
w ith pericho ndrium.
on articular surface Mature bone is composed of structural units called osteons
FIGURE8.2 (Haversian systems)
Structure of a typical long bone. The diaphysis (shaft) of a long bone Bone Cavities
contains a large marrow cavity surrounded by a thick-walled tube of Ma ture bone is la rgely com posed of cylindrica l units
compact bone. A small amount of spongy bone may line the inner Bone cavities are lined by endosteum, a layer of connective called osteons o r Haversian systems (Fig. 8.3 ). The osteo ns
surface of th e compact bone. The proximal and distal ends, or epi- tissue cells that contains osteoprogenitor cells consist of concentric lamellae (sing., la mella) of bone ma-
FIGURE 8.1
physes, of the long bone consist cl1iefly of spongy bone with a thin trix, surrounding a central cana l, the osteonal (Have1'sian)
Epiphysis of an adult long bone. Specimen showing longitudinally
outer shell of compact bone. The expanded or flared part of the dia- The lining tissue o f bo th the compact bone facing the canal, which conta ins the vascula r a nd nerve supply of the
sectioned epiphysis of a long bone. The outer portion of the bone
physis nearest the epiphysis is referred to as the metaphysis. Except marrow cavity a nd the tr a bec ulae of spongy bo ne witlt in
has a solid structure (arrows) and represents compact (dense) bone. osteon. Canaliculi conta ining the processes of osteocytes
for the articular surfaces that are covered by hyaline (articular) carti-
The interior of the bone exhibits a spongy configuration and repre-
lage, indicated in blue, the outer surface of the bone is covered by a
sents spongy (ca ncellous) bone. It consists of numerous intercon-
fibrous layer of connective tissue called the periosteum, indicated in
necting bony trabeculae separated by a Jabyrint11 of interconnecting
pink.
marrow spaces.
Inflammation of the joints (arthritis) can be caused by many fac- ankylosis. Surgery that replaces the damaged joint with a pros-
tors and can produce varying degrees of pain and disability, from thetic joint can often relieve the pain and restore joint motion in
the pathologic response of articular cartilage to injury. seriously debilitated individuals.
Simple trauma to a joint by a single incident or by repeated in- Another common cause of damage to articular cartilages is the
verse is tr ue. H ere, the spongy bone is extensive, and the Q GENERAL STRUCTURE OF BONES sult can so damage the articular cartilage that it calcifies and be- deposition of crystals of uric acid in the joints, particularly those of
compact bone consists of little more than a thin outer shell gins to be replaced by bone. This process can lead to ankylosis, tlie toes and fingers. This condition is known as gouty arthritis or,
(see Fig. 8.1). Outer Surface of Bones i.e., bony fusion in the joint and subsequent loss of motion. The more simply, gout. Gout has become more common because of
Short bones possess a shell of co mpact bone and have foot and knee joints of runners and football players and hand and the widespread use of thiazide diuretics in the treatment of hyper
spongy bo ne and a marrow space o n the inside. Short Bones are covered by periosteum, a sheath of dense fibrous finger j oints of stringed instrument players are especially vulnera- tension. In genetically predisposed individuals, gout is the most
connective tissue containing osteoprogenitor cells ble to this condition. common side effect of these drugs. Gout causes severe, unbearable
bones usually fo rm movable joints with their neighbors;
Immune responses or infectious processes that localize in joints, pain because of the sharp crystals in the joint. The irritation also
li ke long bo nes, their articular surfaces are covered with
as in rheumatoid arthritis or tuberculosis, can also damage the causes the formation of calcareous deposits that deform the joint
hya line carti lage. Elsewhere, periosteum, a fibrous con- Bones are cover ed by a per iosteum except in ar eas
articular cartilages, producing both severe joint pain and gradual and limit its motion.
nective tissue ca psule, covers the o uter surface of the w here they articulate w ith another bone. In the latter case,
bone. '"' the articula ti ng surface is covered by cartilage. The per-
I 84 C H APTER 8 13our CHAPTER 8
are generally arranged in a radial pattern with respect to The blood supply to bone tissue is essentially centrifugal vessels to pass through the compact bone. The smaller Immature bone contains relati vely m ore cells per unit
the canal. The system of cana liculi that opens to the os- blood vessels enter the H aversian canals, w hich contai n a area than does mawre bone.
teonal canal also serves for the passage of substances be- The blood that nourishes bo ne tissue moves from the single arterio le and a venule or a single capillary. A lesser The cells in immature bone tend to be rando mly
tween the osteocytes and blood vessels. Between the os- marrow cavity into and thro ugh the bone tiss ue and o ut sup ply to the bone tissue arises fro m periostea l vessels, arranged, whereas cells in mature bone tend to be
teons are remnants of previo us concentric lamel lae, called via periosteal vei ns; thus its flow is in a centrifugal direc- which usually pr ovide for o nly the outermost portions of arra11ged with their lo ng axes in the same d irection as
interstitial lamellae (Fig. 8.3). Because of this orga niza- tio n. With respect to no urishment of the bone tissue itself, the compact bone. Bone tissue lacks lymphatic vessels; the lamellae.
tion, matme bone is a lso called lamellar bo1~e. Volkman n's canals provide the major route of entry for only the periosteal tissue is provided with lymphatic
The lo ng axis of an osteon is usua ll y parallel to the long drainage.
axis of the bone. The collagen fibers in the concentric
lamellae in an osteon are laid down parallel to o ne another
in any given lamella but in diffe rent directions in adjacent Immature Bone
osteon a I
lamellae. This arrangement gives the cut surface of lamel- artery Bone tissue initially formed in the skeleton of a develop-
lar bone the appearance of pl ywood and imparts grea t collagen f ibers ing fe tus is called immature bone. It differs from mature
strength to the osteon. bone i n several respects (Fig. 8.5) :
Lamellar bone is also fo und at sites other than the os- endosteum
teon. Circumferential lamellae follow th e entire inner a nd Immature bone does not display a n organized lamellated
o uter circumferences of the shaft of a long bone, appearing appearance. On the basis of its collagen fiber ana nge-
much like the growth rings of a tree (see Fig. 8.3). Perfo- ment, such bone is designated nonlamella1: Nonlamellar
rating canals (Volkmann's canals) are channels in lamellar bo ne is also referred to as bundle or woven bone because
bone th rough w hich blood vessels and nerves travel from of the interlacing arrangement of the collagen fibers.
the periosteal and endosteal surfaces to reach the osteona l
canal; they also connect osteonal canals to one another.
The)' usually run at approximately right angles to the long articular cartilage
ax is of the osteons and of the bone (Fig. 8.3). Volkma nn 's
ca nals are not surrounded by concentric lamellae, a key
feat ure in their histOlogic identification.
a
IMMATURE BONE
Mature spongy bone is structurally similar to mature compact
bone Volkmann's
canal
Mature spongy bone is similar in structure to mature
compact bone except that the tissue is arranged as trabec-
ulae or spicules; numerous interconnecting marrow spaces
of va ri ous size are present between the bone tissue. T he
matrix of the bone is lamell ated. If the tra beculae are suf- concentric
ficientl y thick, th ey wi ll contain osteons. lamella
: ..
:
The blood supply to the shaft of a long bone is chiefly periosteum osteon
by arteries that enter the marrow cavity through nutrient FIGURE8.3
foramina Diagram of a section of compact bone removed from the shaft of a
long bone. Tile concentric lamellae and the Haversian canal that they diaphysis
N utrient fo ram ina are o penin gs in the bo ne throu gh surround constitute an osteon (Haversian system). One of the Haver
which blood vessels pass to r each the marrow. The great- sian systems in this diagram is drawn as an elongated cylindrical
est numbers of nutrient foramina are found in the diap h- structure rising above the plane of the bone section. It consists of sev
ys is and ep iphysis (Fig. 8.4). Metaphysea l a rteries suppl e- eral concentric lamellae that have been partially removed to show
ment the blood supply to the bone. D rainage of the bone tile perpendicular orientation of collagen fibers in adjacent layers. In interstitial
terstitiallamel lae result from bone remodeling and formation of new lamellae
is by vei ns that leave thro ugh th e nutrient foram ina o r
Haversian systems. Tile inner and outer surfaces of the compact compact bone
MATURE BONE
through the bone tissue of the shaft an d o ut through the bone in this diagram show additional lamellae-the outer and inner FIGURE 8.5
periosteum. circumferential lamellae-that are arranged in broad layers. The Inner FIGURE 8.4 Diagram of immature and mature bone. Immature bone does not
T he n utrient arteries th at supply the di aphysis and circumferential lamella is covered by a thin layer of endosteum that Diagram showing the blood supply of an adult long bone. Tile nutri display an organized lamellar appearance because of the interlacing
epiphysis arise developmentally as the principal vessel of faces the marrow cavity, similar to the outer surface of the bone, ent artery and the epiphyseal arteries enter the bone through nutri arrangement of the collagen fibers. Tile cells tend to be randomly
the periosteal buds. The metaphyseal arteries, in contrast, which is covered by periosteum. Branches of nutritional arteries ac ent foramina. These openings in the bone arise developmentally as arranged, whereas the cells in mature bone are organized in a circu
arise developmentally from periosteal vessels that become companied by small vei ns are shown within the Haversian and Volk the pathways of the principal vessels of periosteal buds. Metapl1yseal lar fash ion that reflects the lamellar structure of the Haversian system.
incorporated into the metaphysis d uring the growth mann's canals. These arteries also supply the periosteum, endos arteries arise from periosteal vessels that become incorporated into Resorption canals in mature bone have their long axes in tile same di
process, i.e., through the wideni ng of the bone. teum, and bone marrow. tile metaphysis as tile bone grows in diameter. rection as the Haversian canals.
186 CHAPTER 8 Boue CHAP TER 8 Bour 18 7
The matrix of immature bone has more grou nd sub- Q CELLS OF BONE TISSUE (Haversian) canals, and the perforating (Volkmann's) lation leads to differentiation into. a more active secr etory
stance tha n does the ma trix of mature bone. T he matrix canals. Osteoprogenitor cells can divide and prolifer ate, as cell, the osteoblast.
in immature bone stains more intensely with hema- As noted above in this chapter, four designated cells are as- shown by autoradiographic studies. In growing bones, os-
toxylin, whereas the matrix of mature bone sta ins mo re sociated with bone tissue: osteoprogenitor cells, os- teoprogenitor cells appear as flattened cells with lightly Bone-lining cells cover bone that is not remodeling but are
intensely with eosin. teoblasts, osteocytes, and osteoclasts. With the exception staining, elo ngate or ovoid nuclei a nd inconspicuous aci- analogous to osteoprogenitor cells at sites of bone growth
of the osteoclast, each of these cells may be regarded as a dophilic or slightly basophilic cytoplasm . Electron micro-
Although not evident in typical histologic sections (Fig.
differentiated form of the same basic cell type. Each un- graphs reveal profiles of wugh endoplasmic reticulum In sites where remodelin g is not occurr ing in mature
8.6), immature bone is not heavily mineralized when it is
dergoes transformation from a less mature form to a more (rER ) and free ribosomes as well as a sma ll Golgi appara- bone, the bone surfaces are covered by a layer of flat cells
initia lly formed, whereas mature bone undergoes prolonged
mature form in relation to functio na l activity (growth of tus and other organelles. The morphology of the osteo- with attenuated cytoplasm and a p at.=ity of orga nelles be-
secondary minera lization. The secondary mineralization of
bone). In contrast, the osteoclast originates from a differ- progenitor cell is consistent w ith the finding that its stimu- yond the per inuclear region (see Fig. 8.7a). They do no t
mature bone is evident in tnicroradiographs of grou nd sec-
ent cell line and is responsible for bone resorption, an ac-
tio ns that show younger Haversian systems to be less min-
tivity associated with bone remodeling.
eralized than older H aversian systems (see Fig. 8.19).
Immature bone forms more rapidly th an mature bone. Al- Osteoprogenitor Cells
though mature bone is clearly the major bone type in the
adult, and immature bone is the major bone type in the de- The osteoprogenitor cell is a resting cell that can transform
veloping fetus, areas of inunature bone are present in adults, into an osteoblast and secrete bone matrix
especia lly where bone is being remodeled. Areas of inunature
bone are also seen regularly in the alveolar sockets of the Osteoprogenitor cells a re found o n the external and in-
adult oral cavity and where tendons insert into bones. It is ternal surfaces of bones. They comprise the periosteal cells
this immature bone in the alveolar sockets that makes it pos- that form tbe innermost layer of the periosteum and the
sible to undertake orthodontic corrections even in adults. endosteal cells that line the marrow cavities, the osteonal
I . - bone ..
... ."'~:.. '".
;
plasma membra_ne
lipid
FIGURES.?
Electron micrograph of bone-lining cells. a. The cytoplasm of a similar bone spicule stained with H&E, included for orientation pur-
FIGURE8.6 bone-lining cell located on the surface of a spicule of mature bone is poses. The bone-lining cells on the surface of the spicule are indi-
Photomicrographs of decalcified immature and mature bone. canals contain blood vessels and connective tissue. Osteocytes un- very attenuated and contai ns small amounts of rER and free ribo- cated by the arrows. X350 . b. Electron micrograph of the cytoplasm
a. Decalcified Immature bone, stained with H&E, showing the relation- dergo considerable shrinkage during routine slide preparation, reveal- somes. A gap junction is seen between the two adjacent bone-lining of two bone-lining cells observed at higher magnification. The gap
ships of cells to the extracellular matrix. The immature bone has more ing empty lacunae with a small nucleus attached to their walls. Mature cells. In addition, cytoplasmic processes are clearly seen where they junction is clearly seen where the two cells are in apposition. The
cells, and the matrix is not layered in osteonal arrays. x 130. b. This bone has fewer osteocytes per unit area than immature bone. Note the pass through the matrix of unmlneralized bone (osteoid). A fat cell of edge of a fat cell is seen at the top of the electron micrograph; Its
cross section of decalcified mature compact bone stained with H&E presence of interstitial lamellae between neighboring osteons. X160 . the marrow is also present. x 8,900. (From Miller SC, et al. Anat Rec lipid, th in rim of cytoplasm, plasma membrane, and external lamina
shows several osteons (0) with concentric lamellae. Tl1e Haversian 1980;198:163-173.) Inset. High-magnification photomicrograph of a are also evident. x 27,000.
J 88 CHAPTER 8 Bone CHAPTER 8 Bone 1 89
form a complete cellul ar lining on the bone surface; gap from the bone by a light band. This band represents the os- and bone remodeling. As osteoid deposition occurs, the ment of junctions between an osteoblast and adjacent os-
junctions are present where the lining cell processes con- teoid; it is nonmineralized matrix. osteoblast is eventually surrounded by osteoid matrix reocytes (as well as between adjacent osteoblasts) allows
tact one another (Fig. 8.7b). These cells, designated sim- The cytoplasm of the osteoblast is markedly basophilic, and then becomes an osteocyte. neighboring cells within the bone tissue to communicate.
ply as bone-lining cells, are analogous to the osteoprog- and the Golgi apparatus, because of its size, is sometimes The osteoblast cytop.lasm is characterized by abundant
enitor cells but are probably in a more quiescent state observed as a clear area adjacent to the nucleus. Small, pe- Osteoblast processes communicate with other osteoblasts and rER and free ribosomes (Fig. 8.9) . These features are consis-
than those located at sites of bone growth . They are a lso riodic acid-Schiff (PAS)-positive granules are observed in with osteocytes by gap junctions tent with its basophilia observed in the light microscope as
tho ught to funct ion in the maintenance and nutritional the cytoplasm, and a strong alkaline phosphatase reaction well as with its ro.le in the production of collagen and pro-
support of the osteocytes embedded in the underlying associated with the cell membrane can be detected by ap- At the electron microscope level, osteoblasts exhibit thin teoglycans for the extracellular matrix. The Golgi apparatus
bone matrix. This suggested ro le is based on the observa- propriate histochemical staining. cytoplasmic processes that penetrate the adjacent osteoid and surrounding regions of the cytoplasm contain numerous
tion that the cell processes of bon e-lining cells extend into In contrast to the secreting osteoblasts found in active produced by the cell and are joined to similar processes of vesicles with a flocculent content that is presumed to consist
the canalicular channels of the adjacent bone (see Fig. matrix deposition, inactive osteoblasts are flat or attenu- adjacent osteocytes by gap junctions. This early establish- of matrix precmsors. These vesicles are the PAS-staining
8.7b) and communicate by means of gap junctions with ated cells that cover the bone surface. These cells resem-
processes of osteocytes. ble osteoprogenitor cells. Osteoblasts res pond to me- .
The degree of differentiation of the osteoprogen itor chanica l stimuli to mediate the changes in bone growth .. .
,
.... . .
'
three kinds of cells other than osteoblasts (adipose cells, ~., .. '
chondroblasts, and fibroblasts ) suggest that they, like fi- .. \
Osteoblasts
granules seen in light microscopy. The matrix vesicles, also developed Golgi apparatus. Moreover, secondary lyso-
produced by the osteoblast, appear to arise by a different somes are conspicuous (Fig. 8.10c) .
pathway, originating as sphere-li ke outgrowths that pinch That the resorptive osteocyte removes matrix is sup-
off from the plasma membrane to become free in the matrix. ported by the observation that tl1e pericellular space is de-
Other cell organelles include numerous rod-shaped mito- void of collagen fibrils and may contain a flocculent mate-
chondria and occasional dense bodies and lysosomes. rial suggestive of a breakdown product. The more
peripheral, nonresorbed matrix is bounded by an osmio-
Osteocytes philic lamina, which presumably represents the boundary
of the intact mature calcified matrix. Resorption of bone
The osteocyte is the mature bone cell and is enclosed by bone by this mechanism, called osteocytic osteolysis, w ith the
matrix that it previously secreted as an osteoblast concomitant release of calcium ions, allows increases in
blood calcium to mainta in appropriate levels. The stimulus
When completely surrounded by osteoid or bone ma- for tl1e resorption of bone is increased secretion of
trix, the osteoblast is referred to as an osteocyte, the cell parathyroid hormone (PTH).
now responsible for maintaining the bone matrix . Osteo-
cytes can synthesize new matrix, as well as resorb it, at Osteoclasts
least to a limited extent. Such activities help to maintain
the homeostasis of blood calcium. Death of osteocytes, ei- The osteoclast is responsible for bone resorption
ther through trauma, e.g., a fracture, or cell senescence, re-
sults in resorption of the bone matrix by osteoclast activ- Osteoclasts are large, multinucleated cells found at sites
ity, followed by repair or remodeling of the bone tissue by w here bone is being removed. They rest directly on the
osteoblast activity. bone tissue where resorption is taking place (Fig. 8.11 }. As
Each osteocyte occupies a space, o r lacuna, that con- a result of osteoclast activity, a shallow bay called a re-
forms to the shape of the cell. Osteocytes extend cytoplas- sorption bay (Howsbip's lacuna ) can be observed in the
mic processes through the canaliculi in the matrix to con- bone directly under the osteoclast. The cell is conspicuous FIGURE8.10
tact processes of neighboring cells by means of gap not only because of its large size but also because of its Electron micrographs of three different functional stages of an amounts of rER and a large Golgi apparatus (G). Of equal importance
junctions. In hematoxylin and eosin (H&E)-stained sec- marked acidophilia. It a lso exhibits a strong histochemical osteocyte. a. Relatively quiescent osteocyte that contains only a few is the presence of a small amount of osteoid in the pericellular space
tions, the canaliculi and the processes they contain are not reaction for acid phosphatase because of the numerous profiles of rER and a few mitocl1ondria (M). The cell virtually fills the within the lacuna. The osteoid shows profiles of col lagen fibrils (ar
discernable. In ground sections, the canaliculi are readily lysosomes that it contains . lacuna that it occupies; the arrows indicate where cytoplasmic rows) not yet mineralized. The lacuna of a formative osteocyte is not
evident (see Fig. 8.11} . Osteocytes are typically smaller than processes extend into canali culi. Hydroxyapatite crystals have been bounded by an osmiophilic lamina. X25,000. c. A resorptive osteo-
The portion of the cell in direct contact w ith the bone
their precursors because of their reduced perinuclear cyto- lost from the matrix, which is ordinarily mineralized (MM), but some cyte containing a substantial amount of rER, a large Golgi apparatus,
can be divided into two parts: a central region containing
plasm. Often, in routinely prepared microscopic specimens, hydroxyapatite crystals fill the pericellular space. The hydroxyapatite mitochondria (M), and lysosomes (L). The pericellular space is devoid
numerous plasma membrane infoldings for ming microvil- crystals obscure the other substances within the pericellular space. of collagen fibrils and may contain some flocculent material. Tile Ia
the cell is highly d istorted by shrinkage and other artifacts lous-type structures, called the ruffled border; and a ring- The dark band marking tile boundary of the lacuna is the osmioph ilic cu na containing a resorptive osteocyte is bounded by a less conspic-
that result from decalcifying the matrix prior to sectioning like perimeter o f cytoplasm, the clear zone, that demar- lamina (OL). X25,000. b. A formative osteocyte containing larger uous osmiophilic lamina (OL). x2 5,000.
the bone. In such instances, the nucleus may be the only cates the bone area being resorbed. The clear zone
prominent fea ture. In well-preserved specimens, osteocytes contains abundant microfilaments but essentially lacks
exhibit less cytoplasmic basophilia than osteoblasts, but lit- other organelles . The ruffled border stains less intensely
tle additional cytoplasmic detail can be seen. than the remainder of the cell and often appears as a light
Electron microscopy has revealed osteocytes in various band adjacent to the bone at the resorption site (see released into the extracellular space in the clefts between the concept of acid secretion by the osteoclast comes, in
functiona l states. Indeed, there is evidence t hat the osteocyte Fig. 8.11}. the cytoplasmic processes of the ruffled borde1~ a clear ex- part, from the finding that carbonic anhydrase, an enzyme
can modify the surrounding bone matrix through synthetic At the electron microscopic level, hydrm}'apatite
.. crys- ample of lysosomal hydrolases functioning outside the cell. associated with carbonic acid production, is present in the
and reabsorptive activities. Three functional states, each tals from the bone substance are obser ved between t he O nce liberated, these hydrolytic enzymes, which include region of the ruffled border.
with a characteristic morphology, have been described: processes of the ruffled border (Fig. 8.12}. Internal to t he collagenase, digest the organic components of the bone
Quiescent osteocytes exhibit a paucity of rER and a ruffled border and in close proximity are numerous mito- matrix. Before digestion can occur, howeve1~ the bone ma- Osteoclasts are phagocytotic
markedly diminished Go lgi apparatus (Fig. 8 .1 0a) . An chondria and lysosomes. The nuclei are typically located in trix must be decalcified. Current evidence indicates that
osmiophi lic lamina representing mature calci.fied matrix the part of the cell more removed from the bone surface. the dissolution of the calcium sa lts occurs through secre- Numerous coated pits and coated vesicles are a lso present
is seen in close apposition to the cell membrane. In this same r egion are profiles of rER, multiple stacks of tion of organic acids by the membranes of the ruffled bor- . at the ruffled border, suggesting endocytotic activity. Osteo-
Formative osteocytes show evidence of matrix deposi- Golgi saccu les, and many vesicles. der. Moreove1~ a low pH favors the action of acid hydro- clasts are observed at sites w here bone remodeling is in
tion and exhibit certain characteristics similar to those lases. Accordingly, a local acidic environment is created in progress. (The process of remodeling is described in more de-
of osteoblasts. Thus, the rER and Golgi apparatus are Osteoclasts resorb bone by releasing lysosomal hydrolases into the extracellular space between the bone and the osteo- tail shortly.} Thus, in sites where osteons are being altered or
more abundant, and there is evidence of osteoid in the the extracellular space clast. The clear zone adjacent to th e ruffled border seems where a bone is undergoing change dlll'ing the growth
pericellular space within the lacuna (Fig. 8 .10b}. to fo rm a seal against the bone, thus creating a compart- process, osteoclasts are relatively numerous. As noted, an in-
Resorptive osteocytes, like formati ve osteocytes, contain Some, if not most, of the vesicles in the osteoclast are ment at the site of the ruffled border where foca l decalcifi- crease in PTH level promotes bone resorption and has a
numerous profiles of endoplasmic reticulum and a well- lysosomes that develop from late endosomes . They are cation and degradation of the matrix occur. Support for demonstrable effect on osteoclast activity, in addition to its ef-
192 CHAPTER 8 Bo11r C H APTER 8 Bo11e J 93
9 BONE FORMATION
The development of a bone is traditionally classified as
endochondral or intramembranous
.., .::
lage is resorbed, ultimatel y leaving a primary spongy bone.
This spongy bone u ndergoes reorganization through os- = - -...
zone of proliferation
teoclastic activity and add itio n of new bone tissue, t hus ac-
commodating the contin ued growth a nd physical stresses
-...._, -
-}
placed on the bone. ~, .;;
Shortly after birth, a secondary ossifica tion center devel-
ops in the upper epiphysis. T he cartilage cells undergo hy- FIGURE 8.16
...
- .....
pertrophy and degenerate. As in the di aph ysis, calcification Longitudinal section through the """' zone of hypertrophy
distal end of a metatarsal bone of a
of the m atrix occurs, and blood vessels and osteogenic cells
2-month-old infant. The epiphyseal
from the pericho ndrium invade the region , creating a new
(secondary) ossification center is well
marrow cavity (see illustrations 6 and 7 o f Fig. 8.14).
formed. Bone formation is taking
Later, a similar epiphyseal ossification center forms at the place at both the epiphyseal and the
lower end of the bone (see il lustration 8 of Fig. 8.14). This diaphyseal surface of the epiphyseal
center is also regarded as a secondary ossification center, plate. The zonation is apparent on the
a lthough it develops later. With the developm ent of the diaphyseal side because the growth
FIGURE 8.15 secondary ossification centers, the o nly cartilage that re- rate there is so much greater than the
Photomicrograph of a m ixed bone spicule formed during endo- mains from the o rigina l model is the articular ca rtilage at epiphyseal ossification center. Be-
chondral bone formation. In this Mallory-Azan-stained section, bone the ends of the bone and a transverse disc of carti lage, cause both centers are active, the
has been deposited on calcified cartilage spicules. In the center of the known as the epiphyseal plate, w hich separates the epi- zone of reserve cartilage is relatively
photomicrograph, the spicules have already grown to create an anas narrow. H&E x2 80. (From Kelly DE.
physeal and di aphyseal cavities.
tomosing trabecula. The initial trabecula still contains remnants of cal- Wood RL, Enders AC. Baileys Textbook
osteoblasts
cified cartilage, as shown by the light-blue staining of the calcified ma- of Microscopic Anatomy. Baltimore:
cartilage of the epiphyseal plate is responsible for maintaining
trix compared with the dark-blue staining of the bone. In the upper Williams & Wilkins, 1978.)
the growth process
part of the spicule, note a lone osteoclast (arrow) aligned near the sur- DIAPHYSIS
face of the spicule, where remodeling is about to be initiated. x275.
For a bo ne to retain proper proportions and its uniqu e
shape, both extern al and intern al remodeling must occur
Zo ne of proliferation, w hich is adjacent to th e zone of as the bo ne grows in length. Th e proliferative zone o f the fro m the di aphys is, elonga ting the bone. The events that When an indiv,i dual achieves maximal growth, proliferation of
rese rve cartilage in the di rection of the diaphysis. In this epiphysea l plate gives rise to the cartilage on w hich bone is fo llow t his incrementa l growth, namely, hypertroph y, new cartilage within the epi physeal plate t erminates
zo ne, the ca rtilage cells undergo division and o rganize later laid dow n. ca lcification, r esorption, and ossificatio n, simply involve
into distinct columns. These cells are large r than t hose in The thi ck ness of the epip hysea l plate remai ns relatively the mecha nism by wh ich th e newly formed ca rtilage is When prolifera tion of new cartilage ceases, the cartilage
the reserve zone and actively p roduce matrix. consta nt d uring growth. replaced by bone tiss ue during deve lopment. that has a lready been prod uced in th e epiphyseal plate con-
Zone o f hypertrophy, w hich conta ins grea tly enlarged The amou nt of new cartilage p rod uced (zone of pro- Bone increases in width or diameter when appositional tinues to undergo the changes that lead to the deposition of
cartilage cells. The cytoplasm of t hese cells is clear, liferatio n ) equ a ls the a mo un t reso rbed (zone of re- growth of new bone occurs between the cortical lamel- new bone until, fina ll y, there is no remaining cartilage. At
wh ich is a reflection of the g lycogen th at they norma lly so rp ti on). lae mtd the periosteum. The ma rrow cavity then enlarges this point, the epiphyseal and diaph yseal marrow cavities
accumulate (and that is lost d uring fixation ). The matrix The resorbed car tilage is, of course, replaced by spongy by resorpti on of bone on th e endosteal su rface of the become confluent. T he elimination of the epiphysea l plate is
is com pressed in to linear bands between the columns of bone. cortex of the bone. referred to as epiphyseal closure. In illustration 9 of Figure
h ype rtrophied cartilage cells. 8. 14, the lower epiphysea l cartilage is no longer present, and
In reviewing t he gr owth process, it is important to real- As bones elongate. remodeling is required
Zone o f calcified cartilage, in which t he enlarged cells in i.llustration 10, both epiphysea l cartilages are gone.
begin to degenerate and t he ma trix becomes calcified . ize that Growth is now complete, and the only r emaining cartilage
Zone of resorption, which is the zone nearest the diaph- Actual lengthening of the bone occurs when new carti- Remodeling consists o f preferen tia l resorption of bone is fo und on the a rticul ar surfaces of the bone. Vestigial evi-
ysis. T he ca lcified cartilage here is in direct co ntact with lage matrix is pmduced at the epiphyseal plate. Produc- in some areas and deposition of bone in other areas, as de- dence of th e site of the epiphyseal plate is r eflected by an
the co nnective tiss ue of the marrow cavity. tion of new ca rtilage ma tr ix pushes the epiphysis away scribed a bove and outlined in Figure 8.1 7. epiphyseal line co nsisting of bone tissue (see Fig. 8 .2).
I 98 CHAPTER 8 Boue
epiphysis enlarges by
growth of cartilage and
replacement by bone Both nutritional and hormonal factors affect the degree of bone quence of Immobilization (as In a bedridden patient) and in post
mineralization. Calcium deficiency during growth causes rickets, a menopausal women. The factors that cause the imbalance in eel
condition in which the bone matrix does not calcify normally. Rick lular activity are not known, although some relief appears to result
ets may be due to insufficient amounts of dietary calcium or to in from maintaining hormonal (estrogen) levels and dietary fluoride
sufficient vitamin D (a steroid prohormone), which is needed for levels.
absorption of calcium by the intestines. In the adult, the same nu In addition to Its influence on intestinal absorption of calcium,
tritional or vitamin deficiency leads to osteomalacia. vitamin D is also needed for normal calcification. Other vitamins
Although rickets and osteomalacia are no longer major prob known to affect bone are A and C. Vitamin A deficiency suppresses
Iems where nutrition is adequate, another form of insufficient bone endochondral growth of bone; vitamin A excess leads to fragility
mineralization is regularly seen in the condition known as osteo- and subsequent fractures of long bones. Vitamin C is essential for
porosis. In this condition, bone tissue (both mineral and matrix) is synthesis of collagen, and Its deficiency leads to scurvy. The matrix
diminished, presumably because resorption by osteoclasts exceeds produced in scurvy Is not calcifiable.
deposition by osteoblasts. Osteoporosis develops as a conse
added
here
growing shaft is ~- resorbed
remodeled by bone being ... here
new
osteon
OLDER BONE YOUNGER BONE
FIGURE 8.17
Diagram of external remodeling of a long bone. This diagram The bone is now longer, but it has retained Its general shape. To grow
shows two periods during the growth of the bone. The younger bone in length and retain the general shape of the particular bone, bone
profile (before remodeling) is shown on the right; .the older (~fter r~ resorption occurs on some surfaces, and bone deposition occurs on
modeling), on the left. Superimposed on the left Side of the !1gu ~e IS other surfaces, as indicated In the diagram. (Based on Ham AW. J Bone
the shape of the bone (left half only) as it appeared at an earlier t1me. Joint Surg Am 1952;34:701 .)
Development of the Osteonal (Haversian) System cavity, by osteoclast activity. T his resorption cavity will
have the d imensions of the new osteo n. When osteoclasts
osteons typically develop in preexisting compact bone have produced an appropriately sized cylindrical tunn~l
by resorption of compact bone, blood vessels and the1r
Compact bo ne can take several different forms. Com- surrounding connective tiss ue occupy the tunnel. As ~he
pact bone may be for med from fetal spo ngy bone. by co l~ tunnel is o ccupied, new bon e deposition on its wall b~g!ns
tinu ed deposi tion of bone on the spongy bone sp1cules; 1t almost immedi ate ly. These two aspects of cellular actlVIty,
may be deposi ted directly as adu lt compact bo~e (e:g., the namely, osteoclast resorptio n an d osteo blast synthe~ 1s,
circumferential lamellae of an a~ u l t bone); or 1t m1ght be constitute a bone-remodeling unit. A bone-remodeling
unit consists of two distinct pa rts: an advanci ng cutting
d
o lder compact bone consisting of osteons and interstiti~l FIGURE 8.18
lame llae. T he process in which new osteons are formed 1s cone (also called a resorption canal) and a closing cone Diagram of a bone-remodeling unit. A bone-remodeling unit con
(Fig. 8.18). The cutting cone consists of active os~eoclasts cells begin to deposit the osteoid on the wa lls of the canal in succes
referred to as intemal remodeling. sists of an advancing cutting cone and a closing cone. The cutting sive lamellae. Gradual formation of the new bone fills the resorption
followed by an ad vancing ca pilla ry loop an~ pe~tcytes. It cone formed by osteoclasis is responsible for boring the tunnel or re cavity. Note the deposition of the osteoid deep to the osteoblasts
In the development of new osteons, a tunnel is bored through also conta ins numerous dividi ng cells that gtve n se to os- sorption cavity through the compact bone. Its action Is initiated within seen in sections b and c. As successive lamellae of bone are de
compact bone by osteoclasts teo blasts, additional pericytes, and endothelia l cells. (Re- the Haversian canal at the left of the diagram (In t he area correspon posited, the canal ultimately attains the relatively narrow diameter of
call that osteoclasts are der ived fro m blood-borne mon? ding to section a). Tile cutting cone moves along the Haversia n canal, the mature Haversian canal, like that shown in section a. The growth
Formation of a new osteon in compact bone involves cytes.) The osteoclasts cut a canal about 200 fLl11 Ill in the direction indicated by the arrow, to the area corresponding to reversal line that appears at the outer limits of a newly formed osteon
diam eter. This canal esta blishes th e diameter of the future section d. Section d shows the cross section through the cutting cone. represents a border between the resorption activity of the cutting
ini tia lly the creation of a tunn el-like space, the resorption
The resorption cavity is the site wh ere the future osteon is formed by cone and the bony matrix not remodeled by this activity.
the action of the closing cone, which consists of osteoblasts. These
199
200 C HAPTER 8 /3ou e
C H APTE R 8 Bour 20 I
Compact adult bone contains Haversian systems of varying The ~atrix vesicles that accu mula te Ca2+ and cleave PTH acts o n the bone to raise lo~ blood calcium levels
osteonal (H aversian) system . The cutting cone constitu tes
age and size PO~- Ions cause the local isoelectric point to increase to normal.
o nly a small fraction of the length of the bo ne-remodeli ng
w hich. r esults in crystallization of CaP04 in th e sur~ Calcitonin acts to lower elevated blood calcium levels to
unjt; thus, it is seen much less frequently tha n the closing rou ndmg matrix vesicles.
Microradiographic exa minatio n of a grou nd section of normal.
cone. bone reveals t hat younger Haversian systems are less com- The C~P04 crysta ls initiate matrix minera lization by
After the diameter of the future H aversian system is es-
pletely minerali zed than o lder systems {Fig. 8.19) . They fo_r~atJon . and depos!tion o f [Ca Jo{P04)6{0H)z] (hy- PTH acts by stimula ting both osteocytes and osteo-
tablished, osteoblasts begin to deposit the o rga nic matr.ix
undergo a progressive secondary mi neralizatio n that con- di oxya patJte) crystals 111 the matrix surrounding the os- ~las ts to resor b bone, a llowing the release o f calcium
(osteoid ) of bone o n th e walls of the canal in successive
tinues (up to a point) even a fter the osteon has been fully teoblasts. mt_o ~he blood. As described a bove {see page 190), re-
lamellae. With time, the bone matrix in each of th e lamel-
fo rmed. Figure 8.19 also illustrates the d ynamic internal . The ~steoblast-derived matri x vesicles are the essential sorptt?n of bone by osteocytes constitu tes osteocytic os-
lae becomes mineralized. As the successive lamellae of
remodeling o f compact bon e. In the adult, deposition bal- ~actors I_n controlling the initia l site of minera l deposition t~olysts. PT~ also reduces excretio n of ca lcium by t he
bone are deposited, fro m the periphery inward, the canal
ances reso rptio n. In the aged, resorption often exceed s 111 o~te_oid. Once t he initia l crysta ls of hydroxya patite have lod n e~ and stimula tes absorption of calcium by th e small
ultimately atta ins the relatively narrow di am eter of the
deposition. If this imba lance becomes excessive, osteo- pr~Cip i ta~ed, they gr ow rapidly by accretio n until they jo in m_testme,- PTH further acts to maintain homeostasis by
adult osteonal canal. st~m ul a tmg the kid ney to ~xcre te the excess phosp ha te
por osis d evelops (see page 199). ne1ghboru_1g crystals pro duced around o ther matrix vesi-
cles. In th~s way, a wa ve of miner a liza tio n sweeps throu gh pr oduc~d by bo ne reso rption. Calcitonin inhibits bo ne
the osteoid. Other cells that pro d uce o steoid a re the reso rptio n, specificall y inJ1ibiting the effects of PTH on
o steoclas ts.
\1 BIOLOGIC MINERALIZATION ameloblasts an d odontoblasts of d eveloping teeth.
AND MATRIX VESICLES
teoclasts, and gradual remodeling restores the bone to its reapproximating the normal structure, and holding the
original shape. parts in place by internal fixation (by pins, screws, or
In healthy individuals, this process usually takes from 6 plates) or by external fixation (by casts or by pins and
to 12 weeks, depending on the severity of the break and screws) speeds the hea ling process and usually resu lts in
the particular bone that is broken. Setting the bone, i.e., superior structural and functional restoration.
FIGURE 8.20
Photomicrograph of fractured long bone undergoing repair. a shows osteoblasts lining bone trabeculae. Most of the original fi-
a. This low-magnification photomicrograph of a 3-week-old bone brous and cartilaginous matrix at this site has been replaced by bone.
fracture, stained with H&E, shows parts of the bone separated from The early bone is deposited as an immature bone, which is later re-
each other by the fibrocartilaginous callus. At this stage, the ca rtilage placed by mature compact bone. x 300. c. Higher magnification of
undergoes endochondral ossification. In addition, the osteoblasts of the callus from the area indicated by the lower rectangle in a. A frag-
the periosteum are involved in secretion of new bony matrix on the ment of old bone pulled away from the fracture site by the perios-
outer surface of the callus. On the right of the microphotograph, the teum is now adj acent to the cartilage. It will be removed by osteoclast
fibrocartilaginous callus is covered by periosteum, which also serves activity. The cartilage will calcify and be replaced by new bone
as the attachment site for the skeletal muscle. x 35. b. Higher magni- spicules as seen in b. X300.
fication of the callus from the area indicated by the upper rectangle in
C HAPTER 8 Bo11r 205
PLATE 11. BONE, GROUND SECTION
Bone is a specia lized connective tiss ue characterized by a mineralized extracellular matri x. Calcium phosphate, in the form
of hydroxyapatite cJystals (Ca 10(P04)r.OH2) , is deposited along the coll agen fibrils and in the proteoglycan gro und substance.
Bone serves as a storage site for calcium and phosphate, whi ch can be released to the blood to maintain homeostatic levels.
Osteocytes reside in lacunae in the bone matrix a nd extend fi ne cellular processes into canaliculi that connect the lacunae, thus
for ming a continuous network of cells within the mine ralized tissue. Bone s ar e o rgans of the skeleta l system; bone ti ssue is
the structural component of bones.
Ground sections of bone are prepared from bone that has not been fixed but merely allowed to dry. Thin slices of the dried bone
are then cut with a saw and further grou nd to a thinness that allows viewi ng in a light microscope. Slices may be treated with In-
dia ink to fill spaces that were formerly occupied by organic matter, e.g., cells, blood vessels, and unmineralized matrix. A simpler
method is to mount the ground specimen on a slide with a visco us medium that traps air in some of the spaces, as in the specimen
in this plate. Here, some of the osteonal canals and a perforating canal are filled with the mounting medium, making them translu-
cent instead of black. Specimens prepared in thi s manner are of value chiefly to display the architecture of the compact bone.
@
Figure 1, ground bone, human, x80. the concentric la me llae, s utTOLmd the Haversian canal and
Th is fi gure reveals a cross-sectioned area of a lo ng bone appear muc h the same as growth rings of a tree. The canal
at low magni fication and incl udes the outer or peripheral is also s urrounded by concentri c arrangeme nts of lacu nae.
as pect of the bone, identified by the presence of circumfer- These appear as the small, dark, elongate structures.
e ntial lamell ae (CL ). (The ex te rior or periosteal surface of Duri ng the period of bone growth and during adul t life,
the bone is not incl uded in the micrograph.) To the ir right there is constant internal remode ling of bone. T his involves
are the osteons (0) or Haversian syste ms that appear as c ir- the destructi on of osteons and for mation of new ones. The
cular profil es. Between the osteo ns are in terstiti al lamellae breakdown of an osteon is usuall y not complete, however;
( IL), the remnants of previo usly ex isting osteons. part of the osteon may remain intact. Moreover, portions of
Osteons are essentia lly cyli ndrical structures. In the adjacent osteons may a lso be partia lly destroyed. The space
sha ft of a lo ng bone, the long axes of the osteons are ori- created by the breakdown process is reoccupied by a new
e nted parallel to the long axis of the bone. T hus, a cross sec- osteon. The re mnants of the prev iously ex isting osteons be-
tion throug h the shaft of a long bone would reveal the os- come the interstitial la me llae.
teons in cross sectio n, as in this fig ure. At the center of each B lood vessels reach the Haversian canals from the mar-
osteon is an osteon a I (Haversian) canal ( H C) that conta ins row tluoug h other tunnels called perforating (Volkmann's)
blood vessels, connective ti ssue, and cells lini ng the surface canals (VC). In some instances, as here, Volkmann 's canals
of the bone materi al. Because the organ ic materi al is notre- trave l fro m one Haversian canal to anothe r. Vo lkmann 's
ta ined in ground secti o ns, the Haversian canals a nd other canals can be di sti ngui shed from Haversia n canals in that
s paces will appear black, as they do here, if filled with In- they pass throug h la mellae, whereas Haversian canals are
dia ink or air. Co ncentric layers of minerali zed substance, surrounded by concentric ri ngs of lame ll ae.
@
Figure 2, ground bone, human, x 300. thread-like profi les emanating from the lac unae. These
This figure shows a higher-magnification micrograph of thread-like profi les represent the cana li culi , spaces within
the labeled osteon from the upper left of Figure I. It includes the bone matri x that contained cytoplasmic processes of
some of the circumferential lame llae (here labe led IL) that the osteocyte. The cana liculi of each lacuna communicate
are now seen at the bottom of the micrograph (the mic ro- w ith canaliculi of ne ighboring lacunae to form a tlu-ee-
graph has been reorie nted). Note the lacunae (L) and the fine dimensio na l channel syste m tlu-oughout the bone.
KEY
CL, circumferential lamell ae L, lacuna VC, Volkmann's canal
HC, Haversian canal 0, osteon arrow, lamellar boundary
IL, interstitial lamellae
204
CHAPTER 8 13oue 207
PLATE 12. SPONGY AND COMPACT BONE
Hematoxylin a nd eosi n (H&E)-stained sections of decalcified bone exhibit all of the formed soft tissue components that
are seen in other dense connecti ve ti ssues and a llow one to disti nguish the several cell types found in developing and mature
bone. Such preparations also all ow the use of special stains and histochemical methods to study bone development and fu nc -
tion in more detail than is possible with H&E sections.
Figure 1, bone, monkey, H&E xSO; upper inset marrow spaces (M ). In th is sample, the marrow consists pri-
B x 175.
This figure shows a decalcified section of two bones
framing a joint cavity. Artic ul ar cartilage (AC) covers the
surfaces that contact the neighboring bone. The free surface
marily of adipose tissue. In additi on to the marrow spaces,
the bone tissue also contai ns space or tunnels for blood ves-
sels (BV); in this respect, bone differs fundamentall y from
the hyaline cartilage on the articular surface, which is avas-
of each cartilage presents a relatively smooth contour, cular. The essenti al features of the bone tissue are seen at
whereas the junction between the cartilage and the bone higher magnifica tion in the upper inset. T hese are osteo-
(SB) is irregular. cytes (Oc) in lacu nae, an eosinophi lic matrix, and blood
The articular cartilage is hyaline (upper inset). It shows vessels (BV). The spongy bone shown in this figure is non-
the characteristic features of hyaline cartil age seen in Pl ate lame ll ar; i.e., the matri x is not organi zed as lamell ae, but
7, page 173, namely, chondrocytes in lacunae, a homoge- rather, the collagen fibers are in the form of interwoven
neous avascular matrix (homogeneous in that it presents no bundles. Certain fea tures of woven nonlamellar bone are
formed elements visible in the light microscope), a nd vari- also displayed in the upper inset; namely, the cells are un-
able staining of the matrix. At least some of the cartilage evenly and randomly dispersed and are not arranged in an
cells are in lacunae that are close to each other, suggesting oriented pattern around the blood vessels. For comparison,
that they are daughter cells of the same parent cell. note how the lacunae (and, therefore, a lso the osteocytes)
The bone under the articular cartil age is spongy bone. It display an oriented pattern about the Haversian canal tn
consists of spicules or trabeculae of bone tissue as well as Figure 2 of Plate 11.
have the potential to develop into osteoblasts (as do per- identi fication in longitudinal decalcified sections of a long
'"'I
~
. I' ' . _,
iosteal cells) if the need should arise, e.g., in fracture repair. bone as shown in this figure.
~ .r " .
......:.
' ; ,.t ..
..
.... .
M.... '
.... . .
~
Oc
\
KEY
AC, articular cartilage Eo, endosteum Po, periosteum Eo
BV, blood vessel M, manow spaces SB, spongy bone
CB, compact bone Oc, osteocyte
206
C H APTER 8 Bour 209
PLATE 13. ENDOCHONDRAL BONE FORMATION I
Endochondral bone fo rmati on involves the continuing growth of a cartil age precursor, which serves as a feta l skeleton, a nd
the simultaneous removal of the cartil age and its re placeme nt with bone ti ssue. In addition, as a bone grows, so me of the bone
tissue is re moved while newer bone tiss ue is be ing laid down, a process called re modeling. Re modeling that a lters the shape
of the bone is called external remodeling; that whi ch does not alte r the shape of the bone, as in the formation of Haversia n
systems, is called intem al remodeling.
Two specialized cell types are identified with the process of bone growth and remode ling. The osteoblast is engaged in the
fo rmation of bone. Although the removal of bone is not as well described as its forma tion, it has been established that multi-
nucleated cells, called osteocfasts, are engaged in the removal of bone. Osteocytes, also, can alte r and resorb bone in their im-
mediate vicinity. The process is called osteocytic osteolysis. It is important in calcium homeostasis, i.e., the maintena nce of
normal blood calci um concentrations.
Figure 1, developing bone, monkey, H&E x 240. 3. A collar of bone fo rms around the circumference of the
The earl y steps of endochondral bone formation are center of the cartilage model. This bone is called per-
shown in thi s figure. The structure seen he re is the cartilage iosteal bone ( PB ) because the osteobl asts that have pro-
mode l of the bone about to be formed. The steps of bone duced the bone material develop from the periosteum .
formation are (Note that the periosteal bone is, in fac t, intrame mbra-
I . The cartil age (C) cells in the center of the c artilage nous bone [see Plate 15, page 2 13], because it develops
model become hypertrophic (H C). wi thin the connective tissue me mbrane that immediately
2. The matri x of the cartil age becomes calcified (CM ). surrounds the developing bone and not on a spic ule of
(The calcified ma tri x sta ins intensely with hematoxylin calcified cartil age.)
and appears as the darker conde nsed matri x mate ria l be-
tween the e nlarged cartilage cells.)
Figure 2, developing bone, human, H&E x 60. 3. Cartilage cells facing the cavity become hypertrophic.
T he bone in this fig ure shows later events and a contin- 4. Cartilage matri x becomes calcified.
uati on of the earlie r ones just described. A vascul ar bud (not 5. Erosion of cartilage occurs, creating spicules of carti-
shown) and accompanying perivascul ar cells from the per- lage.
iosteum have invaded the shaft of the cartilage model, re- 6. Bone forms o n the spic ules of the c alcified cartilage at
sulting in the formati on of a cavity ( Cav). Exam.ination at the erosion front; this bone is endochondral bone ( EB ).
hi gher magn ification would reveal that the cavity contains As these processes continue in the shaft of the bone, one
fat cells, hematopoie tic ti ssue (the dark-blue-staining com- end of the cartilage model (the epiphysis) is invaded by
ponent), and other connective ti ssue elements. While the blood vessels and connecti ve ti ssue from the periosteum
new steps of bone formati on occur, the earlier steps con- (periosteal bud), and it undergoes the same changes that oc-
tinue: curred earlier in the sha ft (except that no peri osteal bone
1. Cartilage (C) cells proliferate at the epiphyses. They are forms). This same process the n occurs at the other end of
responsible for production of new matrix materi al. It is the bone. Conseque ntly, at each end o f the developing long
this process that creates lengthe ning of the bone. bone, a cartil aginous plate (epiph yseal plate) is created that
2. Periosteal bone (PB) continues to fo rm. lies between two sites of bone fo rmati on.
Figure 3, developing bone, human, H&E x60; in- physeal plate (EP). At the early stage shown in thi s figure,
set x 200. the plate is not well defined. Despi te the enlargement of the
T his shows an earl y stage after the invas ion of the epi- epiph ysea l cavi ty, the remaining cartilage between the two
physis. A secondary ossification center (Os) has formed, cavi ties persists as a disc or plate un til growth ceases. T he
a nd a long with this event, the head of the long bone wi ll de- inset shows some calcified cartil age as well as the deposi-
velop a marrow cavity si m.ilar in its content to that o f the di- tion of endochondra l bone (EB) wi thi n the secondary ossi-
aphys is. The cartilage separating the two cavities is the epi- ficati on cente r.
KEY
C, cart ilage EB, endocho ndral bone J C, j oi nt cavity
Cav, marrow cavity EP, epiphyseal plate Os, secondary ossificat ion center
CC, calci fied cartilage HC, hypertro phic cartilage cell PB, periosteal bo ne
C M, calcified matrix
208
CHA P TE R 8 Boue 2 11
PLATE 14. ENDOCHONDRAL BONE FORMATION II .., :... .. ._: :.~. : ...
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appendages and digits, increase in length to achieve their adult dimensio ns. So long as epiphyseal cartilage ex ists between the
diaph yseal a nd e piphyseal ossification centers, the bone will conti nue to g row. Cessati on of bone growth is the result of the
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cessati o n of interstitial growth of the epiphyseal carti lages. X-ray examination of the bones of late ado lescents can dete rmine .
whethe r there is s till an epiphyseal cartil age plate and , therefore, determine the potential fo r further growth in bone length and
~:: :- _ .. .. ~. ' .. ~~P~~J;~a i .Piat~, .... - .. .. .:.:: ..:. ~_- :. '. :. ,.,. -:. ... . , : .-.. .. ~.- ,~
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B
Figure 1, developing bone, human, H&E x80; Zone of hypertrophic cartilage (HC). The ce lls of this t _ : -_...: .,.; ..._-. - : :w- .:_ -
::-_. ..;;. -- v~ :::. - :.. ... .- S "- ' ...
inset x380. zone are a lig ned in rows and are significantly larger than - -~~ ' .. \?',. ;:-. .... ~ - ...._... - ~ .... c::..~
- ".::o
"' .
-..., - .:::: - .. ! .... ::: ... .. -
This is a photo microg raph of an e piphysis at hi gher the cells in the preceding zone. ~ .. ~; ~ ~ 0 .,, : '
........ :;..
mag nificatio n than that seen in Figure 3 of Plate 13. Differ- Zone of calcified matrix (C). In thi s zone the cartilage
e nt zones of the cartilage of the epiph ysea l plate reflect the matrix is impregnated with calcium salts.
progressive changes that occur in acti ve growth of endo- Zone of resorption. T his zone is represented by eroded
chondral bo ne. These zones are not s harply delineated , a nd cartilage that is in direct contact with the connective ti s-
the bo undaries between them are somewhat arbitrary. They sue of the marrow cavity. Spic ules (actually a honeycomb
lead toward the marrow cavity (M ), so that the first zone is at the level of the advancing blood vessels) of cartilage
furthest fro m the cavity. There are five zones: are formed because the pericapillary cells invade a nd re-
Zone of reserve cartilage (RC). The cartilage cells of this sorb in spea rheads rather than alo ng a stra ig ht front.
zone have not ye t begun to participate in the growth of S pecifically, the peri capillary cells break into the rows of
the bone; thus, they are reserve cells. These cells are hy pertrophie d cbondrocytes, temporaril y leaving the cal-
small, us ually o nly o ne to a lacuna, and not g ro uped . At c ified carti lage between the rows of ce ll s. In this manner,
some time, some of these cells will proliferate and un- s pic ules of calcified cartilage are formed. Endocho ndral
dergo the cha nges o utlined for the next zone. bone ( EB) is then deposited on the surface s of these cal-
Zone of proliferating cartilage (PC). T he ce lls of thi s c ified cartilage spic ules by osteoblasts (Ob), thus fo rming
zone a re increasi ng in number; they are slightl y larger mixed spicules as seen in the inset.
.--..
than the reserve cells and close to their neighbors; they
beg in to fo rm rows.
Figure 2, developing bone, human, H&E x 150; ni fication . No te the os te obl asts (Ob), some of which are
-
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-
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B inset x 380.
This is a higher magni ficatio n of the lower middle area
o f Fig ure I. It s hows calcified cartilage sp icules on whi ch
bone bas been depos ited. In the lowe r po rtio n of the fi gure,
just beginning to produce bone in apposit ion to th e calci-
fied cartilage ( C). T he lower rig ht of the inset shows bone
(EB) w ith an oste ocyte (Oc) a lready embedded in the bone
matrix.
"
-,., HC
the s pic ules have already grow n to create anasto mosing The lowet inset, an e nlargement of the right circle in
bo ne trabeculae. T hese injtia l trabeculae sti ll contain re m- Figure 2, reveals several osteoclasts (Oc/). They are in ap-
nants of ca lc ifi ed cartilage, as shown by the blue color o f positio n to the spic ule, which is mostly cartilage. A small
the cartilage matri x (compared with the red staining of the amount of bone is evident, based on the red-staining mate-
bone). Osteoblasts (Ob) are ali gned o n the surface of the rial in thi s inset. Note the lig ht are a (arrow) representing
spicul es, whe re bone fo rmati o n is active. the ruffled border of the osteoc las t. Exam ination of Figure
T he uppet inset in Figure I shows the s urface of sev- 2 reveals a number of other osteoclasts (Ocl).
eral s pic ules from the leji circle in Fig ure 2, at hi gher mag-
KEY
C, calcified carti lage matrix Ob, osteoblast PC, pro liferat ing cartilage
Ell, endochondral bone Oc, osteo cyte RC, reserve cartilage
ti C, hypertrophic cartilage Ocl, osteoclast arrow, ru ffled border of osteoclast
M, man ow
210
C HAPTER 8 Bo11e 2I3
PLATE 15. INTRAMEMBRANOUS BONE FORMATION
Intramembra nous bone formation is limited to those bones that are not required to perform an early s upporti ng function,
e.g., the Hat bones of the s ku ll. This process requires the proliferation and diffe re ntiation of cells of the mesenchyme to be-
co me osteoblasts, the bone-forming cells. T hey produce ground substance a nd co llagen. This initial matrix, call ed osteoid, cal-
c ifies to form bone.
As the osteoblasts continue to secrete their product, some are entrapped w ithi n their matrix and are then k nown as osteo-
cytes. T hey are responsible for maintenance of the newly formed bone tissue. The remaining osteoblasts conti nue the bone de-
position process at the bone surface. They are capable of reproducing to maintain as adequate population for conti nued growth.
T hi s new ly fo rmed bone appears first as spicules that enhuge and interconnect as growth proceeds, creating a three-
d imensional trabecul ar s tructure similar in shape to the f uture mature bone. The in terstices contai n blood vessels and connec-
tive tissue (mesenchyme). As the bone continues to grow, re modeling occurs. This involves resorption of localized areas of
bone ti ssue by osteoclasis in order to maintain appropriate shape in relation to size and to permit vascular nourishment during
the growth process.
Figure 1, fetal head, human, Mallory trichrome cartilage (MC), also referred to as the mand ibu lar process,
@ x45.
A cross section of the developing lower jaw bone, as seen
at this relatively early stage of development, consists of bone
seen on the left side, and the ora l cavity (OC). The botto m
surface of the specimen s hows the epidermi s (Ep) of the un-
derside of the chin. A large portion of the developing tongue
spicules ( BS) of vario us sizes and shapes. T he bone spicules is seen in the upper half of the figure. The tongue consists
inte rconnect and, in three dimensions, have the general shape largely of developing striated visceral muscle fibers arranged
of the mandible. Other structures present that will assist in in a three-dimensional orthogonal array that is characteristic
orientation include develo ping teeth ( DT), the tip of Meckel's of th is organ.
Figure 2, fetal head, human , Mallory trichrome as well to the cells that will fo rm the vascu lar com ponents
Ed x175.
Th is hig her-magnification view of the boxed area in Fig-
ure 1 shows the interconnecti ons of the bone spicules ( BS)
of the developing mandible. Within and around the spaces
of the bone. The more dense connecti ve tissue (CT) will
differentiate into the perioste um on one side of the devel-
oping ma nd ible. Other structures s hown in the field include
numerous blood vessels (BV) a nd the e namel organ (EO) of
e nclosed by the developi ng s picules is mesenc hyma l ti ssue. a developing tooth.
T hese mesenchymal cells w ill g ive ri se to new osteoblasts
Figure 3, fetal head, human, Mallory trichrome cells adj acent to osteoid. One of the spicules shows a cell
@ X350.
This hig her-magnificatio n mi crograph of a portion of
the fi eld in F ig ure 2 shows to advantage the d istinctio n be-
completely surrounded by bo ne matrix; this is an osteoblast
that has become trapped in its own secretions and is now a n
osteocyte (OC). At this magnification, the very loose con-
tween new ly deposited osteoid, which stains blue, and min- nective tissue characteristics of the mesenchyme and the
eralized bone, which stai ns red. Osteoblas ts are seen in two s parseness of the mesenchymal cells (MC) me well demon-
d ifferent levels of acti vity. T hose that are re latively inactive s trated. T he high ly cellular connec tive tissue (CT) o n the
and are in appositio n to well-forme d osteoid (Ob') ex hibit right margin of the figure is the deve lopi ng perichondrium.
e longate nuclear profiles and a ppear to be flattened o n the Some of its cells will also develop into osteoblasts to a llow
surface of the osteoid. Those osteoblasts (Ob2) that are ac- g rowth of the bone at its surface.
tively secreting new osteoid appear as tall, columnar-like
KEY
BS, bone spicules EO, enamel organ Ob', inacti ve osteoblast
BV, blood vessels Ep, epitheliu m Ob\ active osteoblast
CT, connective tissue MC, Meckel's cartilage OC, oral cavity (Fig. 1.)
DT, developing tooth OC, osteocyte (Fig. 3.)
212
Mai ntenance of homeostasis by acting as a buffer and by t he huffy coat. As Table 9.1 indicates, th ere are nearl y
participating in coagul ation and therm o regula tio n 1000 times more erythrocytes (-5 X 10 12 cells/L of blood)
Tra nsport of humoral agents and cells of the immune than leukocytes (-7 X 109/L o f blood ).
system that protect t he bod y fro m pathogenic agents,
fo reign protein s, an d transformed cells, i.e., cancer cells
\lPLASMA
Blood Blood consists of cells and their derivatives and a protein-rich
fluid called plasma Altho ug h the blood cells are the major objects of inter est
in histology, a brie exa mina tion of plasma is also useful.
Blood cells and their derivati ves incl ude The composition o f p lasma is summarized in Table 9.2.
M ore th an 90% of plasma by weigh t is water, w hich serves
OVERVIEW OF BLOOD 214 E1'ythrocytes, also ca lled red blood cells (RBCs) as the solvent fo r a va riety of so lutes, including p roteins,
Leukocytes, also called white blood cells (WBCs) d issolved gases, electrol ytes, nutrients, regulatory su b-
PLASMA 215 Platelets stances, an d waste materials.
ERYTHROCYTES 217
Plasma is tl1e liquid extrace llula r material t hat imparts Plasma proteins consist primarily of albumin, globulins,
LEUKOCYTES 221 fluid properties to blood. The re lative volu me of cells a nd and fibrinogen
Neutrophils 221 plasma in w ho le blood is approximately 45 and 55%, re-
Eosinophlls 224 specti vely. The voJu me of packed erythrocytes in a sam- Albumin is the ma in protein constituent of the plasma,
Basophils 224
ple of blood is ca lled the hematocrit. It is obtained by accounting for approximately ha lf of the total plasma pro-
Lym phocytes 225
cen trifuging a blood sample to wh ich anticoagu lants have teins. It is the sma llest plasma protein (a bout 70 kDa ) a nd
Monocytes 228
been a dded. The hematocrit reading is then obta.i ned by is made in the liver. Albumin is responsible for exerting the
PLATELETS 229 measuring the perce ntage of the centrifuge tube volume concen tratio n g radient between blood and extrace llular
occupied by the erythr ocytes, compa red with the whole tiss ue flui d. T his ma jor osmotic pressure o n the blood ves-
FORMATION OF BLOOD CELLS (HEMOPOIESIS) 231
bloo d vo lume. A no rm al rea ding is abo ut 39 to 50 in sel wa ll , called t he colloid osmotic p1'essure, mainta ins t he
Monophyletic Theory of Hemopoiesis 233
Development of Erythrocytes (Erythropoiesis) 233
ma les a nd 35 to 45 in females; thu s 39 to 50% or 35 to correct propo rtion of blood to tissue fluid volume. If a sig-
45% of t he bloo d volu me, r espectively, co nsists of eryth- nifican t amou nt o f albu min lea ks o ut of t he blood vessels
Kinetics of Erythropoiesis 236
rocytes. into the loose connecti ve tissue or is lost from the blood to
Development of Granulocytes (Granulopoiesis) 237
Leu kocytes and platelets constitute o nly 1% of the th e u rine in th e kid neys, t he colloid osmotic pr essure of the
Kinetics of Granulopoiesis 2 3 8
blood volume. In a blood sample that has been cen- blood decreases, and fluid accumulates in the tissues. (This
Monocyte Development 239
trifuged, t he cell fraction (the part of the sample that con- increase in tissue flui d is most readily noted by swelling o f
Megak aryocyte Dev elopment 240
ra ins the cells) consists ma inly of packed erythrocytes the ankles at the end of a d ay.) AJbumin a lso acts as a car-
Lym phopoiesis 240
(>99%). The leu kocytes an d platelets are conta ined in a rier protein; it binds a nd tra nsports hormones (thyroxine),
BONE MARROW 240 na rrow layer at the upper part of th e cell frac tio n, ca lled metaboli tes (bilirubin ), and drugs (bar biturates) .
BOXES
sox 9.1. Clinical Correlations: ABO and Rh Blood Group Systems 219
BOX 9.2. Clinical Correlations: Hemoglobin Di sorders 220 TABLE 9.1 . Formed Elements of the Blood TABLE 9.2. Composition of Blood Plasma
BOX 9.3. Clinical Correlations: Hemoglobin Breakdown and Jaundice 237
Cells/L
2 14 2 15
2 I6 CHAPTER 9 Blood CHAPTER 9 Blood 2I7
Globulins include the immunoglobuli1ts (y-globulins), and spread th inly over the surface of the slide, i.e., ration ma y then be examined with a high-power o il- erythrocytes are appropriately r eferred to as the "histo-
the largest component of the globulin fraction, and nonim- "pulled" with the edge of another slide, to produce a immersion lens, with or without a coverslip (Fig. 9 .lb). logic ru ler."
mune globulins (a- and {J-globulins). The im mu noglobu- monolayer of cells (Fig. 9.la ). T he preparation is then air The modified Rom anovsky-type stain commonl y used Because both li vi ng and preserved erythrocytes usually
li ns are antibodies, a class of functional immune-system dried and stained. Another difference in the preparation of for blood smears consists of a mix ture of meth ylene blue appear as biconcave disks, they can give the impressi on
m olecu les secreted by plasma cells. (A ntibodies a re dis- a blood smear is that instead of H & E, special mixtures of (a basic dye), related azu res (also basic dyes ), and eosin (an that.their form is rigid and inelastic (Fig. 9.2 ). T hey are,
cussed in C hapter 13.) dyes are used to stain the blood cells. T he resulting prepa- acidic dye). On the basis of their appearance after staining, in fact, extremely deformable. They pass easi ly through
Nonimm une glob ulins are secreted by the liver. They leu kocytes a1e traditionally di vided into gra nu locytes and the smallest blood vessels by folding upon themselves and
help maintai n the osmotic press ure within th e vascular agran ulocytes. Although both cell types may contain gran- can thus pass through even the narrowest capillar ies.
system and also serve as carrier pro teins for various sub- ules, the gra n ulocytes possess obvious, specifically stained T hey sta in uniformly with eosin. In thin sections viewed
stan ces such as copper (by ceruloplasmin ), iron (by trans- gran ules in theiJ: cytoplasm. In general, the basic dyes stain with the tra nsmission electron microscope (T EM), the
ferri n), and hemog lobin (by haptoglobin). Nonimmune n uclei, granu les of basophils, and the RNA of the cyto- contents of an erythrocyte appear as a dense, finely gran-
glo bulins also include fibronectin, li poproteins, coagul a- plasm , w her eas the acidic d ye sta ins the erythr ocytes and ular mater ia l (Fig. 9.3).
tion factors, and other molecules that may exchange be- the granules of eosinop hi ls. It was or igina lly thought that
tween the blood an d the extravasc ul ar connective tissue. the fine neutrophil granules wer e stained by a "neutral The shape of the erythrocyte is maintained by membrane
Fibrinogen, the largest protein (340 kDa), is made in the dye" that formed when methylene blue an d its r elated proteins
li ver. In cascade reactions with other coagulation factors, azures were combined with eosin. H owever, the mecha-
fibrinogen is transformed into fibrin, which for ms an in- nism by which the specific neutrophil g ranules are stained The cell membrane of an eryduocyte is com posed of a
soluble clot that stops blood flow in the event of damage is not clear. Some of the basic d yes (the azures) are typica l lipid bilayer and contains two functionally sign ifi-
to the blood vessel. m etachromatic and may impart a violet to red color to the cant groups of proteins:
Aside from these la rge proteins and the regulatory su b- mater ial they stain.
Integral membrane proteins repr esent most of the pro-
sta nces, which are small proteins or polypeptides, most of a teins in the lipid bilayer. T hey consist of two major fam-
the other plasma constituents are small enough to pass ilies: glycophorins and band 3 protein. T he extracellular
through the blood vessel wall into the extracel lular spaces \1 ERYTHROCYTES doma ins of these integral membrane proteins are glyco-
of the adjacent connective tissue. sylated and express specific blood group an tigens. Gly-
In general, plasma proteins react with common fixatives; Erythrocytes are anucleate, biconcave disks
cophorin C, a mem ber of the glycophorin fam ily, plays
they a re often retained within the blood vessels in tiss ue an impo rtant role in attaching the underlying cytoskele-
secti ons. Plasma proteins do not possess structura l form Erythrocytes, o r red blood cells (RBCs), are anucleate
ta l protein network to the cell membrane. Band 3 pro-
a bove the molecular level; thus, when they are reta ined in cells devo id of typical organelles. They function only
tein bi nds hemoglobin a nd acts as an additional anchor-
blood vessels in the tissue block, they appea r as a homo- with in the bloodstream to bind oxygen for del ive ry to the
ing site for the cytoskeletal proteins (Fig. 9.4 ).
geneous substance that stains evenl y with eosin in hema- tissues a nd, in exchange, bi nd car bon dioxide fo r removal
Peripheral membmne proteins reside on the inner sur-
toxylin and eosin (H &E)-stained sections. from the tissues. Their shape is tha t of a biconcave d isk
face of the cell membrane. They are organized into a
wi th a di ameter of 7.8 JLm, an edge thickness of 2.6 JLm,
two-dimensional hexagonal la ttice network that lami-
The interstitial f luid of connective tissues is derived from blood an d a central th ick ness of 0.8 JLm. T his shape maximizes
na tes the in ner layer of the membrane. T he lattice itself,
plasma the cell's surface area (-140 JLm 2 ), an important attribute
w hich is positioned parallel to th e membrane, is com-
in gas excha nge.
posed mainl y of spectrin tetramers, actin, band 4.1, ad-
Interstitial fluid, not surprisingly, has an elecuolyte com- ducin, band 4.9, and tropomyosin (see Fig. 9.4 ). T he
positio n th at reflects that of blood plasma, fro m wh ich it lattice is anchored to the lipid bilayer by ankyrin, which
is derived. The composition of interstitia l fl uid in no n- interacts with band 4.2 protein as well as wi th band 3
connective tissues, however, is subj ect to considera ble integral membrane protein.
mod ificatio n by the a bsorptive and secreto ry activities of
epithel ia. Epithelia may create specia l microenvironrnents This unique cytoskeletal arrangement contributes to the
conducive to their function. For exa mple, a blood-bra.in shape of the erythrocyte and imparts elastic properties and
barrier ex ists between the blood and nerve tiss ue. Barriers stability to the membrane. The cytoskeleton is not static; it
a lso exist between the blood a nd the parenchymal tissue in undergoes contin uous rearrangement in response to vari-
th e testis, thymus gla nd, eye, and other epithelia l compart- 7.8,u.m ous physica l factors and chemical stim uli as the cell moves
ments. Fluids, barriers, and their function s a re discussed in through the vascular network. Any defect in the expression
subseq uent chapters that describe these pa rticu lar organs. of genes that encode these cytoskeleto n proteins can result
The life span of the erythrocyte is approximately 120 in abno rma lly shaped and fragile erythrocytes. For in-
Examination of blood cells requires special preparation and days, after which most (-90%) are phagocytosed by stance, hereditary spherocytosis is caused by a primary de-
FIGURE 9.1 macro phages in th e spleen, bone marrow, and liver. The re- fect in spectrin gene expression that results in spherical
staining
Blood smear: preparation technique and overview photomicro- maini ng aged erythrocytes (-10 %) break down intravas- erythrocytes. Hereditary elliptocytosis is caused by a defi-
graph. a. Photograph showing the method of producing a blood cularly, releasing hemoglobin into the blood.
The prepa ra tion method that best d isplays the cell types ciency in band 4. 1 protein that results in ell iptic eryth ro-
smear. A drop of blood is placed directly on a glass slide and spread
of periph eral blood is the blood smear. This method d iffers In H &E- stained sections, erythrocytes are usually 7 to cytes. In both conditions, erythrocytes are unable to adapt
over its surface with the edge of another slide. b. Photomicrograph of
from the usual preparation seen in the histology laboratory 8 JLm in diam eter. Because their size is relatively consistent to changes in their environment (e.g., osmotic pressure and
smear from peripheral blood, stained with Wright's stain, showing
in that the specimen is not embedded in paraffi n and sec- the cells evenly distributed. The cells are mainly erythrocytes. Three
in fixed tissue, they can be used to estimate the size mechanical deformations), which results in destruction of
tioned. Ra ther, a d rop of blood is placed directl y on a slide leukocytes are present. x 350. of other cells and structures in tissue sectio ns' in this ro le , the cells, or hemolysis.
2 18 CHAPTER 9 /3/ood CHA PTE R 9 13/ood 2 19
FIGURE9.2
Erythrocyte morphology. a. Photomicrograph of three capillaries ing through very narrow capillaries. The large round structures are
(Cap) j oining to form a venule (V), as observed in adipose tissue within adipose cells (A). X 470. b. Scanning electron micrograph of erythro-
a full-thickness mesentery spread. The erythrocytes appear in single cytes collected in a blood tube. Note the concave shape of the cells.
file in one of the capillaries (the other two are empty). The light center Tile stacks of erythrocytes in these preparations are not unusual and An important factor in blood transfusion is the ABO blood group resented by an Rh transmembrane polypeptide that shares anti-
area of some of the erythrocytes is due to their biconcave shape. are referred to as rouleau. Such formations in vivo indicate an in- system, which essentially involves two antigens called A antigen genic sites with rhesus monkey erythrocytes. Although the Rh
Erythrocytes are highly plastic and can fold on themselves when pass- creased level of plasma immunoglobulin. X2,800. and B antigen (Table 9.3). These antigens are present on the sur- polypeptide expresses many antigen sites on its extracellular do-
face of the erythrocyte, attached to the extracellular domains of main, only three of them-D. C. and E antigens-have clinical sig-
glycophorins, which are integral membrane proteins. Individuals nificance. An individual who possesses only one of these three
with A antigens possess serum anti-B antibodies that are directed antigens is referred to as Rh positive (Rh +). All three antigens stim-
against the B antigen. Individuals with B antigens possess serum ulate production of anti-Rh antibodies in individuals without the
anti-A antibodies that are directed against A antigen. The presence same antigens.
of A or B antigens and anti-A or anti-B antibodies determines the Rh incompatibility may induce a hemolytic transfusion reaction
four primary blood groups: A, B, AB, and 0. Individuals with blood and in newborns cause the hemolytic disease erythroblastosisfe-
group AB do not have antibodies directed against A or B antigens. talis. Erythroblastosis fetalis occurs in Rh(D)+ newborns delivered
Thus, they are universal acceptors of any blood type. Group 0 in- by Rh(D)- mothers and results from an immune reaction of anti-D
dividuals have both anti-A and anti-B antibodies in their serum an{! immunoglobulins passed across the placenta from the mother. The
neither A nor B antigens on their erythrocytes. Thus, these individ- anti-D antibodies are produced by the mother in response to the D
uals are universal blood donors. If an individual is transfused with antigen expressed on the fetal erythrocytes that leak into her cir-
blood of an incompatible type, the recipient's antibodies will attack culation during pregnancy. Administration of anti-0 antibodies
the donor erythrocytes, causing a hemolytic transfusion reaction, (RhoGAM) to the mother during the pregnancy and following par-
or destruction of the transfused erythrocytes. turition destroy any circulating Rh(D)+ fetal erythrocytes that persist
The other important blood group system, the Rh system, is in the mother's blood, thus preventing Rh Incompatibility reactions
based on the Rhesus (Rh) antigen. In humans, this system is rep- in future pregnancies.
in slightly higher percentages than normal in sickle cell dis- nucleus; thus, they are a lso called polymorphonuclear neu-
ease and tha lassemia, it does not appear to have a patho- trophils or polymorphs. Mature neutrophils possess two to
logic role. A monomer of hemoglobin is similar in compo- four lobes of nuclear material joined by thinner nuclear
sition and structure to myoglobin, the oxygen-binding strands. The arrangement is not static; rather, in living neu-
protein found in striated muscle. trophils the lobes and connecting strands change their
shape, position, and even number.
FIGURE 9.5
The chromatin of the neutrophi l has a characteristic
Structural diagram of the hemoglobin molecule. Each hemoglobin mole Q LEUKOCYTES arrangement. Wide regions of heterochromatin are located
cu le is composed of four subunits. Each subun it contains a heme, the iron-
containing portion of hemoglobin, embedded in a hydrophobic cleft of a
chiefly at the periphery of the nucleus, in contact with the
Leukocytes are subclassified into two general groups. The nuclear envelope. Regions of euchromatin are located
globin chain. The folding of the globin.chain places the heme near the sur
basis fo r this division is the presence or a bsence of pr omi- chiefly at the center of the nucleus, with relatively smaller
face of the molecule, where it is readily accessible to oxygen. There are four
nent specific granules in the cytoplasm. Cells containing regions contacting the nuclear en velope (Fig. 9. 7). In fe-
different types of globin chains: a, {3, 8, and y, which occur in pairs. The
specific gra nules are classified as granulocytes (neu- males, the Barr body for ms a drumstick-shaped appendage
types of globin chains present in th e molecules determine the type of he-
moglobin. The figure illustrates hemoglobin A (HbA), Wh ich is composed of
trophils, eosinophils, and basophils), and cells that lack on one of the nuclear lobes.
two a and two {3 chains. specific granules are classified as agranulocytes (lympho-
cytes and monocytes). Howevet; both agranulocytes and Neutrophils contain three types of granules
granu locytes possess sma ll, nonspecific azurophilic gran-
ules, which are lysosomes. The relative number of the var- The cytoplasm of a neutrophil contains three kinds of
ious leukocytes is given in Table 9.1. granules. The different types of granu les reflect the various
phagocytotic functions of the cell:
ANEMIA of this mutation is an abnormal. ,B-globin chain in which the
Neutrophils
amino acid valine is substituted for glutamic acid in position 6. Specific granules (secondary granules) are the smallest
Anemia is defined clinically as a decrease in the concentration of
hemoglobin in the blood for the age and gender of an indiv idual. Hemoglobin containing this abnormal ,B-glbbin chain is desig- Neutrophils are the most numerous WBCs as well as the most granules and are at least twice as numerous as azuro-
Wh ile in certain anemias this decreased concentration of hemo- nated sickle hemoglobin (HbS). The su.bstitution of th'e hydropho- common granulocyte philic granules. They are barely visible in the light mi-
globin is due to a decrease in the amount of hemoglobin in each bic valine for the hydrophilic glut amic acid causes HbS to aggre croscope; in electron micrographs they are ellipsoidal
cell, most anemias are caused by a reduction in the number of gate under conditions of reduced 'oxygen tension. lristead of the Neutrophils measure 10 to 12 pm in diameter in blood (see Fig. 9 .7). Specific granules contain various enzymes
erythrocytes. Causes of anem ia include loss of blood (hemor- normal biconcave disk shape, many of the erythrocytes become smears and are obviously larger tha n erythrocytes. Al- (type N collagenase, phospholipase) as well as comple-
rhage), insufficient production of erythrocytes, or accelerated de- sickle-shaped at low oxygen tension, hence the nam.e of th is dis- though named for their lack of characteristic cytoplasmic ment activators and other bacteriostatic and bactericidal
struction of erythrocytes in the circulation. Insufficient dietary iron ease (Fig. 9.6). Sickled erythrocytes are more rigid than normal
staining, they are a lso readily identified by their multilobed agents (lysozyme) .
or deficiencies of vitam ins such as vitamin 812 or folic acid can cells and adhere more readily -to the endothelial surface. Thus,
lead to decreased production of erythrocytes. Gastric atrophy, as sickled erythrocytes may pile up in the smallest capilla ries, de
a result of autoimmune disease, with concomitant destruction of priving portions of tissues and organs of oxygen an.d nutrients.
the parietal cells that secrete intrinsic factor, a molecule essential Large-vessel obstructfon may also occur, w hich in children fre
for absorption of vitamin 8,2 by cells in the ileum, is the cause of quently leads to stroke. Sickled erythrocytes are also m'o re fragile
a form of anemia called pernicious anemia. and break down or are destroyed more quickly than normal ery-
throcytes.
SICKLE CELL DISEASE Sickle cell disease is a homozyg~us re.cessive genetic disorder.
However, heterozygous indiViduals may occasionally have clin ical
Sickle cell disease is caused by a single point mutation in the consequences a~ high altitude or under e'xtreme physical stress.
gene that encodes the ,Bglobin chain of hemoglobin A. The result
FIGURE 9.7
Electron micrograph of a human mature
neutrophil. The nucleus shows the typical
multilobed configuration w ith the hetero-
chromatin at the periphery and the euchro-
matin more centrally located. A small Golgi
apparatus (G) is present; other organelles
are sparse. The pu nctate appearance of the
cyto plasm adjacent to the convex aspect of
the nuclear profile is due to glycogen parti-
cles. Adjacent to the concave aspect of the
nuclear profile are numerous granules. Spe-
cific granules appear less dense and more
rounded than azurophilic granules. The lat-
ter are fewer in number and are extremely
FIGURE 9.6 electron dense. x 22,000. (Courtesy of Dr.
Photomicrograph of a sickle cellanemia blood smear. Blood
Dorothea Zucker-Franklin.} For comparison,
smear stained with Wright's stain shows abnormal "boat" and
the inset shows a neutrophil. from a blood
"sickle' -shaped cells from an Individual with sickle cell (!ne-
smear observed in the light microscope.
mia. X400.
Xl ,BOO.
:n o
:2 2 2 C HAPTER 9 Bloor/
immunoglobin superfamily
Azurophilic granules (primary granules) ar e larger and 9.7). The fin ely granular appearance is due to the presence
less numerous than specific granules. T hey arise early in of actin filamen ts, some microtubules, and glycogen,
granulopoiesis and occur in all granulocytes, as well as which are invol ved in the extension of t he cytoplasm to
in monocytes and lymphocytes. The azurophilic gran- form the pseudopod and the subsequent contraction that
ules are t he lysosomes of t he neutrophil and contain pulls the cell forward. O nce the neutrophil enters the con-
myelopemxidase, which appears as a finely stippled ma- necti ve tissue, fur ther migration to the injury site is di-
teria l w it h the TEM. Myeloperoxidase helps to generate rected by a process k nown as chemotaxis, the binding of
highly reactive bactericidal hypochlorite and chlor- chemoattractant molecules and extracellular matrix pro-
amines. In addition to a variety of the typical acid hy- teins to specific r eceptors on the surface of the neutrophil.
drol ases, azurophilic gra nules also contain cationic pro- oD
teins called defensins, which in function are analogous Neutrophils are active phagocytes at the site of inflammation ootJ
to antibodies. C!
heparin & chemoattractant
Tertiary granules in neutrophils are of two types. One Once at the site of tissue injury, the neutrophil m ust rec-
histam ines molecules
type contains phosphatases and is so metim es called a ognize any foreign substance before p hagocytosis can oc-
phosphasome. The other type contains metallopro- cur. Neutrophils can recognjze some bacteria and foreign
teinases, such as gelatinases and collagenases, wh ich are organisms t hat have had no modifications m ade to their FIGURE 9.8
thought to facilitate the migration o f the neutrophil surfaces, w hereas others must be opson ized (coated with Diagram of events in the migration of a neutrophil from a postcap- tile neutrophil, such as integrin s (VLA-5) and the immunoglobulin su-
through t he connective tissue. antibo dies and/or complement) to make them more attr ac- illary venule into the connective t issue. a. Circulating neutrophils are perfamily of ad hesion molecules (e.g., ICAM, VCAM). e. These adhe-
tive to the neutrophil. After r ecognition and attachment, slowed down by the interaction of their surface adhesion molecules, sion molecules allow the neutrophil to bind to adl1esion molecule re-
Aside from these granules, membrane-bounded or- the antigen is engulfed by extended pseudopods of the neu- selectins (CD62L), with the endothelium of the venule (b). c. As the re ceptors on the endothelial cells. f. The neutrophil then extends a
suit of this interaction, the cell rolls on the surface of the endothelium. pseudopod to an intercellular j unction previously opened by hista-
ganelles are sparse. A small Golgi appa ratus is evident in trophil and internalized to form a phagosome (Fig. 9.9).
The neutrophil then adheres to the endoth elium and responds to mine and heparin released from the mast cells in the connective tis-
the center of the cell, and mitochondria are relatively few Specific and azurophilic granules then fuse w ith the phago-
chemokines secreted by the endothelial cells. d. Their secretion in- sue, allowing the neutrophil to migrate through the vessel wall (g).
in number (see Fig. 9.7) . some membr ane, and the lysosoma l hydrolases of t he
duces the expression of other adhesion molecules on the surface of
azurophilic granules digest the foreig n material. After di-
Neuttophils ate motile cells; they leave the circulation and gestion, the degraded material is stored in residual bodies
azurophilic phagosome
migrate to their site of action in the connective tissue or exocytosed. Most neutrophils die in this process; t he ac- pseudopod
ranul e
cum ulation of dead bacteria and dead neutrophils consti- Fe receptor antibody
An important property of neutrophils and other leuko- tutes the t hick yellowish exudate called pus.
cytes is their motility. Neutrophils are the most numero us Neutrophils also secrete interleukin-1 (IL-l), a substance
of the first wave of cells to enter an area of tiss ue damage. kn own as a pyrogen (fever-induc ing agent). IL-l induces
Their migra tio n is con trolled by the expression of adhesion synthesis of prostaglandins, w hich in turn act on the t her-
molecules o n the neutrophi l surface th at interact with cor- moregulatory center of the hypothalamus to produce fever.
responding ligands o n endothelial cells (Fig. 9.8). Fever is therefo re a consequence of acute inflammation in-
The ini tial phase of neutrophil migration occurs in the volving a m assive neutroph ilic response.
postcapillary venules and is r egulated by a mechanism in-
volv ing neutrophil-endothelial cell recognition. Selectins Inflammation and wound healing also involve monocytes,
on the surface of the circulating neutrophil (CD62L) inter- lymphocytes, eosinophils, basophils, and fibroblasts lysosome
act with receptors (GlyCA M-1 ) on the surface of the en-
dothelial cells. The neutrophil becomes partially tethered Monocytes also enter the connective ti ssue as a second- phagolysosome
to the endothelia l cell as a result of tl1is interaction, w hich ary response to tiss ue injury. At the site of tissue injury
slows the neutrophil and causes it to roll on the surface of they transform into macrophages that phagocytose cell
the endothelium. In t he second phase, another group of ad- and tissue debris, fibrin, remaining bacteria, and d ead
hesion molecules on the neutrophil surface, called integ- neutrophils. Normal wound healing d epends o n the p ar -
rins (VLA 5), are activa ted by chemokine signa ls from the ticipation of macrophages in the inflammatory r esp onse;
endo thelial cells. In the third p hase, integrins and other ad- they become the majo r cell type in the inflammatory si te
hesion molecul es fro m the imm unoglobulin superfamily after the neutrop hils a re spent. At the sam e time t hat the
(e.g., ICAM, VCAM) expressed on t he neutrophil surface macrophages become active a t the site of inflammation,
engage w ith their specific receptors on t he endothelial cells, fibrobla sts near the site and undiffe rentiated mesenchy-
attaching the neutrophil to the end otheli al cell. T he neu- ma l cells in t he adventi tia of small vessels at the site be-
trophil then extends a pseudopod to an intercellular junc- gin to divide and d ifferentiate into fibroblasts and myo fi- FIGURE9.9
tion. Histamine a nd heparin r eleased at the injury site by br oblasts t hat w ill secrete t he fiber s and gr ound Neutrophil phagocytosis. a. Phagocytosis begins with recognition release their contents, form ing a pllagolysosome. This fusion and re
perivascular mast cells open the intercellula r junction, al- substa nce of the healing wo und. Like ne utrophils, mono- and attachment of foreign material (antigen), mainly by Fe recepto rs lease of granules Is called degranulation. f. The enzymatic contents of
lowing the neu trop hil to migrate into the com1ective tissue. cytes are attracted to the inflamma tory site by chemo- that interact with tile Fe region of antibodies bound to the antigen. the granules are responsible for killing and digesting the microorgan-
b. The antigen is then engulfed by pseudopods of the neutrophil. ism. The entire digestive process occurs within the phagolysosome,
With the TEM, the cytoplasmic contents of a neutrophil taxis. Lymphocytes, eosinophils, and basophils also play
c. As the pseudopods come together and fuse, the antigen is inter- which protects the cell from self-injury. g. The digested material is ei-
pseudopod appear as an expanse of finel y granular cyto- a role in inflammation, bu t they are more involved in the
nalized. d. Once the phagosome is formed, digestion is initiated by ac~ ther exocytosed into the extracellular space or stored as residual bod-
p lasmic matrix with no membranous orga nelles (see Fig. immunologic aspects of the process (see C hapter 1 3) . tivation of membrane-bounded oxidases of tile phagosome. e. Next, ies within the neutrophil.
both specific and azurophilic granu les fuse with the phagosome and '223
224 CHAPTER 9 Blood C HAPTER 9 Blood 225
Eosinophils and lymphocytes are more commonly found in the lamina propria of the intestinal tract and at other
at sites of chronic inflammation. sites of poten tial chronic inflamma ti on.
Eosinophils Basophils
Eosinophils are named for the large, eosinophilic, refractile Basophils are the least numerous of the WBCs, accounting
granules in their cytoplasm for less than 0.5/o of the total leukocytes
Eosi11ophils are about the same size as neutrophils, and Often, several hundred WBCs must be examined in a
their nuclei are typically bilobed (Fig. 9.10). As in neu- blood smear before one basophil is found. Basophils are
trop hils, the compact heterochromatin of eosinophils is about the same size as neutrophils and are so named be-
chiefly adjacent to the nuclear envelope, whereas the eu- cause the numerous large gran ules in its cytoplasm stain
chromatin is located in the center of the nucleus. The cy- with basic dyes . The lobed basophil nucleus is usually ob-
tOplasm contains two types of granules: numerous, large, scured by t he gra nules in staiped blood smears, b ut its
elongated specific granules and azurophilic gran ules (oth- characteristics are evident in electron micrographs
erwise, t he eosinophil contains only a sparse representa- (Fig. 9.11). Heterochromatin is chiefly in a peripheral lo-
tion of membranous o rganelles). cation, and euchromatin is chiefly centrally located; typical
cytoplasmic organelles are sparse. The basophil plasma
Specific gra11ules of eosinophils contain a aystalloid membrane possesses numerous Fe receptors for im-
body that is read ily seen with the TEM, surrounded by munoglobulin E (1gE) antibodies. 1n addition, a specific
a less electron-dense matrix. These crystalloid bod ies are 39-kDa protein called CD40L is expressed on t he ba-
responsible for the refractivity of the gran ules in the sophil's surface. CD40L interacts with a complemen tary FIGURE 9.10
light microscope. They conta in four major proteins: an receptor (CD40) on B lymphocytes, which results in in - Electron micrograph of a human eosinophil.
arginine- ri ch protein called major basic protei11 (MBP) creased synthesis of IgE. The nucleus is bilobed, but the connecting
that acco unts for the intense acidophilia of the granule, The basophil cytoplasm contains two types of granules: segment Is not within the plane of section.
eosi11ophil catio11ic protei11 (ECP), eosi1wphil peroxi- specific gr anu les that are larger than t he specific granules The granules are of moderate size, compared
dase (EPO), and eosi11ophil-derived 11eurotoxi11 (EDN). of the neutrophjl a nd nonspecific aztJrophilic granules. with those of the basophil, and show a crys
MBP is localized in the crystalloid body; the other three talline body (Cr) within the less electron
proteins ar e found in the granule matrix. Specific gran- Specific granules exhibit a grainy texture and myelin fig- dense matrix of the granule. M, mitochon-
ules a lso contain histami11ase, arylsulfatase, collage- ures when viewed with the TEM. These granules contain dria. x 26,000. (Courtesy of Dr. Dorothea
a variety of substances, namely, heparan sulfate, hista- Zucker-Franklin.) Inset. Light microscopic im-
nase, and cathepsins. MBP, ECP, an d EPO have a strong
mine, and SRS-A. Histamine and the SRS-A are vasoac- age of an eosinophil from a blood smear.
cytotOxic effect on protozoans and helminthic parasites; Xl ,BOO.
EDN causes nervous system dysfu nction in parasitic or- tive agents t hat, among other actions, ca use dilation of
ganisms; histaminase neutralizes t he activity of hista- small blood vessels. Heparan sulfate is a sulfated gly-
mi ne; and arylsulfatase neutral izes slow-reacting sub- cosaminoglycan that is closely related to the hepar in
found in the granules of tissue mast cells. The amount of m ast cells are present in blood but do n ot develop u ntil natural killer (NK) lymphocytes (see below). In the blood-
stance o f anaphylaxis (SRS-A) secreted by basophils (see they leave t he circulation and lodge in tissue sites.
sulfate in this molecule acco unts for the intense basophilia stream, most lymphocytes are small or medium sized, 6 to
C hapter 5, page 145).
of the specific granules of the basophil. No role for hep- 15 ,um in d iameter. The majority-more than 90%-are
A zurophilic granules are lysosomes. T hey contain a va-
riety of the usual lysosomal acid hydrolases and ot her aran sulfate in inflammation has yet been elucidated. Lymphocytes small lymphocytes.
hydrolytic enzymes that function in destruction of para- Azurophilic granules are t he lysosomes of basophils and
contain a va riety of t he usual lysosoma l acid hydrolases Lymphocytes are the main functional cells of the lymphatic or In blood smears, the small lymphocyte approximates the size
sites and hyd rol ysis of antigen-antibo dy complexes in-
similar to th ose in other leukocytes. immune system of a erythrocyte
ternalized by the eo sinophil.
The function of basophils is closely related to that of mast cells Lymphocytes are the most common agran ulocytes and When observed in the light microscope in a blood smear,
Eosinophils are associated with allergic reactions, parasitic account for about 30% of the total blood leukocytes. In the small lymphocyte has an intensely sta ini ng, slightly in-
infections, and chronic inflammation Basophils are functionally related to, but not identical understanding the function o f the lymphocytes, one must dented, spherical nucleus. The cytoplasm appears as a very
with, mast cells of the connective tissue (see Table 5.6) . real ize that most lymphocytes found in blood o r lymph thin, pale blue rim surrounding the nucleus. In genera l,
T he release of arylsulfa tase and histam inase by Both m ast cells and basophils bind an a nti body secreted by represent recirculating immunocompetent cells, i. e., cells there are no r ecognizable cytoplasmic o rga nelles, other
eosinop hils at sites of allergic reaction moderates the po- plasma cells, lgE, t hrough Fe receptors expressed on their that have d eveloped the capacity to recognize and respond than an occasiona l fine azurophilic granu le. The TEM re-
tentially deleterious effects o f inflammatory vasoactive cell surface. The subseq uent exposu re to, and reaction to antigens and are in tra nsit from o ne lymphatic tissue to veals t hat the cytoplasm p rimari ly contains free ribosomes
agents. T he eosinophil also participates in other immuno- with, t he antigen specific for lgE triggers the release of va- another. In the tissues associated with the immune system and a few mitochond ria. Other organelles ar e so sparse
logic responses, and p hagocytoses antigen-a ntibo d y com- soactive agents from the basophil and mast cell gran ul es. (C hapter 13), th ree gro ups of lymphocytes can be iden ti- that they are usua ll y not seen in a t hjn section. Small,
plexes. Thus, the count of eosi nophils in blood samples of These substances are responsible for the severe vascular fied accord ing to size: small, medium, and large lympho- dense lysosomes that correspond to the azurophil ic gran-
individua ls with allergies and parasitic infections is usua ll y distu rbances associated with hypersensitivity and anaphy- cytes, ranging in djameter from 6 to 30 J-1111. The large lym- ules seen in the light m icroscope are occasionally observed;
high. Eosinophils play a ma jor role is host defense aga inst laxis. Furthermore, both basophils and mast cells are de- p hocytes are either activated lymph ocytes, which possess a pair of centri o les and a small Golg i apparatus are located
helminthic parasites. They are also found in large numbers r ived from the sa me hemopoietic ~tem cell. Precursors of surface receptors t hat interact w ith a specific antigen, or in the cell center, the area of t he indentation of th e nucleus.
'216 CHAPTER 9 Blood CHAPTER 9 Blood '2 '2 7
T and B cells are ind istinguishable in blood smears and ment specific T cell fun ctions and are required for the
tissue sections; immu nocytochemical staining for diffe rent recognition or bindi ng ofT cells to antigens displayed on
types of markers and receptors on their cell surface m ust the surface of ta rget cells.
be used to identify them (see below). NK lymphocytes can In h uma n blood, approxima tely 60 to 80% of the lym-
be identified in the light microscope by size, nuclear shape, phoc-ytes are matu re T cells, and 20 to 30% are mature B
and presence of cytoplasm ic granules; however, im muno- cells. Approximately 5 to 10% of the cells do not demon-
cytochemical stain ing for their specific markers is used to strate the surface markers associated with either T or B
confirm microscopic identification. cells. These are NK cells and the rare circulating hemopoi-
etic stem cells (see below). The size d ifferences described
T and B lymphocytes expr ess different surface m olecules above may have functional significa nce; some of the large
lymphocytes may be cells that have been stimulated to d i-
Altho ugh the T and B cells ca nno t be d isti nguished o n vide, whereas others may be plasma cell p recursor s that
the bas is of their morpho logy, their d istinctive surface are undergoing d ifferentiation in response to the presence
proteins (CD proteins) can be used to ident ify the cells of antigen .
with im m unolabeling techniques. In add ition, im-
mun oglobulin molecules (a ntibodies) are expressed on the Three fundamentally different types of T lym phocytes have
surface of B cells tha t fu nction as a ntigen receptors. In been identified: cytotox ic, h elper, and suppressor
contrast, T cells do not have antibodies but express
unique cell sm face recogn ition proteins ca lled T cell re- T he activities of cytotoxic, helper, and suppressor T lym-
ceptors (TCRs). T hese recognition proteins appear d uring phocytes are mediated by mo lecules located on their su r-
FIGURE 9.11 discrete stages in the matmation of the cells within the face. Imm unolabeling tech niq ues have made it possi ble to
Electron micrograph of a human basophil. thymus. In general, the surface molecu les mediate or aug- identify specific types ofT cells and study their function.
The nucleus appears as three separate bod-
ies; the connecting strands are not in the
plane of section. The basophil granules (B)
are very large and irregularly shaped. Some
granules reveal myelin figures (MF). M, mi-
tochondria. x 26,000. (Courtesy of Dr.
Dorothea Zucker-Franklin.) Inset. Light mi-
croscopic appearance of a basoph il from a
blood smear. x l ,BOO.
In the medi um lymphocyte, the cytoplasm is mo re abu n- T cells have a long life span and are involved in cell-me-
dant, the nucleus is larger and less heterochromatic, and diated immu nity. T hey express CD2, CD3, and CD7
the Golg i apparatus is somewhat more developed (Fig. marker proteins on their surface; however, they a re sub-
9.12) . Greater n umbers of mitochondria and polysomes classified o n the basis of the presence or absence of CD4
and sma ll profiles of rough endoplasmic reticulum are a lso and CD8 proteins. CD4 + T lymphocytes possess the
seen in these medi um-sized cells. The ribosomes are the ba- CD4 ma rker and recognize antigens bound to major his-
sis for the slight basophilia d isplayed by lymp hocytes in tocompatabil ity complex Il (MHC II) molecules. CD8+
stained blood smea rs. T lymphocytes possess the CD8 marker and r ecognize
a ntigen bound to MHC I mo lecu les.
Thr ee f unctionally distinct types of lymphocytes are present B cells have variable life spans and are involved in the
in the body: T lymphocytes, B lymphocytes, and NK cells productio n of circulating antibodies . Mature B cel.ls in FIGURE 9.12
blood express IgM and TgD on their surface as well as Electron micrograph of a medium-sized
T he characterization of lymphocyte types is based on M H C II molecules. Their specific markers are CD9, lymphocyte. The punctate appearance of
their function, not on their size or mor phology. T lympho- CD 19, CD20, and CD24. the cytoplasm is due to the presence of
cytes (T cells) are so named because they undergo di ffer- NK cells are programmed du ring their development to numerous free ribosomes. Several mito-
chondria (M) are evident. The cell center
entiation in the thymus. B lymphocytes (B cells) are so kill certain vir us-infected cells and some types of tumor
or centrosphere region of the cell (the area
named because th ey were first recognized as a sepa rate cells. NK cells are larger t han BandT cells (-15 ~-t-m in
of the nuclear indentation) also shows a
population in the bu rsa of Fabricius in birds or bursa- diameter) and have a kid ney-shaped nucleus. Beca use sma ll Golgi apparatus (G) and a centriole
equivalent o rga ns (e.g., bone marrow ) in ma mmals. NK NK cells have severa l large cytoplasmic gra nules easily (C). x2 6,000. (Courtesy of Dr. Dorotl1ea
cells develop from the same precursor cell as B and T cells seen by light microscopy, they are also called large gran- zucker-Franklin.) Inset. Light microscopic
and are so named because they are programmed to ki ll cer- ular lymphocytes (LGLs). T heir specific markers include appearance of a medium-sized lympho-
tain types of tr ansformed cells. CD 16, CD56, and CD94. cyte from a blood smear. x l ,BOO.
228 C HAPTER 9 Blood C HAP TE R 9 /3lood 229
Cytotoxic CDS+ T lymphocytes serve as the primary ef- pressor and/or cytotoxic T cells may also function in Monocytes transform into macrophages, which f u ncti on as
fecto r cells in cell-mediated immunity. CDS+ cells are the regu lation of erythroid cell maturation in the bone antigen-presenting cells in the immune system '!PLATELETS
specifically sensitized T lymphocytes that recognize anti- marrow.
gens through the T CRs on host cells that are infected During inflammation, as indicated, the monocyte leaves Platelets are small, membrane-bounded, anucleate cytoplas-
with viruses or have become neoplastic. Cytotoxic CDS+ the blood vessel at the site of inflammation, transforms mic f~agments derived from megakaryocytes
T lymphocytes only recognize antigens bound to MHC I Monocytes into a tissue macrophage, and phagocytoses bacteria, other
molecules. After the T CR binds the antigen-MHC I com- cells, and tissue debris. The monocyte-macrophage is an Platelets are derived fro m large polyploid cells (cells
plex, the cytotoxic CDS + T lymphocyte secretes lym- Monocytes are the precursors of the cells of the mononuclear antigen-presenting cell and plays an important role in im- whose nuclei contain multiple sets of chromosomes) in the
phokines and perforins that produce ion channels in the phagocytotic system mune responses by partially degrading antigens and pre- bone marrow, called megakaryocytes (Fig. 9.14). In
membrane of the infected or neoplastic cell, leading to its senting their frag ments on the MHC II molecules located platelet formation, sma ll bits of cytoplasm are separated
lysis (see Chapter 13). Cytotoxic CDS+ T lymphocytes Monocytes are the largest of the WBCs in a blood smear on the macrophage surface to helper CD4 +T lymphocytes from the peripheral regions of the megakaryocyte by ex-
play a significant role in rejection of allografts and in tu- (average diameter, 1S flm). They travel from the bone mar- for recognition. tensive platelet demarcation channels. The membrane that
rnor immunology. row to the body tissues, where they differentiate into the
Helper CD4+ T lymphocytes are critical for induction of various phagocytes of the mononuclear phagocytotic
an immune response to a foreign antigen. Antigen bound system, i.e., connective tissue macrophages (histiocytes),
to MHC II molecules is presented by antigen-presenting osteoclasts, alveolar macrophages, perisinusoidal macro-
cells such as macrophages to a helper CD4+ T lympho- phages in the liver (Kupffer cells), and macrophages of
cyte. Binding of the TCR to the antigen-MHC II complex lymph nodes, spleen, and bone marrow, among others (see
activates the helper CD4 + T lymphocyte. The activated Chapter 5) . Monocytes remain in the blood for only about
helper CD4 + T lymphocyte then produces interleukins 3 days.
(mainly IL-2), which act in an autocrine mode to simulate The nucleus of the monocyte is typically more indented
the proliferation and differentiation of more helper CD4+ tha n that of the lymphocyte (Fig. 9.13). The indentation is
T lymphocytes. Newly differentiated cells synthesize and the site of the cell center where a well-developed Golgi ap-
secrete lymphokines that affect hmction as well as differ- paratus and centrioles are located. Monocytes also contain
entiation of B cells, T cells, and NK cells. B cells differen- smooth endoplasmic reticulum, rou gh endoplasmic reticu-
tiate into plasma cells and synthesize antibody. lum, and small mitochondria. Although these cells are clas-
Suppressor and/or cytotoxic CDS+, CD45RA +, T lym- sified as agranular, they contain small, dense, azurophilic
phocytes diminish or suppress antibody formation by B granules. These gra nules contain typical lysosomal en-
cells. They also downregulate the abi lity of T lymph o- zymes similar to those found in the azuro phil ic granules of
cytes to initiate a cellular immune response. The sup- neutrophils.
FIGURE 9.13
Electron micrograph of a human mature
monocyte. The nucleus is marked ly in-
dented, and adjacent to this site, a centriole FIG URE 9.14
(C) and several Golgi profiles (G) are evi- Electron and light micrographs of a megakaryocyte. This electron ular outline. The "foamy peripheral cytoplasm of the megakaryocyte
dent. The small dark granules are micrograph shows a portion of a megakaryocyte from a bone mar- represents areas In w hich segmentation to form platelets is occurring.
azurophilic granules, the lysosomes (L) of row section. Two lobes of the nucleus and the surrounding cytoplasm The sma ller surrounding cells are developing blood cells. x l,OOO.
the cell. The slightly larger and less dense are visible. The cell border is indicated by the dotted line (upper right). Right inset. Higher-power electron micrograph showing a section of
profiles are mitochondria (M). X 22,000. The cytoplasm reveals evidence of platelet formation as indicated by cytoplasm that is almost fully partitioned by platelet demarcation
(Courtesy of Dr. Dorothea Zucker-Franklin.) the extensive platelet demarcation channels. x 13,000. Left inset. channels (arrows). It also shows mitochondria (M), a very dense B
Inset. Light microscopic appearance of a Light micrograph showing an entire megakaryocyte from a marrow granule, and glycogen particles. For comparison, Figure 9.15a shows
monocyte from a blood smea r. x 1,800. smear. Its nucleus is multilobed and folded on itself, giving an lrreg- a mature circu lating platelet. x 30,000.
r
:no CHAPTE R 9 Blood CHA PTER 9 Blood J. 3 I
lines these cha nnels arises by invagination of the plasma cocalyx consists of glycoproteins, glycosaminoglycans, derived growth factor. The contents of these granules the vesse l. Finally, after the clot has served its function, it
membrane; therefore, the channels are in continuity with and several coagulation factors adsorbed from the play an important role in the initial phase of vessel re- is lysed by plasmin, a fibrinolytic enzyme that circulates iJl
the extracellula r space. The continued development and plasma. The integra l membrane glycoproteins function pail, blood coagulatio n, and platelet aggregation. The the p las ma in an inactive form known as plasminogen. The
fusion of the platelet dema rcation membranes result in the as receptors in platelet function. smaller, denser, and .less numerous o granules mainly hydrolytic enzymes released from the A granules assist in
complete partitioning of cytoplasmic fragments to form in- Structural zone. This zone consists of microtubules, contain adenosine diphosphate, adenosine triphosphate, this process . The activator for plasminogen conversion,
dividual platelets . Upon entry into the vascular system actin filaments, myosin, and actin-binding proteins that serotonin, and histamine, which facilitate platelet ad he- tissue plasminogen activator (TPA), is derived principally
from the bone marrow, the platelets circulate as discoid fo rm a network supporting the plasma membrane. Ap- sion and vasoconstriction in the area of the injured ves- from endothelial cells. It is currently used as an emergency
structures about 2 to 3 p.m in diameter. Their life span is proximately 8 to 24 microtubules res ide as a bundle im- sel. The A granules are similar to lysosomes found in treatment to minimize the damage caused by strokes due
about 10 days. mediately below the actin filament network. They are other cells and contain several hydrolytic enzymes. The to clots.
circumferentiall y arranged and responsible for maintain- contents of A granu les function in clot resorption during An additional role of platelets is to help repair the in-
Structurally, platelets may be divided into four zones based on ing the platelet's disk shape. the later stages of vessel repair. jured tissues beyond the vessel itself. Platelet-derived
organization and function Organelle zone. This zone occupies the center of the Membrane zone. This zone consists of two types of growth factor released from the a gran ules stim ulates
platelet. It consists of mitochondria, peroxisomes, glyco- membrane channels. The open canalicular system smooth muscle cells and fibroblasts to divide and allow tis-
The TEM revea ls a structural organization of the gen particles, and at least three types of granules dis- (OCS) is the first type of membrane channel. Th e OCS sue repa1r.
platelet cytoplas m th at can be categorized into four zones persed within tbe cytoplasm. The most nu merous gran- is a developmental remnant of the platelet demarcation
(Fig. 9.1 5): ules are a granules (300 to 500 nm in diameter) , which channels a nd is simply membrane that did not partici-
Peripheral zone. This zone consists of the cell membrane contain mainly fibrinogen, coagulatio n factors, plas- pate in subdividing the m ega ka ryocyte cytoplasm. In ef- \1 FORMATION OF BLOOD CELLS
covered by a thick surface coat of glycocalyx. The gly- minogen, plasminogen activator inhibitor, and platelet- fec t, they are invaginations into the cytoplasm from the (HEMOPOIESIS)
plasma membrane. The dense tubular system (DTS) is
the second type of membrane channel. The DTS con- Hemopoiesis (hematopoiesis ) includes both erythro-
Peripheral Zone Structural Zone tains an electron-dense material originating from the poiesis and leukopoiesis, as well as thrombopoiesis (devel-
rough endoplasmic reticulum of the mega karyocyte, opment of platelets) (Table 9.4). Blood cells have a limited
which serves as a storage site for calcium ions. DTS life span; they are continuously produced and destroyed.
channels do not connect with the surface of the platelet; Both the human erythrocyte (life span of 120 days) and the
myosin II however, both the OCS and DTS fuse in vario us areas of platelet (li fe span of 10 days) spend their entire life in the
the platelet to form m embrane complexes that are im- circul ating blood. WBCs, however, migrate o ut of the cir-
portant in regulation of the intraplatelet calcium con- culation shortly after entering it from the bone ma rrow
A. granule
(lysosome)
centration. and spend most of their variable life spans (and perform all
of their functions) in the tissues.
g lycogen Platelets function in continuous surveillance of blood vessels, In the adult, erythrocytes, granulocytes, monocytes, and
blood clot formation, and repair of injured t issue platelets are formed in the red bone marrow; lymphocytes
a granules
are also for med in the red bone ma rrow and in the lym-
Platelets are involved in several as pect of hemostasis. phatic tissues. To study the stages of blood cell formation,
They continuo usly survey the endothelial lining of blood a sample of bone marrow is prepared as a stained smear in
mitochondria vessels for gaps and breaks. When a blood vessel wall is a manner similar to that described on page 216 fo r the
injured o r broken, platelets adhere to the exposed con- preparation of a smear of blood.
nective tiss ue at the damaged site. The a dhesion of the
platelets triggers a co mplex process that r es ults in aggre- Hemopoiesis is initiated in early embryonic development
open canalicular
system gation of plate le ts into a clot called a primmy hemosta'-
tic platelet plug. Extra vasation of blood is then stopped During fe tal life, both erythrocytes and leukocytes are
by the mass of aggregated platelets. The glycocalyx of the formed in several organs before the differentiation of the
b platelets provides a r eaction sur face for the conversion of bone marrow. The first or yo ll~ sac phase of hemopoiesis
soluble fibrin ogen into fib rin, which stabilizes the initial begins in the third week of gestation and is characterized by
plug. At the sam e time, the activated platelets release the formation of "blood islands" in the wall of th e yolk sac
their a and 8 gra nules, w hi ch contain among other sub- of the em bryo. In the second or hepatic phase, ea rly in fe-
sta nces coagulation factors and serotonin . Serotonin is a tal development, hemopoietic centers appear in the liver
potent vasoconstrictor tha t causes the vasc ular smoo th (Fig. 9.16) . Blood cell forma tio n in these sites is largely lim-
FIGURE 9.15 muscle cells to contract, thereby reducing loca l blood ited to erytluoid cells, although some leukopoiesis occurs in
Platelet electron micrograph and diagram. a. High-magnification flow at the site of injury. In addition, tissue facto rs se- the li ver. The liver is the major blood-forming organ in the
electron micrograph of a platelet situated between an erythrocyte on
creted by the damaged blood vessel cells aid in the for- fetus during the second trimester. The third or bone mar-
the left and an endothelial cel l on the right. Visible organelles include
matio n of a definitive clot known as a secondary hemo- mw phase of feta l hemopoiesis and leukopoiesis involves
a mitochondrion, microtubules, a single profile of the surface-con-
nected open cana licular system, profiles of the dense tubular system,
static plug. the bone ma rrow (a nd other lymp hatic tissues) and begins
o
the moderately dense a granules, a single very dense granule, and After the definitive clot is formed, platelets cause clot re- in the second trimester of pregnancy. After birth, hemo-
glycogen particles. The microfilaments are not evident against the traction, pro bably as a function of the actin and myosin poiesis takes place only in the red bone marrow and lym-
background matrix of the platelet b. Diagram of a platelet showing found in the structural zon~ of the platelet. Contraction of phatic tissues, as in the ad ult (Fig. 9 .1 7). The precursors of
the components of the four structural zones. the clot permits the return of normal blood flow through both the blood cells and germ cells a rise in the yolk sac.
'23'2 CHAPTER 9 Blood CHAPTER 9 Blood '2 3 3
~
@---.- @ / Tcells \
CD4'~ T cells)
Ch
~
/ R e s t r icted CFU
@
CDB+ (cytotoxic T cells)
'iii
Q)
a
c.
0
E
~ ~
Q)
.c
Multipotential
lymphoid ''
stem' cell B cells ''
(CFUl) Restricted CFU Plasma cells ''
~
I I
1 9
~
months gestation birth
Erythrocyte FIGURE 9.17
Erythroblast
@ .. Erythroid CFU (CFUE) ~
Dynamics of hemopoiesis In embryonic and fetal life. During embry-
onic and fetal life, erythrocytes are formed in several organs. Essen-
Plurlpotentlal
stem cell @ ~
/ . ' " t c : phii,CFU (CFU-Q Neutrophi/6 FIGURE 9.16
tially, three major organs Involved in hemopoiesis can be sequentially
identified: the yolk sac in the early developmental stages of the em
bryo; the liver during the second trimester of pregnancy; and the bone
(PPSC. true
~@ ,):;:;.
stem cell) Hepatic stage of hemopoiesis. Photomicrograph of the fetal liver marrow during the third trimester. The spleen participates to a very lim
stained with H&E shows active hemopoiesis. The small round bodies ited degree during the second trimester of pregnancy. At birth, most he
Granulocyte/ ::.'. mopolesls occurs In the red bone marrow, as in the adult.
neutrophil CFU (CFUGM)
.. , .... are mostly nuclei of developing erythrocytes. Although it is difficult to
discern, these cells are located between developing liver cells and the
Monocyte CFU (CFUM) Monocyte wall of the vascular sinus. x 350.
Macrophage"
@
;:;:::.'''
@
~osinophil CFU. (CFUEo)
EosinophiiB
Monophyletic Theory of Hemopoiesis lineage; CFU-GM, a cell that gives rise to the neutrophilic
gra nulocyte and monocyte li neages; CFU-Eo, a cell that
Multipotential According to the monophyletic theory of hemopoiesis, blood gives rise to eosinophils; CFU-Ba, a cell that gives rise to
myeloid ~ cells are derived from a common stem cell basophils; and CFU-Meg, a cell that gives rise to
~~~~~~IM) @; Basophil"
Considerable circumstantial evidence has for many years
megakaryocytes. (Table 9.5). The PPSC is not onl y ca pable
of differentiating in to a ll the blood cell lineages but it is
Basophil CFU (CFUBa) supported the monophyletic (or u1titmian) the01y of he- also capable of self-renewal; i.e., the pool of stem cells is
mopoiesis, in which a ll blood cells arise fro m a common sell-susta ining.
stem cell. T his theory is i11 contrast to the polyphyletic the- Perhaps the easiest way to begin the histologic study of
ory, in which each blood cell type has its own stem cell. blood cell development is to refer to the illustration in Fig-
Decisive evidence for the validity of the monophyletic the- ure 9. 18. T his figure shows the stages of blood cell devel-
ory has come with the isolation and demonstration of the opment in which characteristic cell types can be identified
Megakaryocyte CFU Megakaryoblast Megakaryocyte Platelets8 pluripotential stem cell (PPSC), a descriptive term used to in the light microscope in a tissue section or bone marrow
(CFUMeg) identify the hemopoietic stem cell that gives rise to all smea r. Hemopoiesis is initiated in an apparent random
'Tills table Includes tile most recent concepts of a plurlpotential stem cell, multlpotentlal colonyforrnlng units (CFUs). and restricted CFUs. Cytoklnes (Including lle other progenitor stem cells. These progenitor stem cells are man ner when individ ua l stem cells begin to differentiate
mopoletlc growth factors) may and do act Individually and severally at any point In tile process from tile first stem cell to the mature blood or connectlv~ tis defined by the presence of the CD34' surface marker pr o- into one of the blood cell lineages. Stem cells have surface
sue cell. tei n. PPSCs are not identifiable in the microscope.
Mature functional cells In blood, bone marrow, or connective tissue.
receptors for specific cytokin es and growth fac tors that in-
flue nce a nd direct their proliferation and maturation into a
A PPSC gives rise to multiple colony-forming units (CFUs) specific lineage.
CFU-E . - - - - - CFU-GM - - - - - .
Multipotential Myeloid Stem Cell (CFU-G EMM)
I
CFU- Eo CFU-Ba
,--- -,
CFU-Meg
Proerythroblast Myeloblast
CFU-G
I
TMonoblast
CFU-M
I
Myeloblast
I Myeloblast
I I
Megakaryoblast
12-15 ,urn in diameter 14-20 ,urn in diameter Difficult to identify 14-20 ,urn in diameter 14- 20 JLm in diameter Last cell capable
Mildly basophilic Large, euchromatic spheri- Large, euchromatic spheri- Large, euchromatic spheri- of mitosis
La rge, round nucleus with cal nucleus; 3- 5 nucleoli cal nucleus; 3-5 nucleoli ca l nucleus; 3-5 nucleoli Slightly basophilic
1-2 nucleoli No granules No granules No granules cytoplasm with
I Basophilic cytoplasm 55 hrs Basophilic cytoplasm Basophilic cytoplasm multiple nucleoli
Basophilic erythroblast
I 15- 25 ,urn in diameter
Smaller
Very basophilic
cytoplasm
Promyelocyte
Azurophilic granules pro-
duced in this stage only
Promonocyte
Last cell capable I Promyelocyte
I Round, invaginated
nucleus; may be
binucleate
Smaller, more of mitosis Pro myelocyte Azurophilic granules pro-
Nucleus indented 10- 15 ,urn in diameter
heterochromatic nucleus Azurophilic granules pro duced In this stage only
Nucleoli
1 wk 1 Nucleus large, slightly in- duced in this stage only Nucleus indented
Increased size, 18- 24 ,urn
Polychromatophilic dented Nucleus indented Nucleoli
Chromatin becomes con-
erythroblast 1 or 2 nucleoli Nucleoli Increased size, 18- 24 ,urn
densed
Last cell capable Basophilic cytoplasm Increased size, 18-24 ,urn Chromatin becomes con-
of mitosis No mature granules Chromatin becomes con- densed Promegakaryocyte
Hemoglobin production Neutrophilic myelocyte densed 45 ,urn in diameter
begins Last cell capable More abundant
Cytoplasm acquires gray of mitosis cytoplasm
or dull lilac color
Smaller than basophilic
erythroblast
I
Orthochromatophilic
erythroblast
T
1 wk
Elliptical nucleus
Specific granules appear
and i in number
iM-1 wk
Neutrophilic
J
Monocyte
Large, kidney-shaped nu-
cleus
2 - 3 nucleoli
Eosinophilic myelocyte
Last cell capable
of mitosis
Nucleus indented
Refractile-specific granules
appear and i in number
Basophilic myelocyte
Last cell capable
of mitosis
Nucleus elliptical
Specific granules appear
and i in number
5 days
Nucleus enlarged
Eosinophil
I I
Acidophilic cytoplasm with Neutrophil Nucleus bilobed Basophil
trace of earlier gray Nucleus, 3 - 5 segments or Mature cells stored in mar- Nuclear shape obscured
I lobes row before release by granules
Erythrocyte Mature cells stored In mar- Macrophage Life span: Mature cells stored in mar- Platelets (constantly
Acidophilic row before release Can divide in CT in blood, 8-12 hr row before release produced In marrow)
Biconcave disk Life span: Granules sometimes in CT, unknown Life span: Life span:
7-8 ,urn in diameter in blood, 8-12 hr evident; represent in blood, 8 hr in blood, 7-10 days
Life span: in cr.
1-2 days lysosomes in CT, unknown
in blood, 1-120 days Life spa n:
in CT, unknown
This table summarizes the maturation of blood cells with histologic characteristics at the various stages, maturation time, and life span after leaving the marrow. Times indicated along vertical lines are the approxi-
mate time between recognizable stages. i M- 1 wk indicates Increase in number by mitosis for 1 week before differentiation begins. cr means connective tissue.
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first recogni zable erythrocyte precursor, the proerythro- sinus of the red bone marrow. Some polyribosomes that creted via the gallbladder as the bilirubin glucuronide of
blast. can still synth esize hemoglobin are retained in the cell. bile.
These polyri bosomes impart a slight basophilia to the oth-
The first recognizable precursor cell in erythropoiesis Is called erwise eosin ophil ic cells; for this reason, these new cells are
Dev~lopment of Granulocytes (Granulopoiesis)
the proerythroblast called polychromatophilic erythrocytes {Fig. 9.20). The
polyribosomes of the new erythrocytes can also be demon- Neutropbils originate from the multipotent ia l CFU-
The proerythroblast is a relatively large cell measuring strated with special sta ins that ca use t he p olyribosomes to GEMNl stem cell, which is induced to differentiate into
12 to 20 ,urn in diameter. It contains a large spherical nu - clump a nd form a reticular networ k . Consequently, poly- CFU-GM by cytokines such as GM-CSF, G-CSF, and IL-3.
cleus with one or two visible nucleoli. The cytoplasm chromatophilic erythrocytes ar e also (and more com- T he neutrophil undergoes six morphologically identifiable
shows mild basophi lia because of the presence of free ri- monly} called reticulocytes. In no rma l blood, r eticulocytes stages .in the process of maturation: myeloblast, promyelo-
bosomes. Although recogn izable, the proerythroblast 1s (new eryt hrocytes) consti tute about 1 to 2% of the total cyte, mye locyte, metamyelocyte, band cell, and mature
not easily identified in routine bone ma rrow smears . erythrocyte coun t. However, if incr eased numbers of eryth- neutroph il. Eosinoph il s and basophils un dergo a morpho-
rocytes enter the bloodstream (as during increased eryth- logic maturation si milar to that of ne utrophils. Al l three
The basophilic erythroblast is smaller than the proerythroblast, ropoiesis to compensate for blood loss), the number of lineages originate from the m ultipoten tial CFU-GEMM
from which it arises by mitotic division reticulocytes inc reases. cell. This cell is induced by GM-CSF, IL-3, and IL-5 to dif-
ferentiate into CFU-Eo, which eventually matures into an
The nucle us of the basophilic erythroblast is smaller eosinophil. Lack of IL-5 causes the stem cell to d ifferen ti-
Kinetics of Erythropoiesis
(10 to 16 pm in diame ter ) and progressively more h ete- ate into CFU-Ba, which matures into a basophil. One can-
roc hromatic with repeated mitoses. The cytop lasm shows not differentiate eosinophilic or basophilic precursors from
Mitoses occur in proerythroblasts, basophilic erythroblasts,
strong basophilia because of the la rge number of free ri- neutrophilic precursors morphologically in the light mi-
and polychromatophilic erythroblasts
bosomes {polyribosomes) that synth es ize hemoglobin. croscope until the cells reach the myelocyte stage, when the
T he accumulation of hemoglobin in th e cell gradual ly specific gra nules appear.
At each of these stages o f development, the eryth roblast
changes the staining reaction of the cytoplasm, so that it
divides several times. It takes about a week for t he pr ogeny FIGURE 9.20
begins to stain with eosin. At the stage when the c yto- Myeloblasts are the first recognizable cells that begin
of a new ly formed basophi lic eryth ro blast to reach the cir- Electron micrograph of a polychromatophilic erythrocyte (reticulo-
plasm displa ys both acidophilia, because of the stainin g the process of granulopoiesis
of hemoglobin, and basoph ilia, becau se of the sta ining of cyte). The nucleus is no longer present, and the cytoplasm shows the
characteristic fimbriated processes that occur just after nuclear extru-
the ribosom es, the cell is ca lled a polyc hromatophilic The myeloblast is the earliest recognizable neutrophi l
sion. Mitochondria are still present, as are early and late endosomes
erythroblast. precursor cell in the bone marrow. It has a large, euchro-
and ribosomes. X16,500. (Courtesy of Dr. Dorothea zuckerFranklin.)
ma tic, spherical nucleus with 3 to 5 nucleoli. It measures
The polychromatophilic erythroblast shows both acidophilic 14 to 20 ,um in diameter and has a large nuclear-to-
and basophilic staining of cytoplasm cytoplasmic volume. T he small amount of agranular cyto-
plasm stains intensely basophilic. A Golgi area is often
The stai ning r eactions of the polychromatophilic eryth- culation. Nearly all erythrocytes are released into the cir- seen where the cytoplasm is unstained. The myeloblast ma-
roblast may blend to give a n overall g ra y or lilac color to cula tion as soon as they are formed; bone marrow is not a tures into a promyelocyte.
the cytoplasm, or distinct pink (acidophilic) a nd purple stor age site for erythrocytes. Erythrocyte formation and
(basophilic) regions may be resolved in t he cytoplasm. The re lease are regulated by erythropoietiu, a 34-kDa glyco-
n ucleus of the cell is smaller than tha t of th e basophilic protein hormone synthesized and secreted by the kidney in
erythroblast, a nd coarse heterochromatin gra nules form a response to decreased blood oxygen concentration. Ery-
checkerboard pattern that helps identify thi s cell type. thropo ietin acts on the specific receptors expressed on th~
su rface of CFU-E.
The orthochromatophilic erythroblast is recognized
by its increased acidophilic cytoplasm and dense nucleus Erythrocytes have a life span of about 120 days in humans
When erythroc ytes are about 4 months old, they be- If the conjugation of bilirubin or Its excretion into bile by the liver
The next named stage in e ryth ropoiesis is the or-
cells is inhibited, or if blockage of the bile duct system occurs,
thochromatophilic erythroblast (normoblast). This cell come senescen t . The macrophage system of the spleen,
bilirubin may reenter the blood, causing a yellow appearance of
has a small, compact, densely sta ined nucl eus. The cyto- bone marrow, and li ver phagocytoses and degrades the
the sclera of the eye and the skin. This condition is called jaun-
plasm is eosino philic beca use of the large amount of he- senescen t erythrocytes. The heme and globin dissociate, dice. Jaundice can be caused by an increase in erythrocyte
moglobin (Fig. 9.19) . It is only slightly larger than a ma- and t he globin is hydrolyzed to amino acids, which enter destruction, which is characteristic of hemolytic anemia. This
FIGURE 9.19 the metabolic pool for reu se. The iron on the heme is re-
ture erythrocyte. At this stage, the orthochromatophil ic condition results from either Inherited defects in the erythrocyte
Electron micrograph of a orthochromatophilic erythroblast (nor-
erythroblast is no longer capa ble of di vision . leased, enters the iron storage pool in the spleen in the (e.g., hereditary spherocytosis) or external factors such as pat11o
moblast). The cell is shown just before extrusion of the nucleus. The
for m of hemosiderin or ferritin, and is stored for reuse in genic microorganisms, animal venoms, chemicals, or drugs.
cytoplasm contains a group of mitochondria located below the nu
The polychromatophilic erythrocyte has extruded its nucleus hemoglobin synthesis. The rest of the heme moiety of the Some jaundice is common In newborn infants (physiologic jaun
cleus and small cytoplasmic vacuoles. The cytoplasm is relatively
hemoglobin molecule is partially degraded to bilirubin, dice) because of Inefficiency of the bilirubin-conjugating system
dense because of its hemoglobin content. The fine, dense particles
bou nd to alb umin, released into the bloodstream, and in the newborn liver.
The orthochromatic erythroblast loses its nucleus by ex- scattered in the cytoplasm are ri bosomes. x 10,000. (Courtesy of Dr.
truding it from the cell; it is then ready t o pass into a blood Dorothea ZuckerFranklin.) tran spo rted t o the liver, where it is conjugated and ex-
'}3 8 CHAPTER 9 Blood CHA PTER 9 Blood 2 ~9
Promyelocytes are the only cells to produce azurophilic of band cells in the circulation is a lmost always low (0 to TABLE 9.6. Hemopoietic Cytokines, Their Sources, and Target CeiJsA
granules 3%), it may increase in acute or chronic inflamma tion and
Cytokine symbol Source Target
infection.
The promyelocyte has a large spherical n ucleus with Granulocyte-macrophage GM-CSF T cells, endothelial cells, fibroblasts CFUGEMM, CFUE, CFU-GM, CFUEo, CFUBa, CFUMeg.
azurophilic (primary) gran ules in the cytoplasm. Azuro- colony-stimulating factor all granulocytes, erythrocytes
Kinetics of Granulopoiesis
philic gran ules are produced onl y in promye locytes; cells Granulocyte colony GCSF Endothelial cells, monocytes CFU-E, CFUGM, CFUEo, CFU-Ba, CFUMeg
in subseq uent stages of granulopoies is do not make Cell division in granulopoiesis stops by the late myelocyte stage stimulating factor
azurop hilic granu les. For thi s reason, the number of Monocyte colony- MCSF Monocytes, macrophages, CFUGM, CFU-M, monocytes, macrophages
The mitotic p hase in granulopoiesis lasts abou t a week. stimulating factor endothelial cells
azurophi lic gra nul es is reduced with each division of the
p romyelocyte and its progeny. Promyelocytes d o not ex- The postmitotic p hase-from metam yelocyte to mature Erythropoietin EPO Kidney, liver CFUE, CFUGEMM
hibit subtypes. Reco gnition of the neutrophil, eosi no- granulocyte-also las ts a bout a week. The time it takes for Thrombopoietin TPO Bone marrow CFUMeg, megakaryocytes
phil, and basophil lines is possible on ly in the next stage, half of the circulating segmented neutrophils to leave the Interferon-,. IFN'Y C04 ' T cells, NK cells B cells, T cells, NK cells, neutrophils, monocytes
the myelocyte, when specific (secondary) and tertiary peripheral blood is about 6 to 8 ho urs. Neutrophils leave lnterleukinl IL-l Neutrophils, monocytes, rnacrophages C04' T cells, B cells
gr anu les begin to fo rm. t he blood random ly; i.e., a given neutrophil may circulate endothelial cells
for only a few m inu tes or as long as 16 hours before en- lnterleukin2 IL2 C04 ' T cells T cells, B cells, NK cells
Myelocytes first exhibit specific granules tering the perivascular co nnecti ve tissue. lnterleukin3 IL-3 C04 ' T cells CFUGEMM, CFUE, CFUGM, CFUEo, CFUBa, CFUMeg,
Neutrophils live for 1 to 2 days in t he connective tis- all granulocytes, erythroid cells
Myelocytes begin w ith a more o r less spherical nucleus sue, a fter w hich they are d estroyed by apoptos is and are lnterleukin4 IL4 C04 T cells, mast cells B cells, T cells, mast cells
t hat becomes increasing ly heteroc hromatic and acquires a subsequ ently eng ulfed by macrop hages. A lso, large n um- lnterleukinS IL-5 C04 ' T cells CFUEo, eosinophils, B cells
distinct indentation during su bsequent divisions. Specific bers of ne utrophils are lost via migration into the lumen lnterleukin6 IL6 Endothelial cells, neutrophils, CFUGEMM, CFUE, CFU-GM, 8 cells, T cells.
granules begin to emerge from the convex surface of th e of the gastrointestinal tract fro m w hic h th ey are dis- macrophages, T cells rnacrophages, hepatocytes
Golgi apparatus, whereas azurophilic granules are seen at cha rged with the feces. As a result of t he release of neu- lnterleukin 7 IL? Adventitial cells of bone marrow Early preB, preT cells
the concave side. The significa nce of this separation is un- tropbils from th e bone marrow, app roximately 5 times lnterleu kinB ILB Macrophages, endothelial cells T cells, neutrophils
clea r. Myelocytes continue to divide and give rise to as many mature and near-mature neutrophils are nor- lnterleukin9 IL9 C04 ' T cells CD4 + T cells, CFU-GEMM, CFUE
metamyelocytes. mally present in t he bone marrow as are present in the
lnterleukinlO ILlO Macrophages, T cells T cells, 8 cells, NK cells
circu lation . This r eserve pool co nstantl y re leases neu-
lnterleukin-11 IL11 Macropl1ages CFUGEMM, CFUE, CFUGM, T cells, B cells,
The m etamyelocyte is the stage at which neutrophil, t ro phils into the circulation a nd is repleni shed by matur-
macrophages, mega karyocytes
eosinophil, and basophil lines can be clearly identified by t he ing cells. The rese rve neu trophi ls can be released
abruptly in response to inflammation, infectio n, or stren- AHemopoletic cytokines include colony-stimul ating factors (CSFs), lnterleukins, and inhibitory factors. They are almost all glycoprotelns with a basic polypeptide
presence of numerous specific granules
chain of about 20 kDa. Nearly all of them act on stem cells, colony-forming units (CFUs). colony-forming cells (CFCs), committed cells, maturing cells, and ma
uous exercise . The entire hemopoietic process is summa- ture cells. Therefore, the targets listed above are target lines rather than Individual target cells.
A few h un dred g ranu les are present in the cyto plasm rized in Table 9.5.
o f each metamyelocyte, and t he specific granules of each A reser voir of neu troph ils is a lso present in t he vascular
variet y o u tnumber the azurop hilic gra nules. In the neu- compartment. T his reserve consists o f a freely cir culating
troph il , t his ratio of specific to azurophilic gran ul es is pool and a m arginated pool, w ith the latter contained in
abou t 2 to J. The nucleus becomes mo re heterochro- small blood vessels. T he neutroph ils ad here to the en- recently isolated factors are several that stimulate gra nu- Monocyte Development
matic, and the indentation deepens to fo rm a kidney dothelium much as they do prior to leaving the vasculatu re locyte and macrophage for mati o n, GM-CSF, G-CSF, and
bea n-shaped str ucture. Theoretica lly, the meta myelocyte at sites of inj ury or infection (see page 222) . The normally M-CSF. Interleukins, produced by lymphocytes, act o n The multipotential myeloid st em cell (CFU- GEMM) also g ives
stage in granu lopoiesis is followed by th e ba nd stage and marginated neutrophils, however, loosely adhere to the en- other leukocytes and t heir progenitors. TL-3 is a cytokine . rise to the cells that develop along the monocyte-macroph age
then th e segmented stage. Although these stages are ob- dothelium through the action of selectin and can be re- that appears to affect most CFUs and even termina lly dif- pathway
vio us in the neutrop hil line (see below), th ey are rare ly crui ted very qu ickl y. T hey are in d ynamic eq uilibriu m w ith feren tiated cells. Any pa rticular cytokine may act at one
if ever obser ved in the eos inophil and basophil lines the circula ting pool. or mo re stages in hem opoiesis, affecting cell division, d if- Monocytes are produced in the bone ma rrow from a
in w hi ch the next easil y reco gni zed stages of deve lop- fere n tiation, or cell function. T hese factors <He sy nthesized bipotentia l stem cell (CFU-GM ) that can ma ture into ei-
men t are the m ature eosinophil and mat~t1'e basophil, Cytokines are glycoprotein hormones and stimulating factors by many d ifferent cell t ypes, includ ing kidney cells (er y- ther m onocytes o r neutrop hils. The differ entiation and
respective ly. that regulat e all stages of hemopoiesis thropoietin), T lymph ocytes (IL-3 ), end o th el ia I cells (IL- growth of CFU-GM into monocytes is stimulated by GM-
6), adventitia l cells in th e bone marrow (IL-7), and CSF, TL-3, and M-CSF. T he monocyte precursors in bo ne
In the neutrophil line, the band (stab) cell precedes In addition to id entifying th e va rious types of progen i- macrophages (the CSFs that affect g ra n ulocyte a nd marrow are monoblasts and promonocytes. Rapidly divid-
development of the first distinct nuclear lobes tor and precur sor cells, recent studies have iden tiii.ed a nd macrophage development). ing promonocytes constitute about half o f t he progeni tor
begun to characterize numerous g lycoprotei ns th at act as T he isolation, characterization, man ufacture, and clini- cells o f dtis li ne in the bone marrow. T he other ha lf appear
T he nucleus of the ba11d (stab) cell is elongated and of both circul ating hormones and local mediators to regulate cal testing of cytok ines in the t reatment o f huma n disease to be promonocytes th at divide slowly and ser ve as a re-
nea rl y un ifo rm width, giving it a horseshoe-like a ppear- hemopoiesis and the differentiatio n of specific cell types is a majo r activity of the burgeo ning biotechnology ind us- serve population of progenito r cells. The t ransformation of
ance. N uclea r constrictions then develop in th e band neu- (Table 9.6). One fac tor, erythropoietin, d iscussed above, t ry. Several hemopoietic and lymphopoietic cytokin es have CFU-M to monocyte takes abo ut 55 hours, and the mono-
trophil a nd become more prominent until two to four n u- regulates erytlu-ocyte develo pmen t. Other factors, collec- been manufactured by recombinant DNA techno logy and cytes remain in the ci rculatio n for o nly about 16 hours be-
clea r lobes are recognized; the cell is then considered a tively called colony-stimulating {acto1s (CSFs), are sub- are already used in clinical settings. These include recom- fo re emigrating to the tiss ues, where t hey differentiate into
matuxe neutrophil, also called a polym01'phouuclear neu- classified according to the specific cell or groups of cells bina nt eryth ropoi etin, G-CSF, GM-CSF, and IL-3; others macrophages. The su bsequ ent life span is not yet fu ll y elu-
trophil (segmented neutrophil). Although th e percentage t hat they affect. The most completely characterized o f t he are under active development. cidated.
140 CHA PTER 9 13/ood CHAPTER 9 Blood J4 I
Figure 1, blood smear, human, Wright's stain 1-1m in blood smears, and 6 to lO f-Lm , depending on the
X400. method used for preserving the tissue, in sectioned materi aL
This is a low-magnification photomicrograph of a smear (A size of 7 f-LITI for the erytJu-ocyte in sectioned material is
with the blood cells well di stributed. M ost of the cells are useful to remember. It e nables o ne to estimate the size of
erythrocytes (RBC). They are readil y identified because of other structures in a histolog ic section by comparison with
their number and lack of a nucleus. Scattered among the red the RBC without resorting to a micrometer.) Erythrocytes
cells are th ree whi te blood cells that can be di stingui shed stain uniformly with eosin, a component of the usual dye
fro m the erythrocytes wi tho ut diffi culty by their larger size mixture (e.g., Wrig ht's) used to stain blood smears. Because
and their staining characteris tics. Interspersed among the of the biconcave form of tbe erythrocyte, however, its center
cells are numerous sma ll speck-li ke objects. These are is thinner and appears li ghter than the periphery.
blood platelets that have aggregated into s mall gro ups and, To disting uis h the differe nt kinds of leukocytes in a
thus , can be read ily observed even at this low magnifica- blood smear, it is advantageous to use the highest available
tion. They can be visuali zed better at higher magnifi cation magnification , usually an oil- immersion le ns. This enables
in Figures 2 to 4 (a rrows). one to use the morpho log ic featu res of the cytoplasm in ad-
Erythrocytes have a biconcave s hape. They measure dition to nucl ear morphology and cytoplasmic staining in
about 8.0 f-LITI in diameter in the circulating blood, about 7.5 identi fy ing the cell type .
Figures 2-7, blood smear, white blood cells, hu- distinct, lightl y stained Golg i area is evident. In addition,
man, Wright's stain x 1800. lymphocyte cytoplasm may conta in azuroph ilic granules,
Figures 2 to 4 illustrate c haracteri stic features of lym- as shown in Figures 3 and 4.
phocytes. The nucleus stains intensely, generall y has a Figures 5 to 7 show characteristic features of monocytes.
rounded s hape, and, as illustrated in Figure 2, may possess These cells measure approximate ly 12 and 15 1-1m in diam-
a slight indentatio n. These cells measure about 8, I 0, and eter, respectively (monocytes range from 9 to 18 1-1m). The
12 f-Lill in diamete r, respective ly (c ircul ating lymphocytes nucleus is somewhat less "compact" than the nucle us of
range from 6 to 12 1-1m). In a s ma ll lymphocyte (Fig. 2), lymphocytes. The cytoplasm, li ke that of lymphocytes,
on ly a small amoun t of cytoplasm is evident, and the nu- stains lightly but tends to have a grayer or duller blue lint.
cleus seems to consti tute most of the cellular volume. Tn Azurophilic granules are also present in the cytoplasm.
large lymphocytes of c ircul ating blood (Figs. 3 and 4), Lymphocytes and mo nocytes are classified as agranulo-
there is a larger amount of cytoplasm. (Large lymphocytes cytes; i.e., they are us ually free of speci fic cytoplasmic
of c irculating blood are equivalen t to the medium -sized g ranul es. Moreover, their nuclei are nonlobed , although
lymphocytes of lymphati c tissue. The large lymphocytes of monocyte nucle i may occasionally s how a deep inde ntation
lymphatic ti ssue are not a characteris tic feature o f c irculat- (Fig. 6). Thus, they are distingui shed from granul ocytes,
ing blood except in certain abnormal conditi ons.) The cyto- whkh possess specifi c cytoplasmic granul es as well as a
plasm of ly mphocytes may stain a pale blue; sometimes, a lobed or segmented nucleus.
KEY
arrows, blood platelets
242
r
CHAPTER 9 Blood 245
PLATE17. GRANULOCYTES
Granulocytes are characterized by a lobed nucleus and by the specific staining c haracteristics of granules in the cytoplasm.
Three ki nds of granulocytes are present in a peripheral blood smear: neutmphils (polym01phonuclear leukocytes), 55 to 60%;
eosinophils, -2 to 5%; and basophiL~. l % or less . All of the granul ocytes leave the bloodstrea m and enter the con nective tis-
sue to pe rform the ir spec ific functions.
Neutrophil s are acti vely phagocytic cells that have both specific granules and azwvphilic granules. T he azurophilic gran-
ules are the lysosomes of the neutrophil ; the specific granules contain bacteriostatic and bactericidal agents, such as lysozyme.
At sites of injury or infection, neutrophils e ngage in active phagocytosis of bacteria and other fo reign organisms and passive
phagocytosis of damaged connective tissue cells, red blood cell s, and fibrin. M any ne utrophils d ie in this process. The accu-
mulation of dead neutrophil s and dead bacteria constitutes p us. Eosinophils contain nume rous large s pecific granules charac-
terized by the presence of a CI)IStalloid inclusion contai11ing major basic pmtein, the materi al responsible fo r the intense aci-
dophil ia. The g ranules also conta in histaminase and my/sulfatase, the actions of which serve to moderate the potentially
deleterio us effects of the infla mmatory vasoactive agents histamine and slow-reacting substance (SRS) of anaphylaxis.
Eosi no phils are commonly fo und at sites of c hronic infectio n and inflammatio n, and thei r number is e levated in ind ividual s
w ith allergies and pa rasitic infectio ns. They phagocytize antigen- antibody complexes.
Basoph ils have specific gra nules that contain hydrolytic enzymes, heparan sulfate, hista mine, and SRS. The intense ba-
sophi lia is due to the anio nic nature of the he paran sulfate. Basophils bind immunoglobuli n E (secreted by plasma cells) on thei r
s urface; when s ubsequently exposed to the s pecific antigen that s timulated synthesis of that antibody, the basophils release their
vasoactive agents, causing the severe vascular dis turbances associated with hypersensitivity reactions and anaphylaxis.
Figures 1-6, blood smears, human, Wright's stain ogni zab le d rumstick profi le is fo und.
x 1800. Eosinophils are shown in Fig ures 3 and 4. T hese cells
Neutrophils develop in the red bone marrow fro m cells measure about I 3 IJ.I11 in d iameter (eos inophils range fro m
that have a rounde d nuc le us. During the ir maturatio n, the I 0 to 14 ~J.m) . The most conspic uous feature o f eosinoph ils
nucle us changes from a ro unded to a segmented or lobed is the presence of nume ro us cytoplasmic granu les that stain
form. A full y developed neutrophil nucleus may have as with eos in. The granules virtually fill the cytoplasm. The
many as fi ve lobes. The config uratio n and num ber of lobes eosinophilic granules have s pecific mo rphologic character-
var y fro m one cell to another (Figs. I and 2), and 011 tlle ba- istics that can be used in the identi fication of the cells. T hey
sis of the variable nuc lear mo rphology, these cells are are relati vely uniform in size within a particular cell, are
sometimes c alled polymo rphonuclear leukocy tes. It shoul d abo ut 0.6 IJ.m in diameter, sig nificantly la rger than granu les
be understood, however, that each cell has only one nu- of neutrophil s, and are ty pically closely packed. In goi ng
cleus, with each lobe bei ng jo ined to its neighbor by a " throug h focus," eosi noph il ic granules o ften display a
strand of nuclear mate ria l. marked refracti lity. The nucleus of the eosinoph il is usually
Neutrophils us ua lly measure 9 to 14 IJ.m in diamete r. bilobed, as seen in Figures 2 and 3.
The cytoplasm of these cells contains granules that range Basophi ls are shown in Figures 5 a nd 6. T hey measure
from O.J to 0.4 IJ.Ill in diameter and stain variably, e ither abo ut 8 and 12 j..Lm in diame ter, respectively (range of ba-
azu re, li g ht blue, or vio let. A ltho ugh ne utrophils contain soph il size is 8 to 14 ~J. m) . T hese cells contain cytoplasmic
specifi c g ranul es, the identificatio n of these cells can usu- granules of variable size that stain intensely with the meth-
all y be accomplished on the basis of the d isti nctive lobu la- yle ne blue of the blood stain . T he gra nules are randomly
ti o n of the nucleus. Moreove r, because these cells a re the d istri buted througho ut the cell , usua lly s upe rimposed over
most numero us of the leukocy tes in a smear of normal the nuc leus and obscuri ng it to such a degree that its bound-
blood, the ir number is an aid in the ir identi ficatio n. aries bare ly can be dis tinguished. In Fig ure 6, some of the
T he ne utrophil in F igure 2 s hows a s mall projection granules are larger than the eosinoph ilic granules, others
from one of the nuclear lobes ( anmv). T his is referred to as are s mall er than the eosinophil ic granules, and some are as
a drumstic k. Lt is the inactive fe male X chromosome. Its small as those found in the ne utrophils. The range in size of
presence is sufficient to identify the blood as having come basoph il gra nules (in contrast to the more uniform size of
from a fe ma le, assuming that the norma l comp lement o f granu les in eosinophils) is a nother cha racteri stic that may
chromoso mes is present. Because the visualizatio n of the aid in the identification of these cells. Because the basophi l
drumstick requires a fortuito us orientation of the nuclear is so rare, it may be necessary to exami ne a large area of a
lobes, many cells usua ll y need to be examined before a rec- blood smear before one can be found.
KEY
arrow, drumstick (inactive X chromosome)
244
J- l
------------------------------------------------------------------------~,_.--~------------------------------------------------------------------------------~
Thick filaments (- 15 nm in diameter, 1.5 p.m long), Muscle is classified on the basis of the appearance of the
composed of the protein myosin II. Each thick filament contractile cells
I I consists of 200 to 300 m yosin II molecules. The long,
Muscle Tissue The two types of myofilaments occupy the bulk of the
cytoplasm, which in muscle cells is a lso called sarcoplasm
Smooth muscle, in which the cells do not exhibit cr oss-
striations
Striated muscle tissue is further subclassified o n the ba-
{Gt: sarcos, jlesh; plasma, tiling]. Acti n and myosin are also pres-
sis of its locatio n:
ent in most other cell types (although in considerably
OVERVIEW AND CLASSIFICATION OF MUSCLE 246 sma ller amo unts), w here they play a r ole in cellula r activi- Skeletal muscle is attached to bone and is responsible
ties such as cyto kinesis, exocytosis, and cell migratio n. In for movement of the axia l and appendicula r skeleton
SKElETAl MUSCLE 248 contrast, muscle cells contain a large num ber of aligned and for maintenance of body positio n and posture. In
Myofibrlls and Myofilaments 249 contractile filaments that the cells use fo r the single pur- addition, skeleta l muscles of the eye (extraocu lar mus-
The Contraction Cycle 254 pose of prod uci ng mechanical work. cles) pr ovide precise eye movement.
Motor Innervation 257
Sensory Innervatio n 260
Development, Repair, Healing, and Renewal 261
BOXES
BOX 10.1. Functional Considerations: Muscle Met abo lism and Ischemia 250
BOX 10.2. Clinica l Correlations: Muscular Dystrophy-Dystrophln and
Dystrophin-Associated Proteins 254
BOX 10.3. Functional Considerations: The Sliding Filament Model 256
BOX 10.4. Clinical Correlations: Myasthenia Gravis 259
BOX 10.5. Functional Considerations: Complexity of Smooth Muscle
Innervation 269
BOX 10.6 . Functional Considerations: Comparison of the Three
Muscle Types 270
Visceml striated muscle is morphologically identical with force tra nsduction. At the end of the muscle, the connec- succm1c dehydrogenase and NADB-TR histochemical
skeletal muscle but is restricted to the soft tissues, namely, tive tissue continues as a tendon or some other arr ange- sta ining reactions (see Fig. 10.2). Red fibers are typica lly
the tongue, pharynx, lumbar part of the diaphragm, an d ment of collagen fibers that attaches the muscle, usua lly, to found in the limb muscles of mammals and in the breast
upper part of the esophagus. These muscles play essential bone. A rich supply of blood vessels and nerves travels in m uscle of migrating bir ds. More importantly, they ar e
roles in speech, breathing, and swallowing. the connective tissue. the principal fibers of the long m uscles of the back in hu-
Cardiac muscle is a type of striated muscle found in the The connective tissue associated w ith muscle is named mans, where they are particula rl y adapted to the long,
wa ll of the heart and in the base of the large veins that according to its relati o nship with the muscle fibers: slow contractions needed to maintain erect posture.
empty into the heart. White fibers are large fibers with less myoglo bin and fewer
Endomysium is the delicate layer of reticu lar fibers that cytochromes and mitochondria. They make up fast-
The cross-striations in striated muscle are produced immediately surrounds individual muscle fibers. Only twitch mot01' units, fa tigue rapidly, and generate a large
largely by the specific cytoarchitectural arr angement of small-diameter capillaries and the finest neurona l peak muscle tension. Thus, white fibers are adapted for
both thin and thick myofilaments. This arra ngement is the branches are present within the endomysium, running rapid contraction and precise, fine movements. They con-
same in all types of striated muscle cells. The main differ- parallel to the muscle fibers. stitute most fibers of the extraocular muscles and the
ences between skeletal muscle ce.lls and cardia c muscle Perimysium is a thicker connective tiss ue laye r tha t muscles that control the movements of the digits. White
cells are in their size, shape, and organization r elative to surrounds a group of fibers to form a bundle or fasci- fi bers have a greater number of neuromuscular junctions
one another. cle. Fascicles are functiona l units of muscle fibers than do red fibers, thus allowing more precise neuronal
Smooth muscle cells do no t exhibit cross-striations be- that tend to work together to perform a specific func- control of movements in these muscles.
cause the myofilaments do not ach ieve the same degree of tion. Larger blood vessels and nerves travel in the peri- Intermediate fibers are of intermediate size. The amount
order in their arrangem ent. In addition, the myosin- mysium. of m yoglobin and the number of m itochondria they con-
containing myofilaments in smooth muscle are highly la- Epimysium is the sheath of dense connective tissue that tain are a lso intermediate between those of reel and
bile. Smooth muscle is restricted to the viscera and vascu- surro unds a collection of fascicles that constitutes the white fibers.
lar system, the arrector pili muscles of the skin, and the in- muscle (see Fig. 10.1a). The major vascular an d nerve
trinsic muscles of the eye. supply of the muscle penetrates the epimysium .
Myofibrils and Myofilaments
There are three types of skeletal muscle fibers: red, white, and
9 SKELETAL MUSCLE intermediate The structural and functional subunit of the muscle fiber is the
myofibril
A skeletal muscle cell is a multinucleated syncytium Skeletal muscle fibers differ in diameter and in their nat-
ura l color in vivo. The color differences are not apparent Skeletal muscles are composed of fascicles, which in
In skeletal muscle, each muscle cell, more commonly in hematoxylin and eosin (H&E)-stained sections. How- turn are composed of individ ual muscle fibers. The mus-
called a muscle fiber, is actu ally a mu ltinucleated syn- ever, special cytologic and histochemical reactions based cle fiber is filled with longi tud inally arrayed subunits
cytium. A muscle fiber is formed during development by on oxidative enzyme activity, specifica ll y the succinic called myofibrils (Fig. 10.3 ). Myofibrils are visible in fa-
the fu sion of small, individual muscle cells called myo- dehydrogenase and nicotinamide adenine dinucleotide- FIGURE 10.2 vorable histologic preparati o ns and are best seen in cross
blasts. When viewed in cross secti on, the mature multinu- tetra zolium (NADH-TR) reactions, confirm the observa- Cross section of white and red skeletal muscle fibers. This cross sec- sections of muscle fi bers. In these sections they give the
cleated muscle fiber reveals a polygonal shape with a di- tions of fresh tissue and reveal several types of skeletal tion of muscle fibers stained with the NADH-TR reaction demon- fiber a stippled appearance. M yofibrils extend the en tire
ameter of 10 to 100 p.m. Their length varies from a lmost muscle fibers (Fig. 10.2 ). The most o bvio us are red fibers, strates two fiber types. The deeply stained, smaller muscle fibers ex-
length of the m uscle cell.
a meter, as in the sartorius muscle of the lower limb, to as white fibers, and intermed iate fibers. The histochemical hibit strong oxidative enzyme activity and correspond to the red
staining and enzyme activity of these tlu-ee types of muscle muscle fibers. The lighter-staining, larger fibers correspond to the
little as a few millimeters, as in the stap edius muscle of the Myofibrils are composed of bundles of myofilaments
white fibers. x280. Inset. Portions of the two fiber types at higher
middle ear. (Note: A muscle fiber should not be confused fibers reflect their functional diffe rences . Typically, all three
magnification. The reaction also reveals the mitochondria that con-
witJ1 a connective tissue fiber; muscle fibers are cellular el- fiber types are pr esent in a ny given muscle. The proportion Myofilaments are the individual filamentous polymers
tain the oxidative enzymes. The contractile components, the myofib-
ements, whereas connective tissue fibers are extracellular of each type va ries according to the functional role of th e rils, are unstained. xsso. (Original slide specimen courtesy of Dr. of myosin II (thick fi la ments} and actin and its associated
products of connective ti ssue cells.) muscle. Scott W. Ballinger.) proteins (thin filaments). lVIyofi laments are the ac tual con-
The nuclei of a skeletal muscle fiber are located in the cy- tractile elements of stria ted m uscle. The bundles of myofil-
toplasm immediately beneath the plasma membrane, also Fiber type is mainly attributable to myoglobin content and aments that make up the myofibril are surrounded by a
called the sarcolemma. In the past, the term sarcolemma mitochondrial number well-developed sm ooth endoplasmic reticulum (sER), also
was used to describe a thick " membrane" that was thought called the smcoplasmic reticulum. This reticulum forms a
to be the cytoplasmic bOLmdary of the muscle cell. ft is now Myoglobin is an oxygen-bind ing protein that closely re- Red fibers are small fibers w ith large amounts of myo- highly organized tubular network aro und the contr actile
known that the thick sarcolemma actually represents the sembles hemoglobin fo und in er ythrocytes and occurs in glo bin and cytochrome complexes and many mitoc ho n- e lements in all striated muscle cells. M itochondri a and
plasma membrane of the cell, its external lami na, and the va rying a mounts in muscle fibers. It provides a read y dria. They make up slow-twitch motor units (a twitch is glycogen deposits are loca ted between the myofibrils in as-
surrounding reticular lamina. source of oxygen for mu scle metabo lic r eactions. Classifi- a single, brief contraction of the muscle). Red fibers have sociation with the sER.
cation of skeletal muscle fibers into red, white, and inter- great resistance to fat igue but generate relatively less
A skeletal muscle consists of striated muscle fibers held mediate fibers reflects the myoglobin content and the num- muscle tension than white fibers. M yosi n adenos ine Cross-striations are the principal histologic feature of striated
together by connective tissue ber of mitochondria with their constituent cytochrome triphosphatase (ATPase) activity, essential for contrac- muscle
electron transport complexes . T hese complexes are essen- tion, is greatest in red muscle fibers. The large numbers
Th e connective tissue that surrounds both individua l tial for oxidative phosphorylation to produce adenosi.ne of mitochondria in red fibers are characterized by high Cross-striations are evident in H &E-stained preparations
muscle fibers and bundles of muscle fibers is essential for triphosphate (ATP), the energy source for muscle. levels of o xidative enzym es, as demonstrated by strong of longitudinal sections of muscle fibers. They may also be
250 C H APTER 1 0 Musclr Tissue CHAPTER 1 0 Nl 11srle Tiss11r 25 I
The functional unit of the myofibril is the sarcomere, the
line and extend into the A ba nd to the edge of the H band.
segment of the myofibril between two adjacent z lines Portions of two sarcomeres, o n either side of a Z line, con-
stitute the I band and contain only t hi n filaments. In a lon-
T he sarcomere is the basic contractile unit of striated m us- gi tu d inal sectio n of a sarcomere, the Z line appears as a
cle. It is the portion of a myofibril between two adjacent Z zigzag structure, with matrix m aterial, the Z matrix , bi-
Like all cells, muscle cells depend on the energy source con-
lines. A sarcomere measures 2 to 3 J.Lm in relaxed mam- secti ng the zigzag. T he Z line and its matrix material an-
tained in the high-energy phosphate bonds of ATP and phos-
phocreatine. The energy stored in these high-energy phos-
ma lian muscle. It may be stretched to more than 4 J.Lm and, cho r the thi n filaments from adj acen t sarcomeres to the an-
phate bonds comes from the metabolism of fatty acids and
during extreme contraction, may be red uced to as little as 1 gles of the zigzag by the actin-binding pro tein a-actinin.
glucose. Glucose is the primary metabolic substrate in actively J.LI11 (Fig. 10.5). The entire m uscle cell exhibits cross-striations These featu res are illustrated in Figure 10.3.
contracting muscle. It is derived from the general circulation as because sarcomeres in adjacent myofibrils are in register.
well as from the breakdown of glycogen, which is normally F- actin. t roponin, and tropomyosin in thin filaments and
stored in the muscle fiber cytoplasm. As much as 1% of the The arrangement of thick and thin filaments gives rise to the myosin II in thick filaments are the primary proteins in the
dry weight of skeletal and cardiac muscle may be glycogen. density differences that p roduce the cross-striations of the contract ile apparat us
In rapidly contracting muscles, such as the leg muscles in
m yofibril
running or the extraocular muscles, most of the energy for
contraction is supplied by anaerobic glycolysis of stored glyco- T hin filaments contain F-actin, trop omyosin, and t ro-
gen. The buildup of intermediary metabolites from this path-
The myosin-containi ng tbick fi laments a re about 1.5 J.Lm po nin. Thick filaments contai n only myosin ll.
way, particularly lactic acid, can produce an oxygen deficit lo ng and are restricted to the cen tra l portio n of the sar- G-actin is a small, 4 2-kDa molecule that polymerizes to
that causes ischemic pain (cramp) in cases of extreme muscu- comere, i.e., t he A ba nd. The thin fi laments attac h to the Z for m a dou ble-stranded helix, t he F-actin filament. T hese
lar exertion.
Most of the energy used by muscle recovering from con-
traction or by rest ing muscle is derived from oxidative phos-
phorylation. This process closely follows the .a-oxidation of
fatty acids in mitochondria that liberates two carbon frag-
ments. The oxygen needed for oxidative phosphorylation and
other terminal metabolic reactions is derived from hemoglo- sarcomere Z line
bin in circulating erythrocytes and from oxygen bound to
Z line
myoglobin stored in the muscle cells.
thin filament . I
thick filament troponin complex
I
TnCTnT
I
I 2 l
Tnl
~~~~f~~~~
~~ ~
=
Ciiffi
;; L..--
~~~Z i ne actin
==
==
Myosin II, a 5 10-kDa protein, is composed of two
polypeptide heavy chains (222 kDa each) and four light
c:::::J
== chains. Light chains are of two types (18 kDa and 22 kDa),
and one molecule of each type is present in association w ith
each myosin head. The phosphorylation by myosin light
chain kinase of one of the two types of myosin light chains
initiates contraction in smooth muscles (see page 267). Each
heavy chain has a small globu lar head that projects at an ap-
proximately right angle at one end of the long rod-sh aped
molecule. This globu.lar head has two specific binding sites,
one for ATP and one for actin. It also demonstrates ATPase
a
and motor activity. The myosin molecules aggregate tail to
FIGURE 10.5 tail to form the thick filaments; the rod-shaped segments
Sarcomeres in different functional stages. In the resting state (mid A band
overlap, so that the globular heads project from the thick fil- H band
die), interdigitation of thin (actin) and thick (myosin) filaments is not
complete; the H and I bands are relatively wide. In the contracted ament. The "bare" zone in the middle of the filament, i. e.,
state (bottom), the interdigitation of the thin and thick filaments is in the portion of the filament that does not have globular pro- Z line :~:Miine
I I
Z line
creased according to the degree of contraction. In tile stretched state jections, is the H band. The projecting globular heads of the
(top), the thin and thick filaments do not interact; the H and I bands myosin molecules form cross-bridges between the thick and
are very wide. The length of the A band always remains the same thin filaments on either side of the H band (see Fig. 10.5).
and corresponds to the length of the thick filaments; the lengths of 18-kDa light chain 22-kDa light chain
the H and 1 bands change, again in proportion to the degree of sar-
comere relaxation or contraction. . heavy chain ~ J actin-
~
yosm molecule binding site
ATP-
binding site
tail head ""' actin-binding site
thick
filament
actin filaments are polar; all G-actin molecules a re o riented
in the same direction. The plus end of each filament is
bound to the Z line by a-actinin; the minus end extends to-
ward theM line. Each G-actin molecule of the thin filament
has a binding site for myosin. C protein tropomodulin b
Tropomyosin is a 64-kDa protein that also consists of a FI GURE 10.6
double helix of two polypeptides. It forms filaments that Accessory proteins maintain precise alignment of thin and thick
Electron micrograph of skeletal muscle and corresponding molecu- Tile accessory proteins are titin, a large elastic molecu le t11at anchors
filaments
r un in the groove between the F-actio molecules in the thin lar structure of a sarcomere. a. This high-magnification electron mi- tile t11ick (myosin) filaments to the z line; aactinin, wl1ich bundles
filament. In resting muscle, tropomyosin and the troponins crograph shows a longitudinal section of the myofibrils. The I band, thin (actin) filaments into parallel arrays and anchors tilern at the Z
mask the myosin-binding site on the actin molecule. To maintain efficiency and speed of muscle contraction, wh ich is bisected by the z line, is composed of barely visible, thin line; nebulin, an elongated inelastic protein attached to the Z lines
Troponin actua lly consists of a complex of three globu- both thin and thick filaments in eacl1 myofibril must be (actin) filamen ts. Tiley are attached to the Z line and extend across 'that wraps around the thin filaments and assists aactinin in anchor-
lar subunits. Each tropomyosin molecule conta ins one tro- aligned precisely and kept at an optima l dist ance from one tile I band into the A band. Tile thick filaments, composed of myosin, ing the thin filament to z lines; tropomodulin, an actin-capping pro-
ponin complex. Troponin-C (TnC) is the smallest subunit a nother. Proteins known as access01y proteins are essential account for the full width of the A band. Note that in the A band there tein that maintains and regulates the length of the thin filaments;
in regu lating the spacing, attachment, and alignment of the are additional bands and lin es. One of t11ese, theM line, is seen at tile tropomyosin, whicll stabilizes thin filaments and, in association with
of the tropon in complex (18 kDa). It binds Ca 2 ; , the es-
myofilaments. These structura l protein components of middle of the A band; another, the less electron dense H band, con- troponin, regulates binding of calcium ions; and myomesin and C pro-
sential step in the initiation of contraction (see below). Tro-
skeleta l muscle fibrils constitute less than 25% of the total sists on ly of thick filaments. The lateral parts of tile A band are more teins, myosin-binding proteins that 11old t11ick filaments in register at
ponin-T (TnT), a 30-kDa su bunit, binds to tropomyosin, electron dense and represent areas where tile thin filaments interdig- tile M line. The interactions of these various proteins maintain the
anchoring the troponin complex. Troponin-I (Tnl), a lso a protein of the muscle fiber. They include (Fig. 10.6)
itate with the thick filaments. x 35,000. b. Diagram illustrating the dis- precise alignment of the thin and thick filaments in tile sarcomere.
30-kDa subLmit, binds to actin, thus inhibiting actin- Titin, a large (2500-kDa) protein, forms an elastic lattice tribution of myofilaments and accessory proteins witl1in a sarcomere.
myosin interaction. that anchors thick filaments in the Z lines. Two spring-
2 54 CHAPTER 1 0 Muscle Tissue CHAPTER 10 lvlttscle Tisme '2 55
like portions of the protein adjacent to the thin filaments ity that begins at the moment of death is due to lack of Force generation is the fourth stage of ttie cycle, in which the
help stabilize the centering of the myosin-containing ATP and is known as rigor mortis. In an actively con- myosin head releases inorganic phosphate and the power
thick filament, preventing excessive stretching of the sar- tracting muscle, this step ends with the binding of ATP to stroke occurs
comere. d1e myosin head.
a-Actini~t, a short, bipolar, rod-shaped, 190-kDa actin- Dystrophin is a rod-shaped cytoskeletal protein with a short . STAGE4:
Release is the second stage of the cycle, in which the myosin FORCE GENERATION
binding protein, bundles thin filaments into parallel ar-
rays and anchors them at the Z line.
Nebulin, an elongated, inelastic, 600-kDa protein, is at-
head and a long tail that is located just beneath the skeletal
muscle cell membrane. F-actin is bound at the end portion of
the tail. Two groups of transmembrane proteins-o:- and jl-
head is uncoupled from the thin filament
STAGE2:
<--___,.<
dystroglycans and o:-, jl-, "{- , and 5-sarcog/ycans-participate
tached to the Z lines and runs parallel to the thin fila- in a dystrophin-glycoprotein complex that linl<s dystrophin to RELEASE
ments. It helps a-actinin anchor thin filaments to Z lines the extracellular matrix proteins laminin and agrin. Dystrogly-
and is thought to regulate the length of thin filaments cans form the actual link between dystrophin and laminin;
during muscle development. sarcoglycans are merely associated with the dystroglycans in
Tropomodulin, a small , -40-kDa actin-binding protein, the membrane.
is attached to the free portion of the thin filament. This Recent research has successfully characterized the dys-
actin-capping protein maintains and regulates the length trophin gene and its products. Several forms of muscular dys-
of the sarcomeric actin filament. Variations in thin fila- trophy are attributed to mutations of single genes encoding
ment length (such as those in white and red muscle several proteins of the dystrophin-glycoprotein complex.
fibers) affect the length-tension relationship during mus- Ouchenne's and Beckertype muscular dystrophy are associ-
ated with mutations that affect dystrophin expression; different
cle contraction and therefore influence the physiologic
forms of limb girdle muscular dystrophy are caused by muta-
properties of the muscle. tions in the genes encoding the four different sarcoglycans; POWER STROKE
Desmin, a type of 53-kDa intermediate filament, forms a and another form of congenital muscular dystrophy is caused
lattice that surrounds the sarcomere at the level of the Z by a mutation in the gene encoding the o: 2 chain of muscle The m yosin head binds weakly to its new binding site
lines, attaching them to one another and to the plasma laminin. on the neighboring actin molecule of the thin filament,
membrane, thus forming stabilizing cross-links between In this stage of the contraction cycle, ATP binds to the
myosin head and induces conformational changes of the causing release o f the inorganic phosphate. This r elease
neighboring myofibrils. has two effects. First, the binding affinity betwee n the
Myomesin, a 185-kDa myosin-binding protein, holds actin-binding site. This change reduces the affinity of the
myosin head for the actin molecule of the thin filament, myosin bead and its new attachment site increases. Sec-
thick filaments in register at the M line. ond, a force is generated by the myosin head as it returns
C protein, one of possibly several myosin-binding pro- causing the myosin head to uncouple from the thin filament.
The Contraction Cycle to its origina l unbent position. Thus, as the myosin head
teins (140 to 150 kDa ), serves the same func tion as myo- stra ightens, it forces movement of the thin filament
mesin and forms several distinct transverse stripes on ei- Shortening of a muscle involves rapid contraction cycles Bending is the third stage of the cycle, in which the myosin along the thick filament. This is the "power stroke" of
ther side of the M line. that move the thin filaments along the thick filament. Each head, as a result of hydrolysis of ATP, advances a short distance the cycle. During thi s stage, ADP is lost from the myosin
Dystrophin, a large 427-kDa protein, is thought to link contraction cycle consists of five stages: attachment, re- in relation to the thin filament bead.
laminin, which resides in the externa l lamina of the lease, bending, force generation, and reattachment.
muscle cell, to actin filaments. Absence of this protein STAGE 3:
BENDING Reattachment is the fifth and last stage of the cycle, in which
is assoc iated with progressive muscular weakness, Attachment is the initial stage of the contraction cycle, in which
the myosin head binds tightly to a new actin molecule
a condition called Duchenne's muscular dystrophy. Dy- the myosin head is tightly bound to the actin molecule of the
strophin is encoded on the X chromosome, which ex- thin filament
STAGE 5:
plains why only boys suffer from Duchenne's muscular STAGE 1: REATTACHMENT
actin filament
dystrophy. Recently, characterization of th e dystrophin ATTACHMENT (after power stroke)
gene and its prod uct h as been clinically im portant (see
Box 10.2)
Although an individual myosin head may detach from The depolarization of the T-tubule membrane triggers the
the thin filament during th e cycle, other myosin heads in release of Ca2 + from the terminal cisternae to initiate muscle
the same thick filament will attach to actin molecules, contraction
thereby resulting in movement. Because the myosin h eads
are arranged as mirror images on either side of the H band, When a nerve impulse arrives at the neuromuscular
this action pulls the thin filaments into the A band, thus junction, the release of neurotransmitter (acetylcholine )
shortening the sarcomere. from the nerve ending trigger s a localized plasma mem-
brane depolariza tion of the muscle cell. The depolariza-
Regulation of contraction involves Ca2+, sarcoplasmic t ion, in turn , causes voltage-gated Na+ channels in th e
reticulum, and the transverse tubular system plasma membrane to open, allowing an influx of Na+
from the extracellular space into th e muscle cell. The in-
Ca 2 + must be available for the reaction between actin flux of Na+ results in general depo larization, which
and myosin. After con traction, Cal+ must be removed. spreads rapidly over the entire plasma membrane of the
This rapid delivery and remova l of Ca 2 + is accomplished muscle fiber. When the d epolarization encounters the
by the combined work of the sarcoplasmic reticulum and opening of the T tubule, it is transmitted along the mem-
the transverse tubular system. bra nes of the T system into the depths of the cell. Electri-
The sarcoplasmic reticulum is arranged as a repeating cal charges activate voltage sensor proteins located in the
series of networks around the myofibrils . Each network membrane of the T tubule. The activation of these sen-
of th e reticulum extends from one A-1 junction to the sor s, in turn , opens gated Ca2+ -release channels in adja-
next A-I junction within a sarcomere. The adjacent net- cent terminal sacs of the sarcoplasmic reticulum, ca using
work of sarcoplasmic reticulum continues fro m the A-1 the massive, rapid r elease of Ca 2 + into the sarcoplasm.
junction to the nex t A-1 junction of the neighboring sar- The inc reased concentration of Ca 2 + in th e sarcoplasm ini-
comere. Therefore, one network of sarcoplasmic retic u- "triad" t iates contraction of the myofibril by binding to the TnC
terminal cisterna
lum surrounds the A band, and the adjacent network sur- T tubule of sarcoplasmic portion of the tropooin complex on the thin filaments (see
rounds the l band (Fig. 10.7 ). Where the two n etworks reticulum page 252). The change in molec ular co nformation of TnC
meet, at the junction between A and I bands, the sar- FIGURE 10.7 ca uses the Tni to dissociate fro m the actin molecules, al-
c oplasmic reti culum forms a slightly more regular ring- Diagram of the organization of striated muscle fiber. This diagram il- lowing the troponin complex to uncover myosin-binding
like channel called the terminal cisterna. The terminal lustrates the organization of the sarcoplasmic reticulum and its rela- sites on the actin molecules. The myosin heads are now FIGURE 10.8
cisternae serve as reservoirs for Ca 2 + . To release CaH into tionship to tile myofibrils. Note that in striated muscle fibers, two free to interact with actin mol ec ules to initiate the muscle Photomicrograph of neuromuscular junction. This silver preparation
the sarcoplasm, the plasma membrane of the terminal cis- transverse (T) tubules supply a sarcomere. Each T tubule is located at contra ction cycle. shows a motor nerve and its final branches that lead to the neuro-
terna e contains an abundance of gated Ca2 +-release an A-1 band junction and is formed as an invagination of the sar- Simultaneously, a Ca 2+ -activated ATPase pump in the muscular junctions (motor end plates). The skeletal muscle fibers are
channels. Also located around the myofibrils in associa- colemma of striated muscle. It is associated with two terminal cister- mem brane of the sarcoplasmic reticulum transports Ca2+ oriented horizontally in the field and are crossed perpendicularly by
nae of the sarcoplasmic reticulum that surrounds each myofibril, one tile motor nerve fibers. Note that these fibers distally lose their myelin
tion witb the sarcoplasmic reticulum are large numbers of back into the terminal c isternae. The resting concentra-
cisterna on either side of the T tubule. The triple structure as seen in sheath and divide extensively into small swellings forming a cluster of
tion of Ca 2 + is restored in the cytosol in less than 30
cross section, where the two terminal cisternae flank a transverse neuromuscular junctions. X620.
msec. This res toration of resting Cal+ concentration near
tubule at the A-1 band junction, is called a "triad: Depolarization of
t he myofilaments normally ca uses contraction to stop.
the T tubule me mbrane initiates the release of calcium ions from the
sarcoplasmic reticulum and eventually triggers muscle contraction. C ontraction wi ll continue, however, as long as nerve im-
(Courtesy of Dr. Charles P. Leblond.) pulses continue to depolarize the p lasma membrane of
the T tubules. of end branches, each of which lies in a sha llow depres-
The sliding filament model postulates that the ratchet-like sion on the surface of the muscle fiber, the receptor
movements of the myosin heads bound to actin produce the region (Fig. 10.9). The axon ending is a typical presy-
movement of the thin filaments relative to the thick filaments,
M otor Innervation naptic structure and contains numerous mitochondria
mitochon dria and g lycogen granules, bo th of which are
which in turn causes the sarcomere to shorten. Although the involved in providing the energy necessary for the reac- Skeletal muscle fibers are richly innervated by motor neu- and syn aptic vesicles that contain the neurotransmitter
sliding filament model can explain contraction in a single sar- tions involved in contraction. rons that originate in the spina l cord or brain stem. The acetylcholine.
comere, it cannot adequately explain the shortening of a myo- The transverse tubular system, or T system, consists of axons of the neurons branch as they near the muscle, giv-
fibril of a muscle fiber. Obviously, if the activity just described
numerous tubular invaginations of the plasma membrane; ing rise to twigs or termina l bra nc hes that end on individ- Release of acetylcholine into the synaptic cleft initiates
were to occur simultaneously In adjacent sarcomeres, no con-
each one is called a T tubule. T tubu les penetrate to all lev- ua l muscle fibers (Fig. 10.8). depolarization of the plasma membrane, which leads to
traction could occur. Equal and opposite forces would be ex-
erted on either side of the Z line, and the contraction of any els of the muscle fibe r and are located between adjacent muscle cell contraction
given sarcomere would be prevented by the contraction of its termina l cisternae a t the A-I junctio ns (see Fig. 10.7) . They The neuromuscular junction is the contact made by the
two immediate serial neighbors. Recent studies with ultrahigh- contain voltage sensor proteins, depolarization-sensitive terminal branches of the axon with the muscle The muscle fiber p lasma membrane that underlies the
speed photography have demonstrated that an extremely transmembrane channels that are activated when the synaptic cleft has many deep junctional folds (subneural
small temporal delay occurs between the contraction of adja- plasma membrane depolarizes. Conformational changes of At the neuromuscular junction (motor end plate), the fo lds). Specific acetylcholine receptors are limited to the
cent sarcomeres, so that a wave-like contraction actually oc- these proteins affect gated Ca 2 +-release channels located in mye lin covering (myelin sheath) of the axon ends, and plasma membra ne immediately border ing the cleft and at
curs In each muscle fibril and, consequently, in each muscle the adjacent p lasma membrane of the terminal cisternae. t he terminal portion of the axon is covere d by only a thin the top of the fo ld s. The external lamina extends into the
fiber. The complex of T tubule and the two adjacent terminal portion of the neurilemmal (Schwann) cell and its exter- subneural folds (see Fig. 10.9). The synaptic vesicles of the
cisternae is called a triad. nal lamina. Th e end of the axon ramifies into a number axon terminal release acetylcholine into the cleft, which
158 CH AP TER 10 C H A PTER 1 0 Muscle Tissue 2 59
Sensory Innervation an i11temal capsule. A fluid-filled space separates the in- stretch receptor. W hen skel eta l muscle is stretched , nerve
ternal capsule from an o uter extemal capsule. One type endings of sensory nerves become activa ted. They convey
Encapsulated sensory receptors in muscles a nd tendons of spindle cell, the 11uclear bag fiber, contains an aggre-
provide informa tio n about the degree of tension in a mus- their impulses to the central nervous system, which in
gation of nuclei in an expanded midregion; the other turn mod ulates the activity of moto r neurons innervating
cle and its position. type, called a 11uclear chai11 fiber, has many nuclei that particular mu scle.
arranged in a ch ain. The muscle spindle transmits infor- Recent real-time studies w ith computed tomogr aphy
The m uscle spindle is the specialized stretch receptor located mation abo ut the degree of stretching in a muscle. The (CT) scans of living muscle in different states of contrac-
within the skeletal muscle sensory (afferent) nerve fibers carrying information from tion suggest that muscle spindles may a lso represent the
the muscle spindle h ave endings that are spirally arranged axes of functional units withi n large skeletal muscles. Such
The muscle spi11dle is a specia lized recep to r unit in aro und the midregio n of both types of spindle cells. In functi onal units precisely regulate contr actions of portions
m uscle; it consists of two types of modified muscle fi bers ad dition, spindle cells receive motor (efferent) innerva- of the muscle by creating "fixation points" within the mus-
caJled spi11dle cells and neuron terminals (Fig. 10.11 ). ti on from the spinal cord and brain by -y efferent nerve cle substance.
Both types of modified muscle fibers are surrounded by fibers, which are thou ght to regulate the sensitivity of the Similar encapsulated receptors, te11do11 organs, are
fo und in the tendons of muscle and also respond to stretch.
These receptors contain only affer ent fibers.
primary
afferent neuron nuclear
trail ending of
terminal chain fiber Development, Repair, Healing, and Renewal
Y3 efferent fiber
FIGURE 10.12
In skeletal muscle development, myoblasts fuse to form Photomicrograph of developing skeletal muscle myotubes. This
multinucleated myofibers photomicrograph shows a cross section (on the left) and a longitudi-
internal nal section (on the right) of developing skeletal muscle fibers in tile
capsule Myoblasts are derived from a self-renewing population stage of secondary myotubes. These myotubes are formed by se
quential fusion of myoblasts forming elongated tubular structures.
subcapsular
space
I of multipotential myogenic stem cells that originate in the
embryo from unsegmented paraxia l mesoderm (cranial Note that the myotubes have a small diameter and widely spaced,
centrally positioned nuclei that gradually become displaced into the
muscle progenitors) or segmented mesoderm of somites
cell periphery by tile increased number of newly synthesized myofil
(epax ial and hypaxial muscle progenitors). Developing aments. In the mature multinucleated muscle fiber (upper left), all nu-
spindle . muscle contains two types of myoblasts: clei are positioned in tile peripheral sarcoplasm, just inside the
cells plasma cell membrane. x220.
Early myoblasts ar e responsible fo r the fo rmation of pri-
extern al
mary myotubes, chain-like structures that extend be-
capsule tween tendons of the developing muscle. Primary m yo-
tubes are formed by nearl y synchrono us fusion of ea rly blends in with the muscle cell sarcoplasm w hen viewed in
myoblasts. Myotubes undergo further differentiation the light microscope, thus making them difficult to iden-
into mature skeleta l m uscle fibers. Primary myotubes tify. Each satellite cell has a single nucleus with a chro-
a. motor fiber observed in the light microscope exhibit a chain of mul- matin network denser and coarser than that of muscle cell
tiple central nuclei containing myofilaments. nuclei. T he regenerative capacity of skeletal muscle is lim-
external Late myoblasts give rise to seco11dary myotubes, w hich ited. Satellite cells function as stem cells that, after injury,
/ capsule ""' ar e fo rm ed in the innervated zone of developing muscle . proliferate to give rise to new myoblasts. As long as the ex-
where the myotubes have direct contact w ith nerve ter- tern al lamina remains intact, the myoblasts fuse within the
minals. Secondary myotubes continue to be formed by external lamina to form myotubes, which then mature into
a sequential fusion of myoblasts into the a lready-formed a new fiber. In contrast, if the external lamina is disrupted,
secondary myotubes at random positions a lo ng their fibro blasts repair the injured site, wi th subsequent scar tis-
FIGURE 10.1 1 length . Second ary myotubes are characterized by a sue fo rmation.
Muscle spindle. a. Scl1ematic diagram of a muscle spindle. The diam- the encapsulated, fluid-filled receptor. In one bundle, several of the small er diameter, more widely spaced nuclei, and an in- M uscular d ystrophies are characterized by progressive
eter of the spindle is expanded to illustrate structural details. Each spindle cells are cut at the level that reveals their nuclei. An internal creased number of myofilaments (Fig. 10.12) . In the degeneration of skeletal muscle fibers, which places a con-
spindle contains approximately two to four nuclear bag fibers and six capsule surrounds the spindle cells. The external capsule of the mus mature m ultinucleated muscle fiber, the nuclei are all in stant dema nd on tl1e satellite cells to r eplace the degener-
to eight nuclear chain fibers. In the nuclear bag fibers, the muscle cle spindle and the adja cent perimysium can be seen as a faint dou-
the peripher a l sa rcoplasm, just inside the plasma mem- ated fibers. Ultimately, tbe satellite cell pool is exhausted.
fiber nuclei are clumped in the expanded central portion of the fiber, ble-layer boundary of the receptor. Immediately above and outside of
brane. New experimental da ta indicate that dming this process,
hence the name bag. In contrast, the nuclei concentrated in tile cen- the muscle spindle is a nerve that may be supplying the spindle. Tile
tra l portion of the nuclear chain fibers are arranged in a chain. Botll several types of nerves associated with the spindle cells as well as the additional m yogenic cells are recruited from the bone mar-
afferent (sensory) and efferent (motor) nerve fibers supply muscle type of spindle cells cannot be distinguished in this H&E-stained sec- Some nuclei that appear to belong to the skeletal muscle fiber row an d supplement the ava ilab le satellite cells. The rate of
spindl e cells. Tile afferent nerve fibers respond to excessive stretching tion. Near one of the bundles of spindle cells is a small blood vessel. are nuclei of satellite cells degeneration exceeds the rate of regeneration, however, r e-
of the muscle, which in turn inhibits the somatic motor stimulation of The flocculent material within the capsule consists of precipitated pro sulting in loss of mu scle fu nctio n. A fut ure treatment strat-
the muscle. The efferent nerve fibers regu late the sensitivity of the af- teoglycans and glycoproteins from th e fluid that filled the spindle be- Satellite cells are interposed between the plasma m em- egy for muscular dystrophies may include the tra nsplanta-
ferent endings in the muscle spindle. b. Photomicrograph of a cross fore fixation. x sso. brane of the musde fiber and its external lam ina. T hey are tion of satellite cells or their myogenic bone marrow
section of a muscle spindle, showing two bundles of spi ndle cells in small cells with scant cytoplas m. The cytoplasm typ ically counterparts into damaged muscle.
26'2 C H APTER 10 /Vlusclr Ti ssue CHAPTE R 10 Muscle Tissru 263
The sER in cardiac muscle cells is organize d into a single (0.1 %), it suggests t hat d a maged cells ca n p o tentially be
network along the sarcomere, extending from z line to z line replaced. T his fi nding s uggests that in the futu re, a me th od
mig ht be d eveloped t hat could induce human cardiac m us-
T he sER o f cardiac muscle is not as well orga nized as cle to regen era te in to hea lthy t issue.
tha t of skeletal muscle. It d oes n ot separate bu nd les of my-
ofila me nts into discrete myofi bri ls. T he T t u bules in car-
diac muscle pe netrate in to the myofi la ment bundles a t t he Q SMOOTH MUSCLE
level of t he Z line, bet ween the ends of the sER ne two rk.
T hus, there is only o ne T t ubule per sa rcomere in ca rd iac Smooth m uscle genera lly occ urs as bu11dles o r sheets of
mu scle. Sma ll termin al cist ernae o f the sER in teract with elongate fusifo rm cells w ith fi ne ly tapered ends (Fig.
the T tubules to fo r m a diad a t the level of t h e Z line (see 10.16). The cells, a lso ca lled fibers, range in length fro m
F ig. 10.14). The ex te rna l la mina a dheres to th e invagi- 2 0 fLI11 in the wa lls of sma ll blood vessels to a bo ut
gap junctions nated p lasma me m bra ne of the T tub ule as it pen etrat es 2 00 fLI11 in the wa ll of the intestine; they may be as la rge as
into t he cytoplasm of the m uscle cell. T he T t ubules a re 500 fL111 in th e wall of the uterus during pr egnancy.
macula adhere ns
larger a nd more numerous in ca rd iac ventricular mu scle Smooth m uscle cytoplasm sta ins ra ther evenly w ith eos in
t ha n in skeleta l muscle. They are less numerous, however, in ro utine H&E preparatio ns beca use o f the concentra-
in cardiac a t ria l m uscle. tions of actin an d myos in tha t these cells contain . The nu -
clei o f smoot h muscle cells a re loca ted in the center of t he
Cardiac muscle cells exhibit a spontaneous rhythmic contraction cell and o ften have a corkscrew appea rance in longitud inal
sectio n . This ch a racteristic is due to contractio n of the cell
i~ T he intr in sic spon taneous contraction o r bea t of cardiac
'. during fixatio n and is o ften useful in d istinguishing sm ooth
muscle is evident in em br yonic cardiac muscle cells as we ll
as in cardi ac muscle cells in tiss ue cult ure. T he heartbeat is
ini tia ted, loca lly regula ted , a nd coord inated by specia lized,
modifi ed cardiac muscle cells called cardiac conducting
cells. These cells a re organized in to no des a n d highly sp e-
cia li zed condu cting fibers (Pu1-kinje fibers) that gen erate
an d rapidly tra nsmi t the contractile imp ulse to va rio us
pa rts of the myocardium in a precise seq uence. Both
pa rasym pathe tic a nd sympa thetic ne rve fi bers termi na te in
t he n odes. Sym path etic sti m ulation accelerates the hea rt-
bea t by increasing the frequ ency of impu lses to the ca rdiac
co nducting cells. Pa rasympa th etic stim u lation slows dow n
t he heartbeat by decr easing the freq uency of the impulses.
T he impulses carried by these nerves do not in itiate con-
traction but o n ly m odify the rate of intrinsic card iac mu s-
cle contraction by t heir effect at t he nodes. The struc ture
a nd functio ns of the conducting system of the hea rt are de-
scribed in C ha pter 12.
RELAXED CONTRACTED passing nerve fiber, or bouton en passant (see page 289),
occur adjacent to the muscle cells to be innervated. The en-
largements contain synaptic vesicles with neuromuscular
s~
nucleus
transmitter s. However, the neuromuscular site is not com- D
par able to the neuromuscular junction of striated muscle.
Rather, a considerable distance, usually 10 to 20 ,um (in
some locations, up to 200 ,um), may separate the nerve ter-
mina l and the smooth muscle. The neurotransmitter re-
a-actinin-containing actin-myosin leased by t he nerve terminal must diffuse across this dis-
cytoplasmic densities filaments tance to reach t he muscle.
No t all smooth muscle cells are exposed directly to the
FIGURE 10.19
A suggested model for smooth muscle cell contraction. Bundles of
intracellular analogs of striated muscle Z lines. They contain the
actin-binding protein a -actinin. Because the contractile filament neurotransmitte r, however. As discussed above, smooth s
myofilaments containing thin and thick filaments, shown In dark bundles are oriented obliquely to the long axis of the cell, their con- muscle cells make contact with neighboring cells by gap
brown, anchor on cytoplasmic densities, shown in beige. These den- traction shortens the cell and produces the corkscrew- shape of the junctions. As in cardiac muscle, contraction is propagated D
sities, in turn, anchor to the sarcolemma. Cytoplasmic densities are nucleus. from cell to cell via gap junctions, thus producing coordi-
na ted activity wi thin a smooth muscle bundle or layer. The
FIGURE 10.20
gap junction between two smooth muscle cells was origi-
Autoradiograph of rabbit smooth muscle from the wall of the colon.
nall y designated a nexus, a term still in use.
The animal was injected with tritiated thym idine 21 days before the
myosin head dissociates from actin. This phosphoryla ti on may contract in a wave- like manner, producing peristaltic tissue was sampled. In th is nest of labeled cells, both heavily labeled
occurs slowly, with maximum contractio n often taking up movemen ts such as those in the gastro intestinal trac t and Smooth muscle cells also secrete connective tissue matrix
stem cells (S) and lightly labeled daughter cells (D) are visible. These
to a seco nd to achieve. the male genital tract, or contraction may occur along t he are frequently adjacent to each other. x 700.
Smooth muscle cell myosin hydrolyzes ATP at about entire muscle, producing extrusive movements, e.g., those Sm ooth muscle cells have organelles typical of secre-
10% of the rate of skeletal muscle, producing a slow cross- in the urinary bladder, gall bladder, a nd uterus. Smooth tory cells. A well-developed rER and Golgi apparatus are
bridging cycle t ha t resu lts in slow contraction of these m uscle exhibits a spontaneous contractile activity in the found in the perinuclear zone. Smooth muscle cells syn-
cells. Thus, smooth muscle cells, and no nmuscle cells tha t a bsence of ne rve stimuli. thesize both type IV (basal lamina) collagen and type III
contract by this same m ech a n ism, are capable of sustained Contraction of smooth m uscle is usual ly regulated by (reticula r ) collagen as well as laminin, elastin, and pro-
contractio ns over long periods of time wh ile using o n ly postganglionic neurons of t he autonomic nervous system teoglycans. Except at the gap junction s, smooth m uscle
10% of t he ATP that wou ld be used by a stria ted muscle (ANS); most smooth m uscle is directly innervated by bo th cells are surrounded by an external lamina. In some lo-
cell performing the same work. symp athetic and parasympathetic nerves. In the gastroin- catio ns, such as the walls of blood vessels and the uterus,
The description of autonomic innervation of smooth muscle
testinal tract, the third component of t he ANS, th e enteric sm ooth muscle cells secrete large amounts of both type I
according to the sympathetic and parasympathetic classifica-
division, is the p rimary source of ne rves to the muscular co llagen and elastin. tion and their respective adrenergic and cholinergic transmit-
Smooth muscle cells have a membrane system of sarcolemmal
invaginations, vesicles, and sER but lack a T system layers. ters may be more complex than traditionally thought. Viewed
Although most Ca1 + enters the cytoplasm d uring de po- Renewal, Repair, and Differentiation with the TEM, nerve termina ls with synaptic vesicles that ap-
lariza ti on by voltage-gated Ca2+ chann els, som e Ca 2 + chan- pear to be empty are considered cholinergic (i.e., secreting the
A c ha racteristic feature of smooth muscle cells is th e nels, called ligand-gated Ca2 ' channels, are activated by neurotransmitter acetylciJOiine); nerve terminals with synaptic
presence of large numbers of in vaginations of t he cell Smooth muscle cells are capable of dividing to maintain or in- vesicles filled with dense granular material are considered
hormones. Thus, smooth muscle contraction may also be
membrane th at resemble caveolae (see page 266). Beneath crease their number adrenergic (i.e., secreting the neurotransmitter norepineph-
initiated by certain hormones secreted from the posterior pi-
the plasm a membra ne and often in p roximity to the sparse rine). Other neurotransmitters have been identified and are
t uitary g land (e.g., oxytocin and, to a lesser extent, antidi-
profiles of t he sER are cytoplasmi c vesicles. It is tho ught Smooth muscle cells may respond to injury by undergo: collectively called purinerglc. They are likely to be contained
uretic hormone, ADH [see p age 657]). In add ition, smooth in large vesicles with an opaque content.
tha t the invaginations of the cell membrane a nd t he un - muscle cells may be stimulated o r inhibited by hormones se- ing m itosis. In addition, smooth muscle contains regularly
Nerve endings in smooth muscle tissue that contain primar-
derly ing vesicles a long w ith the sER function in a ma nn er creted by the adrenal m edulla ( e.g ., epinephrine and norep- rep licating populations of cells. Smooth musc le in the
ily mitochondria and no vesicles are considered sensory. Both
a na logous to the T system o f striated muscle to d eliver inephrine). OxytociJl is a p oten t stimu lator of smooth mus- ute ru s pro liferates d uring the norma l menstrual cycle and
sympathetic and parasympathetic fibers innervate smooth
CaH to the cytoplasm . The vesicles a nd t he sER sequester cle contraction, and its release b y the posterior p ituita ry d uring pregnancy; both activities are under hormonal con- muscle, and it is difficult to distinguish between the fibers. In
Ca2+ fro m the extracellular matrix a nd release it during p lays a n essential role in uterine contraction during parturi- trol. T he smooth muscle cells of blood vessels also divide some smooth muscle, the adrenergic neurotransmitters stimu-
cell depolarization. T he Ca2+ binds to calmodulin, which tion. It is often used to induce or enhance labor. Many pep- regularly in the adult, presumably to replace damaged or late and the cholinergic transmitters inhibit contraction; in
acti vates phosphoryla tion of the myosin light c ha in kinase tide secretions of enteroendocrine cells also stimu late or senile cells; the smooth muscle of the muscul aris externa of other smooth muscle, the reverse is true.
to initiate contraction. inhibit smooth muscle contractio n, particularly in the ali- the sto mach and colon regularl y replicates and may even
mentary can al and its associated organs. slowly thicken during life (Fig. 10.20).
New smooth muscle cells have been shown to d evelop
Functional Aspects of Smooth Muscle from und ifferentia ted mesenchymal cells in the adventitia
Nerve terminals in smooth muscle are observed only in the
of blood vessels. Smooth muscle cells have also been cytoplasmic morphology is d ifficult to distinguish from
connective t issue adjacent to the muscle cells shown to develop from the division and differentiation of
Smooth muscle is specialized for slow, prolonged contraction that of the endothelial cell. In postcapillary venules a nd
endothelial cells and pericytes in developing vessels. Peri- pericytic venules, they may for m a nearly complete invest-
As noted above, smooth muscle cells may remain con- Nerve fi bers pass throug h t he connective tissue with in cytes are stellate cells located within the basal lamina of ment of the vessel with cells that resemble smooth muscle
ttacted for long periods of time without fatigu ing. They the b und les of smooth muscle cells; en la rgements in the cap illaries and postcapillary venules. In capillaries, their cells (see Chapter 12).
CHAPTER 10 Mrrsclc Tissrre 27 I
BOX
Functional Considerations: Com~arison Fibroblasts in healing wounds may develop morphologic cells). Myoid cells of the testis have 'a contractile function
and functional characteristics of smooth muscle cells in the seminiferous tubules, and cells of the perineurium, a
Cardiac muscle shares structural and functional characteristics smooth muscle cells have a spontaneous beat that is regulated (myo fibroblasts; see page 141). Epithelial cells in numer- concentric layer of connective tissue that surrounds groups
with skeletal muscle and smooth muscle. In both cardiac and but not initiated by autonomic or hormonal stimuli. Both have
skeletal muscle, the contractile elements-thick and thin fila centrally located nuclei and perinuclear organelles. These com
ous locations, particularly sweat glands, mammary glands, of nerve fibers and partitions peripheral nerves into dis-
ments-are organized into sarcomeres surrounded by sER and mi mon characteristics suggest that cardiac muscle may have salivary glands, and the iris of the eye, may acquire the tinct fascicles, function as contractile cells as well as trans-
tochondria. Both cardiac and smooth muscle cells retain their in evolved in the direction of skeletal muscle from the smooth mus characteristics of smooth muscle cells (myoepithelial port barrier cells.
dividuality, although both are in functional communication with cle of primitive circulatory systems. A summary of major charac
their neighbors through gap junctions. In addition, cardiac and teristics of all three muscle types is provided in Table 10.1.
Structural features
Muscle cell Large, elongate cell, Short, narrow cell, Short, elongate, fusiform cell,
10-100 ~-tm in diameter, up 10-15 ~-tm in diameter, 0.2-2 ~-tm in diameter,
to 100 em in length (sartorius m.) 80-100 ~-tm in length 20-200 ~-tm in length
Location Muscles of skeleton Heart, superior and inferior vena Vessels, organs, and viscera
visceral striated (e.g., tongue, cava, pulmonary veins
esophagus, diaphragm)
Connective tissue Epimysium, perimysium, Endomysium (subendocardial and Endomysium, sheaths
components endomysium subpericardial connective tissue) and bundles
Fiber Single skeletal muscle cell Linear, branched arrangement Single smooth muscle cell
of several cardiac muscle cells
Striation Present Present None
Nucleus Many peripheral Single central, surrounded Single central
by juxtanuclear region
T tubules Present at A-1 junction (triad: Z lines (diad : with small terminal Replaced by invagination
with two terminal cisternae), cisternae), one T tubule/sarcomere and vesicle similar to caveolae
two T tubules/sa rcomere
Cell-to-cell junctions None Intercalated disks containing Gap junction (nexus)
1. Fasciae adherentes
2. Macula adherens (desmosome)
3. Gap junctions
Special features Well-developed sER Intercalated disks Dense bodies, caveolae,
and T tubules and cytoplasmic vesicles
Functions
Type of innervation Voluntary Involuntary Involuntary
Efferent innervation somatic Autonomic Autonomic
Type of contraction 'All or none (red and white 'All or none rhythmic (pacemakers, Slow, partial, rhythmic,
fibers) conductive system of the heart) spontaneous contractions
(pacemakers of stomach)
Regulation By binding of Ca >+ to TnC, By binding of Ca >+ to TnC, causes By phosphorylation of myosin
of contraction causes tropomyosin movement tropomyosin movement and exposes light chain by myosin light chain
and exposes myosin-binding sites myosin-binding sites kinase in the presence
on actin filaments on actin filaments of ca>+-calmodulin complex
Growth and
regeneration
Mitosis None None (in normal condition) Present
Response to demand Hypertrophy Hypertrophy Hypertrophy and hyperplasia
Regeneration Limited (satellite cells and None (in normal condition) Present
myogenic cells from bone marrow)
270
C H APTE R 1 0 Muscle Tissur 273
Figure 1, skeletal muscle, H&E x 400. sects the I b and; this is the Z line. The di stance between ad-
Figure 2, skeletal muscle, H&E x 260. cle cells, to the capi llary e ndothe lial ce lls, to satellite ceUs,
Figure 3, skeletal muscle, H&E x 640. The c ut e nds of the myofibrils account for the sti ppled ap-
KEY
A, A band I, I band arrows, red blood cells in capillaries
nv, blood vessels (sma ll artery and vein) M , muscle fi ber asterisks: Fig. I , myofibril-free region of cy-
C, capil lary N, nucle i of muscle cell s topl asm; Fig. 3, e mpty capillaries
C T, connective tissue (perimys iu m surround- Z, Z line
ing muscle fascic les)
272
CH APTER 10 Muscle Tismr :2 7 5
T
BJ
Figure 1, musculotendinous junction, H&E x 350. clei, this separation tends to show their general direction.
In this figure, the muscle fibers appear to terminate di- Cross-striations can be identified at right angles to the d i-
rectly on the tendon. T he muscle fibe rs (M ) are in the left rection of the fibe rs. In contrast, the tendon g ives no obvi-
half of the fig ure. They stain redder than the tendon (T),
which ty pica ll y stai ns pale pink with eosin. The skele tal
ous ind ication of how the collagen fibers are arranged. T hi s
needs to be surmised from the orientati o n of the fibroblast
\
muscle fibers have been cut obliquely, and the boundaries nuclei, which usually have their long axes parallel to the di-
between ind ividual muscle cells are not distinct. ln many rection of the fibers. Although the nuclei of the fibrobl asts
places, however, there is a slight separati on of the muscle are readily identified, the cytoplasm of these cells is not d is-
fibers, and a long with the orientatio n of the muscle cell nu- tingu is hable from the collagen of the tendon.
Figure 2, musculotendinous junction, electron the plasma mem brane (PM) of the musc le cell and foll ows
BJ micrograph x 24,600.
At the actual junction between the muscle cell and te n-
don, the end of the cell becomes serrated , and the cytoplas-
mic projectio ns of the muscle cell interdig itate with the col-
the fin ger-l ike projections. Actin filaments (anvws) of the
terminal sarcomeres extend into the fin ger-like projections
and insert into dens ities on the inner face of the pl asma
membrane (arrowheads). Note that the termi nal sarcomeres
1
lagen fibrils of the tendo n. This arrangement is, at best, o nly possess o nl y o ne Z di sk (ZD). Also to be seen with in the
s uggested in Fi gure I, but it is evide nt in an electron mi- muscle cell cytoplasm are triads (Tr), g lycogen granules
\.
crograph of the juncti o n, such as that shown here. (G), and mitochondria (Mi). External to the cell are fi bril s
This fig ure shows four fin ger-like projections of the of the tendon (T).
muscle ce ll. The external lamina (BL) is directly adj acent to
Figure 3, neuromuscular junction, Golgi stain and fina lly, as it nears the muscle cells, the nerve fiber
BJ X280.
In the neuro musc ular junction shown here, a special
stain has been used to visuali ze the neural ele ments. This
staini ng procedure does not reveal the skeletal muscle cell s
branches to make contact with several mu scle cells. At the
terminal between nerve fi ber and each mu scle cel l, the
nerve fib er arborizes to fo rm a disk -like structure, the mo-
tor end p late (MEP), o n the surface of the muscle cell s. T he
to best advantage. They are ho rizontally di sposed in the il- motor e nd plate is the phys iologic contact between nerve
lustrat ion; cross-striations (arrows) are v isible in some and muscle; it is, in fac t, a ne uromuscul ar sy napse at wh ich
mu scle fibe rs. The nerve (N} e nters the fie ld from the left, the neurotransmitter acety lcholine is liberated. This trans-
initiall y d ips downward, then turns in an upward direction. mi tter initi ates the seq uence of mu scle membrane events
As it does, it can be seen to divide into s maller branches, that leads to contractio n of the musc le.
KEY
BL, basal lamina N, nerve ZD, Z disk
G, g lycogen PM, plasma membrane (sarcolemma) arrowheads, attachment of actin fi laments
M, striated muscle T, tendon into plasma membrane
ME P, motor end plate Tt, triad arrows, actin fil aments (Fig. 2.)
Mi, mitochondria arrows, cross-striations (Fig. 3.)
274
CHAP TE R 10 A1usclr Tissur '2 7 7
tE
Figure 1, heart, H&E x 160. identifyi ng cardiac muscle . In tercalated di sks are opposing
T hi s figure s hows a longitud ina l sectio n of cardiac mus- ce ll -to-ce ll contacts. Thus, cardiac muscle fibers differ in a
cle. The muscle fibers are di sposed horizontally in the il- very fu ndamenta l respect fro m fibe rs of skeletal muscle.
lustratio n and show cross-stri ations. Tn add itio n to the reg- The cardiac muscle fiber consists of an end-to-end align-
ular cross-striations (those of greate r frequency), however, ment of ind ividua l cells; in contrast, the skeletal muscle
there is another group of very pronounced cross-bands, fiber is a sing le multinuc leated protoplasmic unit. In exam-
namely, the intercalated dis ks (!D). Intercalated d isks most in ing a lo ngitud ina l sectio n of cardi ac muscle, it is useful to
ofte n a ppear as a straight band, but sometimes they are scan specific fibe rs a lo ng their long axes. By doing so, one
arranged in a stepwise manner (see a lso Fig. 2). These d isks can find places whe re the fi bers obviously branch. Two * *
are not always di splayed in routine H&E sections; the re- such bra nchi ngs are indicated by the arrows in this fig ure .
fore, o ne may not be able to depend on these structures for
tE
Figure 2, heart, H&E x 400. nective ti ssue either above or below the " in-focus" plane o f
Like ske letal muscle , the cardiac muscle is composed of section. O fte n, the staining of muscle cell nuclei in a spe-
linear contractile units, the myofibrils. These are ev ide nt in c ifi c s pecime n is very characteristic, es pecially when seen
thi s fig ure as the longitudinall y d isposed linear structures in face view as here. Notice, in the nucleus between the as-
that extend through the le ngth of the cell. T he myofibrils terisks, the well-stai ned nuc leolus and the delicate pattern
separate to bypass the nuclei, and in doing so, they delin- of the remainde r of the nuc leus. Once such fea tu res have
eate a perinuclear regio n of cyto plasm tha t is free of myo- bee n characterized for a particular s pecimen, it becomes
fibrils and the ir cross-striations. These perinuclear cyto- easy to identify nuc le i w ith similar staining characteristics
plasmic a reas (asterisks) con tai n the cyto plasmic throughout the specime n. For exam ple, s urvey the field in
organelles that are not directly invo lved in the contractile Figure l for nuclei w ith similar features. Having done thi s,
process. Many cardiac muscle cells are binucleate; both nu- it is substantia ll y easier to identify nuclei of connective tis-
cle i typically occupy the myofi bri l-free region of cyto- s ue cells (CT), which display d ifferent s taining properties
plasm, as shown in the cell marked by the asterisks. The and are not posi tioned in the same relations hip to the mus-
third nuc le us in this region appears to belong to the con- cle cells.
tE
Figure 3, heart, H&E x 160. and ind ica ted by the asterisks in Fig ure 2. Delicate connec-
T hi s figure shows c ross-sectioned card iac muscle fibers. tive ti ssue surrounds the ind iv idual muscle fi bers. This con-
Many have rounded or s mooth-conto ured po lygonal pro- tains capillaries and sometimes larger vessels, such as the
fi les. Some fibe rs, however, are generall y more irregular venule (V) in the cente r of the bundl e of muscle fibers.
and elongate in profi le. These probably re fl ect a pro fil e of Larger amou nts of con nective tiss ue (CT) surro und bund les
both a fiber and a branch of the fiber. T he more lightly of fibers , and thi s tissue conta ins larger blood vessels, such
stained region in the cente r of many fibers re presents the as the arterio le (A ) ma rked in the fi g ure.
myofi bril-free reg ion of the cell already referred to above
tE
Figure 4, heart, H&E x 400. by myofi brils. Remember, in con trast. that nuclei of s kel e-
At hi ghe r magni fication , it is possible to see the c ut ends ta l muscle fibers are located at the peri phery of the cell.
of the myofibrils. These a ppea r as the numerous red areas Note, also, that as mentioned, the nucleus-free central area
that give the cut face of the muscle cell a stippled appear- of the ce ll , devoid of myofibrils, shows areas of perinuclear
ance. The nuclei (N) occupy a central position surrounded cytoplasm simi lar to that marked w ith asterisks in Fig ure 2.
KEY
A, arteriole ID, intercalated d isks arrows, sites where fibers branch
C , capillaries N, nuclei of cardiac muscle cells asteris ks, perinuc lear cytoplasmic areas
CT, connecti ve tissue V, venule
276
CHAPTER 10 Musdr Tissur 2 79
B
Figure 1, heart, sheep, H&E x 160. the field . Connective tissue separates groups of Purki nje
A sectio n of cardiac muscle and Purki nje fibers is shown fibe rs fro m each other and fro m the cardi ac muscle. Small
in a re lative ly low-magnifi cati on view in thi s fi gure . The blood vessels (BV) and ne rves (NF) are a lso present w ithin
cardiac muscle fibers (CM ) appear in the le ft of the fi gure; the connective tissue .
the Purkinje fibers (PF) occupy much of the remainder of
D
Figure 2, heart, sheep, H&E x350. cells, the nucle i are often not incl uded in the sectio n, and
The nature of the Purkinje fi bers and their architecture one may get a mis leading impression of the disposi tion and
are seen more advantageously here at higher magnificati on. number of cells that make up a fi ber. On the othe r hand , be-
The fibe rs are made up of individual cells of irregul ar shape cause the myofi brils tend to be located at the peri phery of
that maintain extensive co ntact with one another. Interca- the ce ll , they can be used to locate the cell boundaries and,
lated disks are no t observed, but maculae adhere ntes a re thus, help deli neate the indi vid ua l cells of the bundle . The
present , joining adjacent cells of the fi ber. Purki nje fibers ultimately term inate by joining cardiac
The cytoplasm of a Purkinje cell contains a large muscle fibers, thereby permi tt ing direct passage of the im-
a mount o f glycogen that is usually extracted during fi xation pu lse to the cardiac muscle fi ber.
and dehydration of the tissue. Thus, the glycogen-rich areas The connective tiss ue (CT) thro ugh which the Pu rki nje
(G) appear as homogeneous, pale-stai ning regions that usu- fibers course may also contain nerves (NF) and ganglion
a ll y occupy the cente r portio n of the cell. The periphery of cells (GC). T hese neural e le me nts be long to the autonomic
the cell contains the myofibril s (Mf). The nucleus (N) is ne rvous system, whic h regulates the activity of the Purkinje
ro und and much larger than the nucl eus of the cardiac mus- fibers and heart muscle .
cle cell. Because of the considerable size of the Purkinje
KEY
BV, blood vessel G , g lycogen-rich area N, nucleus of Purkinj e cell
CM , cardiac muscle fi bers GC, gang lion cell NF, nerve fibers
CT, connective tissue Mf, myoti brils PF, Purkinj e fibers
278
CHAPTER 1 0 i\llusdr Tissur '2 8 I
Figure 1, intestine, monkey, H&E x900. ration, the nuclei appear slightly twisted, like a corkscrew;
Figure 2, intestine, monkey, H&E x 900. pering ends, in which case only the cytoplasm is seen (as-
Figure 4, uterus, human, H&E x 160. examinatio n of these areas wil l reveal nuclei whose profi le
' ,
KEY , I
,
,,
I
\
BY, blood vessel SM , smooth muscle cell asteris ks, cytoplasm of smooth muscle cell \ ~ ,
CT, connective tissue arrows, nucle i of cross-sectioned smooth interrupted lines, boundaries of bundles of ' - ~"" ...
F, nuc leus o f fibroblast muscle cells smooth muscle cells
L, lumen o f arteriole arrowheads, nuclei of longitudinally sec-
N, nuclei o f smooth muscle cells tioned smooth muscle cells
280
~
...... ,_
u
Supporting cells are nonconducting cells th at are in inti-
SYSTEM mate apposition to the neu rons. In the CNS they are called
neuroglia or, simply, glia. In the PNS they are called
The nervous system enables the body to r espond to con- Schwann cells and satellite cells. Schwa nn cells surro und
tinuo us changes in its external and internal environment. the processes of ne rve cells and isola te them from adjacent
It controls a nd integrates th e functional activities of the or- cells and extracellula r ma tri x. Within ganglia the support-
ing cells are called satellite cells. They surro und the nerve
Nerve Tissue ga ns a nd organ systems. Anatomically, the nervous system
is divided into the cell bod ies, th e part of th e cell that contains the nucle us,
a nd are a na logo us to the Schwann cells.
Central nervous system (CNS), consisting of the brain Supporting cells provide
a nd the spinal cord, loca ted in the cranial cavit y and
spinal canal, respectively. Physical support (protection ) for delicate ne urona l
OVERVIEW OF THE NERVOUS SYSTEM 283 Peripheral nervous system (PNS), consisting of crania l, processes
spinal, and peripheral nerves that cond uct impulses Electrica l insula tion for nerve cell bodies and processes
COMPOSITION OF NERVE TISSUE 283 Metabolic exchange pa thways between the vascu lar sys-
from (efferent or motor nerves) and to (afferent or sen-
THE NEURON 284 sory nerves) the CNS, collections of nerve cell bodies tem and the neurons of th e nervous system
Cell Body 286 o utside the CNS called ganglia, a nd specialized ne rve
Dendrites and Axons 287 In addition to neuron s and supporting cells, an extensive
endings (both motor and sensory).
Synapses 288 vascul ature is present in both t he CNS and the PNS . The
Synaptic Transmission 290 Function ally, t he n ervous system is divided into the blood vessels are separated from the ner ve tissue by the
Neurotransmitters 291 basal laminae and variable amounts of connective tissue,
Axonal Tra nsport Systems 293 Somatic nervous system (SNS), consisting of somatic depending on vessel size. The bo undary between blood
{Gr. soma, body] parts of the CNS and PNS. It provides sen- vesse ls and nerve tiss ue in the CNS excludes many sub-
SUPPORTING CElLS OF THE NERVOUS SYSTEM 293 sta nces tha t normally leave blood vessels to enter other tis-
sory a nd moto r inne rva tion to a ll parts of the body ex-
Schwann Cells and the Myelin Sheath 293 sues. This selecti ve res tr ic tion of blood-borne substances in
cept viscera, smooth muscle, and g lan ds.
Satellite Cells 295 the CNS is call ed th e blood-bmin barrie1; w hic h is di s-
Autonomic nervous system (ANS), consisting of a uto-
Neuroglia 297 cussed on p age 313 .
n omic parts of the C NS and PNS. It provides effer ent in-
Impulse Conduction 301
vo lunta ry motor innervation to smooth muscle, the con-
ORIGIN OF NERVE TISSUE CELLS 303 ducting system of the h eart, and glands. It also provides The nervous system allows rapid response to external stimuli
ORGANIZATION OF THE PERIPHERAL NERVOUS SYSTEM 303 afferent se nsory innervation from the viscera (p ain and
auton omic reflexes). The ANS is further subdi vided into The nervous system evolved from the simp le neuroeffec-
Peripheral Nerves 303
a sympathetic division and a parasympathetic division. tor system of in vertebrate a nimals. In primitive nervous
Connective Tissue Components of a Peripheral Nerve 304
A third element, the enteric division, is sometimes in- systems, o nly simple rece ptor-effector reflex loops exist to
Organization of tl1e Spinal Cord 306
corporated into the ANS subdivision (see page 310). respond to exte rnal stimul i. In higher animals a nd humans,
Afferent (Sensory) Receptors 307
t he SNS retains the abili ty to respond to stimuli fro m the
Autonomic Nervous System 307
external en vironment through the action of effector cells
A Summarized View of Autonomic Distribution 310
Head 3 10 9 COMPOSITION OF NERVE TISSUE (such as skeleta l muscle), but the ne uronal responses are
infinitely mor e varied. They ran ge from simple reflexes
Thorax 310
that req uire only the spin al cord to comp lex op erations of
Abdomen and Pelvis 310 Nerve tissue consists of two principal types of cells, neurons
t he b rain, including memory a nd lea rning.
Extremities and Body Wall 3 70 and supporting cells
ORGANIZATION OF THE CENTRAL NERVOUS SYSTEM 311 The autonomic part of the nervous system regulates the
The neuron, or nerve cell, is the func tional unit of the
Cells of tile Gray Matter 311 function of internal organs
nervo us system ; it consists of a cell body, co nta ining the
Connective Tissue of th e Central Nervous System 311
nucleus, a nd several processes of vary ing length. Ne rve
Blood-Brain Barrier 313 Th e specific effectors in the internal organs that respond
cells a re specialized to receive stimu li from ot her cells and
RESPONSE OF NEURONS TO INJURY 313 to t he inform ation carried by autonomi c nemons include
to conduct elect ri cal impulses to o the r parts of the sys te m
Degeneration 313 via their processes. They are arranged as an integrated Smooth muscle, whose contraction mo di fies the diame-
Scar Formation 314 co mm unications network, wi th severa l neurons in a ter o r shape of tubular o r hollow viscera such as t he
Regeneration 315 chain -like fashion typically in vo lved in sending impulses b lood vessels, gut, ga llbladder, and urinary bladder.
fro m one part of t he systern to anoth er. Specia lized con- Cardiac conducting cells (Purl~inje fibers) located
BOXES tacts between neurons th at provide for transmission of within th e conducti ve system of the heart. T he in herent
BOX 11.1. Clinical Correlations: Parkinson's Disease 292 info rmation from o n e neuron to the next are called freq uency of Purkinje fiber depolarization regu lates the
BOX 11.2. Clinical Correlations: Demyelinating Diseases 297 synapses. rate of ca rdi ac muscle contraction and can be modified.
282 183
184 CHAPTER 11 Nrrve 71sme CHAPTER 11 Nemt Tissue 18 5
large
QTHE NEURON motor
neuron
The neuron is the structural and functional unit of the nervous
PERIPHERAL
system NERVOUS
SYSTEM
The hum an ne rvo us system co ntains over 10 billion ne u-
rons . A lthough ne uron s show the greatest var ia tion in size
a nd shape o f any group of cells in the body, they fa ll into
three genera I categories:
Sensory neurons convey impulses from receptors to the
CNS. Processes o f these neurons a re included in somatic
afferent and visceral afferent nerve fibe rs. Somatic af-
ferent fibers co nvey sensations of pain, tempera t ure,
to uc h, and p ressure from the bo dy surface. ln add ition,
these fibe rs convey pain and proprioception (noncon-
scio us sensa tion) from organs w ithin the body (e.g.,
FIGURE 11.1 -.It-
Diagram of a motor neuron. The perikaryon, dendrites, and initial
muscles, tendons, a nd joints} ro p rovide the brain with part of the axon are within the CNS. The axon leaves the CNS and,
in fo rm atio n related tO the o ri entatio n of the body and while in the PNS, is part of a nerve (not shown) as it courses to its ef-
li mbs. Visceral afferent fibers transm it impulses of pain fectors (striated muscle). In the CNS, the myelin for the axon is pro-
and other sensations from mu cous membranes, gla nds, duced by, and is part of, an oligodendrocyte; in the PNS, the myelin striated
a nd blood vessels . is produced by, and is part of, a Schwann cell. (Adapted from Jun- (skeletal)
Mot01' neurons con vey imp ulses from the CNS or ganglia queira LC. Carneiro J, Kelley RO. Basic Histology. 9th ed. Norwalk, CT: muscle
to effecto r cells. Processes o f these ne uro ns a re included Appleton & Lange, 1998.) FIGURE 11.2
in somatic effel'ent and visceral effereltt nerve fibers. So- Diagram illustrating different types of neurons. The cell bodies of the CNS; many of them have elaborate dendritic arborizations that
matic efferent ne urons send vo lunta ry impulses to skele- pseudounipolar (unipolar), bipolar, and postsynaptic autonomic n~u facilitate their identification. a, axon.
tal muscles. Visceral effe re nt ne urons transm it in volun- rons are located outside the CNS. Integrative neurons are restricted to
tary im pu lses to smoot h m uscle, cardiac conducting cells
(Purkinje fi bers), and glands (Fig. 11.1 ).
cia lized termi nal (sy na pse), that makes con tact w ith an -
Tutemeurons, also ca lled intercalated nett1'01ts, form a other ne uron o r a n effector cell (e.g., a muscle cell or glan -
communicating and integ rating netwo rk be twee n th e Motor neurons and interneurons are multipolar Sensory neurons are unipolar
dular e pithelial cell ). A neu ro n usually has many dendl'ites,
se nso ry a nd motor neurons. It is estimated that mo re
shorte r p rocesses t hat tra nsmit imp ulses fr o m the perip h-
than 99.9 % of a ll neurons belong to t his integrating ne t- In terneurons constitute most of the neurons in the nerv- T he cell body of a senso ry neuron is situated in a dor-
e ry (i .e., other neurons) towa rd th e cell bod y.
work. o us system. The direction of impulses is from dendrite to sal root ganglion close to the CNS (Fig. 11.3 ); one ax-
Neurons are classified on t he basis of the number of
ce ll body to axon or from cell body to axon. Thus, func- onal branch exte nd s to the periphery, and one extends to
processes extending from the cell bod y (Fig. 1 1.2 ):
The functional components of a neuron include the cell body, tionally, the dendrites and cell body of multipolar neurons the CNS. The two axonal branches are the conducting
axon, dendrites, and synaptic junctions Multipolar ne urons have o ne axon and two or more a re the receptor portions of the cell, and their plasma uni ts. Functionally, impu lses are genera ted in the peri-
dendrites. membrane is specially adapted fo r impulse gene ration. pheral arborizations (branches) of the neuron; th ese
The cell body of a neuron co ntain s the nucle us a nd those Bipolar ne u rons have one axon and one dend rite. The axon is the conducting portion of the cell, and its arborizations are the receptor portion of the cell. Unipo-
organelles that maintain the cell. The processes extending Uuipolm- (actua ll y pseudmmipolar) neurons have one plasma membrane is specialized for impulse conduction. lar neurons are also sometimes called psendounipolar
fro m t he cell bod y constitute th e sing le common structu ral process, the axon, w hich div ides close to the cell body The termina l portion of the axon, the synaptic ending, because during development they exist as bipolar neu-
c ha racteristic of a ll neurons. Most ne urons have on ly one into two long processes. The vas t majority of unipolar co ntai ns various neurotransmitters, i.e., small molecules rons. T hey become unipo lar as their processes migrate
axon, usuall y the longest process extendi ng from the cell, ne urons are located in t he do rsa l root gang lia an d cra - whose release at tbe synapse affects other neurons as we.ll around the cell bod y and fuse into a single process as the
wh i.c h transmi ts impulses away from the cell body to a spe- nia l nerve ganglia . as m uscle cells and glandular epithelium. cell matures .
'286 CHAPTER 11 Nrwr Tissur CHA PTER 11 Neme Tissue '2 8 7
epineurium feature consistent with its protein synthetic activity. In t he level of anabolic activity needed to m a intain these large
blood vessels light microscope the ribosomal content appears as small cells_
perineu riu m
bodies, called Nissl bodies, that stain intensely w ith basic
dyes and metachr omat ically with thionine dyes (Fig. 11.4). Neurons do not divide; they must last for a lifetime
Each Nissl body corresponds to a stack of rER. The perin-
ucle ar cytoplasm also contains numerous mitochondria, a Although neurons do not replicate, the subcellular com-
lar ge perin uclear Golgi apparatus, lysosomes, micro- ponents of the neurons turn over regularly and have mo-
t ubules, neurofilaments (intermediate filaments), transport lecula r lifespans measured in hours, days, and weeks. T he
vesicles, a nd incl usions (Fig. 1 1.5 ). Nissl bodies, free ribo- constant need to replace enzymes, transmitter substances,
so mes, and, occasion ally, the Golgi apparatus exten d into membrane components, and other complex molecules ex-
the dendrites but not into the axon. This area of the cel l plains the m orphologic featu res characteristic of a h igh
body, called the axon hillock, is free of large cytoplasmic level of synthetic activity. Newly synthesized protein mol-
organelles a nd serves as a landmark to d istinguish between ecules are transported to dista nt locations within a neuron
axons and dendrites in both light microscope and TEM in a process referred to as axonal trmtsport (page 293).
dorsal preparations.
root
SPINAL CORD The euchromatic nucleus, large nucleolus, prominent
Golgi apparatus, and Nissl substance indicate the high
Dendrites and Axons
cell body Dendrites are receptor processes that receive stimuli from
of sensory other neurons or from the external environment
neuron neuron
T he main function of dend rites is to receive information
~---' spinal nerve from other neurons or from the external environmen t and
carry that information to the cell body_ Generally, den-
ve ntra l drites are located in the vicinity of the cell body. T hey have
cell body of root Pacinian a greater diameter than axons, are unmyeli nated, are usu -
motpr ne uron corpuscle
a lly tapered, and form extensive arborizations called den-
dritic trees. D endritic trees significan tly increase the recep-
tor surface area of a neuron. Many neuron types are
characterized by t he extent and shape of their dendritic
FIGURE 11.3 trees (see Fig. 11.2). In genera l, the contents of the cel l
Schematic diagram showing arrangement of motor and sensory (posterior) root. Note the location of its cell body in the dorsal root body and dendrites are similar, w ith the exception of the
neurons. The cell body of a motor neuron is located in the ventral ganglion (sensory ganglion). A segment of the spinal nerve is en- Golgi apparatus. Whereas the Golgi network remains close
(anterior) horn of the gray matter of the spinal cord. Its axon, sur- larged to show the relationship of the nerve fibers to the surrounding to the n ucleus, other organelles characteristic of the cell
rounded by mye lin, leaves the spinal cord via a ventral (a nterior) root connective tissue (endoneurium, perineurium, and epineurium). In ad- body proper, including ribosomes and rER, are fou nd 111
and becomes part of a spinal nerve that carries It to its destination on dition, segments of the sensory and motor neurons have been en- the dendrites, especially in the base of the dendrites.
striated (skeletal) muscle fibers. The sensory neuron originates In the larged to show the relationship of the axons to the Schwann cells and
skin within a receptor (here, a Pacinian corpuscle) and continues as a myelin. (Autonomic nerve fibers are not shown in the diagram.)
component of a spinal nerve, entering the spinal cord via the dorsal Axons are effector processes that transmit stimuli to other
ne urons or effector cells
FIGURE 11.6
Schematic diagram of different types of synapses. a. Axodendritic synapse may enhance or Inhibit the axodendritic (or axosomatic)
or axosomatic. b. Axodendritic, in which an axon terminal synapse. (Modified from Barr ML. The Human Nervous System. New
synapses with a dendritic spine. c. Axoaxonic. The axoaxonic York: Harper a Row, 1979.)
FIGURE 11.7
FIGURE 11.5 Representation of a neuron cell body in the CNS. a. This drawing il
Electron micrograph of a nerve cell body. lustrates the cell body of a neuron. Axon endings forming synapses
The cytoplasm is occupied by aggregates of are shown as the numerous ovoid bodies with tail-like appendages.
free ribosomes and profiles of rough endo Each represents an axon terminal from a different neuron making
plasmic reticu lu m (rER) that constitute the contact with the cell body or its dendrites. b. A drawing of the area
Nlssl bodies of light microscopy. Tile Golgi within tile rectangle in a. Tile drawing shows the axon endings and
apparatus {G) appears as isolated areas their synapses with the neuron cell body. c. Enlargement of the axon
containing profiles of flattened sacs and ending within the rectangle in b, illustrating its appearance with the
vesicles. Ot11er characteristi c organelles in- transmission electron microscope, which reveals its significant struc-
clude mitochondria (M) and lysosomes (L). tural features. (From DeRobertis EDP, Nowinsky WW, Saez FA. Biolo-
The neurofilaments and microtubules are gia Celulm: Buenos Aires: El Ateneo, 1970.)
difficult to discern at this relatively low mag-
nification. x 15,000.
a
tone extra cts of brain and intestine), hypothalamic releas- Neurotransmitters released into the synaptic cleft may be Axonal Transport Systems now used to trace neuronal pathways a nd to identify the
ing hormo1tes, enkephalins, vasoactive intestinal peptide degraded or recaptured perikarya related to specific nerve en dings.
(VIP), cholecystokinin (CCK), and neurotensin. Many of Substances needed in the axon and dendrites are synthesized
D endritic tra nsport appears to have the same characteris-
these sa m e su bstances are synthesized a nd released by en- The most co m m o n process of remova l of the ne uro- in the cell body and require transport to those sites
t ics and to serve the same fu nc t ions fo r the dendrite as ax-
te roendocrine cells of the intestinal tract. They may act im- transmitter following its re lease into the synaptic cleft is
ona l tra nsport does for the axon.
mediately on ne ig hboring cells (paracrine secretion) or be called high-affinity reuptake. About 80% of released ne u- Most neurons in t he bo d y possess elaborate axona l an d
carrie d in th e bloodstream as hormones to act o n distant rotransmitters a re removed by this mechanism. T hese and de ndritic processes. Beca use the synthetic activity of the
target cells (endocrine secretion). They ar e also synthesized other transm itte rs a re r eincorpora ted into vesicles in t he ne uron is con centrate d in the perika ryon , axonal transport Q SUPPORTING CEllS OF THE
and released by endocrine organs and by the neurosecre- presyn aptic component by end ocytosis and are available is req ui red to c o nvey newly sy nthesized ma terial to the NERVOUS SYSTEM
tory neurons of the hypothalamus. for recycli ng. Enzymes a ssoc ia ted w it h t he p ostsynap t ic p rocesses. Axona l tra nsport is a bid irection al mecha n ism .
In the past decade, nitric oxide (NO), a simple gas with membra ne degrade the remaining 20% of neurotra nsmi t- lt serves a s a mode of intercellular comm unication, carry- Schwann Cells and the Myelin Sheath
free radica l properties, also has been identifie d as a ne uro- ters. For example , acetylcholinesterase (AChE) degrades ing mo lecules a nd informa t ion along t he microtubules and
tra nsmitte r. At low concentratio ns, NO carries nerve im- ACh; catechol-o-methyltransferase (COMT) as well a s in te rmedi a te fila men ts fro m the axon ter mi nal to the Axons in the peripheral nervous system are described as
pulses from one nemon to another. Unlike othe r ne uro- monoamine oxidase (MAO) rapidly degrade NE. T he pe rika r yon and from t he perikaryon to t he axo n term ina l. myelinated or unmyelinated
tra n sm itters , w hich are synthesized in the ner ve cell bod y degradati o n or recapt ure o f neurotransm it ters is necessary Axona l transport is described as
and stored in synaptic vesicles, NO is synthesized within to limit the dura ti o n o f stimu la t ion o r inhibition of t he Myel inated axons are s urrounded by a lipid-rich layer
Anterograde transp01't carries material fro m the
the synapse and used immediately. lt is postu lated that ex- postsyna ptic membra ne . called t he myelin sheath.
pe rikaryon to the periphery. Kinesin, a microtu bule-
citatory neurotransmitter GLU induces a cha in reaction in Normall y, membrane a dd ed to the plasma membra ne of External to, and contiguous with , the myelin sheath is a
associated motor p rotei n that uses ATP, is involved in
w hich NO synthase is activated to produce NO, which in the ner ve ending by exocytosis whe n sy naptic vesicles fuse thin layer of Schwa nn cell cyt oplasm called the sheath of
a nterograde t ra n sport.
turn d iffuses from the presyna ptic knob vi a the syna ptic with it is retrieved by endocytosis and is reprocessed in to Schwann, o r the neurilemma (Fig . 11.10) . T his layer con-
synaptic vesicles b y t he smoo th endoplasmic ret icu lu m
Retrograde transport ca rri es material rom the axon ter-
cleft and postsynaptic membrane t o the ad jacent cell, re- ta ins the n ucleus and most of the organelles of the
rn.i na l a nd the de ndrites to the perikar yon. T his trans-
sulting ultimately in generation of a n action pote ntial. (sER) loca ted in the nerve end ing. Schwann cell. Surrou nding the Sch wann cell is a basal or
po rt is m e diated by a nother microtubu le-associated m o -
externa l lamina.
tor p rotein, dynein.
F unctionally, the myelin sheath with its external lamina
The t ranspo rt systems may a lso be disti nguish ed by the and the neurilemma isolates the axo n from the smround-
ra te a t wh~ich s ubsta nces are tra nsported: ing ext ra cell ul ar compa rtment. T he a xon hillock and the
termi nal arborizations where t he axon synapses wit h its
A slow transport system con veys substances from the target cells do not have a myelin sheath.
cell body to the term ina l bouton at t he speed of 0.2 to
4 mm /da y. It is o n ly a n a n terogra de t ransport system. The myelin sheath is composed of multiple layers of Schwann
Parkinson's disease is a slowly progressive neurologic disorder used in the treatment of neurologic disorders (e.g., neuroleptics Structural e le ments suc h as tubu lin mo lecules (micro- cell membrane wrapped concentrically around the axon
caused by the loss of dopamine (DA)secreting cells in the substan- used to treat schizophrenia); and repetitive trauma. Symptoms witll
tubule precu rsors), actin molecules, and t he proteins that
tia nigra and basal ganglia of the brain. DA is a neurotransmitter these causes are called secondary parkinsonism.
for m n eurofilaments are car ried from the perikaryon by To produce the myelin sheath, each Schwan n cell wraps
responsible for synaptic transmission in the nerve pathways coor- On the microscopic level, degeneration of neurons in the sub-
th e slo w tra nsport system . So, too, a re cytoplasmic in a spiral around a short (0.08 to 0.1 mm ) segment of the
dinating smooth and focused activity of skeletal muscles. Loss of stantia nigra is very evident. This region loses its typical pigmen-
tation, and an increase in the number of glial cells is noticeable ma tri x proteins, such as actin, cal modu lin, an d various axon . D u ri ng the wrapping of the axon , cytoplasm is
DA-secreting cells is associated with a classic pattern of symptoms,
(gliosis). In addition, nerve cells in this region display characteris- meta bolic enzymes. squeezed out from between t he membrane of the concen-
including
tic intracellular inclusions called Lewy bodies, which represent ac- A fast transport system conveys su bstances in both direc- tric layers of t he Schwann cell. T he inner leaflets of the
Resting tremor in the limb, especially of the hand when in a cumulation of intermediate neurofilaments in association with tions a t a rate of 20 to 400 mm/day. T hus, it is both a n p lasma membrane then fuse. With the TEM, these fused
relaxed position; tremor usually Increases during stress and is proteins a-synucleln and ublquitln. anter ograde and a retrograde system. T he fast anter~ in ner leaflets are electron op a q ue , a p pearing as the m aj01'
often more severe on one side of the body Treatment of Parkinson's disease Is primarily symptomatic and grade transp011 system carries to the axon termina l dense lines in the TEM image of the myelin . T hese con-
Rigidity or increased tone (stiffness) In all muscles must strike a balance between relieving symptoms and minimiz- d ifferent mem brane-lim ited o rganelles, such as sER com- centric dense lamellae alterna te wi th the slightl y less de nse
Slowness of movement (bradykinesia) and inability to initiate ing psychotic side effects. L-Dopa is a precursor of DA that can
movement (akinesia)
ponen ts, synaptic vesicles, m itochon d ria; and low- intraperiod lines tha t are fo rmed by fusio n of the outer
cross the blood- brain barrier and is then converted to DA. It is of- membra ne leaflets (F ig. 11.11 ).
Lack of spontaneous movements molecular-weight ma terials such as suga rs, am ino ac ids,
ten tile primary agent used to treat Parkinson's disease. Other
Loss of postural reflexes, which leads to poor balance and ab- nucleo tides, some neurotransmitters, and calcium. T he The m yelin sheath is segmen ted beca use it is for med by
drugs that are used Include a group of cholinergic receptor block-
normal walking (festinating gait) ers and amantadine, a drug that stimulates release of DA from
fast retrograde transp011 system carries to the perikar yon numerous Sch wann cells a rrayed seq uentially a long the
Slurred speech; slowness of thought; and small, cramped hand- neurons. many o f the same ma terials as well as proteins and other axon. T he ju nction where two ad jacent Schwa1111 cells
writing If drug therapies are not effective, several surgical options can molecules endocytosed at the axon ter minal. Fast t rans- meet is devoid of myelin . T hi s site is called the node of
The etiology of idiopathic Parkinson's disease, In which DA- be considered. Stereotactic surgery, In which nuclei in selective port in either di rectio n requires ATP, which is used by Ranvier. T herefore, t he m yelin between two sequential
secreting neurons in the substantia nigra are damaged and lost by areas of tile brain (globus pallid us, thalamus) are destroyed by a m icrotubule-associated motor proteins, and depends on nodes of R anvier is called an internodal segment.
degeneration or apoptosis is not known. However, some evidence thermocoagulative probe inserted into the brain, can be effective the microtu bu le arrangement that extends from the D uring formation of t he myel in sheath, the axon ini-
suggests a hereditary predisposition; about 20% of Parkinson's pa- in some cases. Several new surgical procedures are being devel- perik ar yon to the term ina tion of the axon. R etrograde t ia lly lies in a g roove on t he s urface of the Schwann cell
tients have a family member with simila r symptoms. oped and are still in experimental stages. These Include trans- tra nsport is the pat hway fo llowed by toxins and viruses (Fig. ll. lla) . Fusion of the edges of the groove to en-
Symptoms that resemble idiopathic Parkinson's disease may also plantation of DA-secreting neurons into the substantia nigra to tha t enter the CNS at nerve endi ngs. R etrograde transport close the axon pr oduces th e inner mesaxon, the narrow
result from infections (e.g., encephalitis), toxins (e.g., MPTP), drugs replace lost ne urons. o f exogenous enzymes, such as horseradish peroxidase, intercell ular space of the innermost ri ngs. The first few
a nd o f rad io la beled or imm unolabeled trace r materials is lamel lae are not compactly arra nged; i.e ., some cyto-
'294 CHAPTER 11 Nerr>r Ti ss ue CHAPTER 11 Nerve Tissue '2 9 5
plasm is left in the fi rs t few concentric layers (Fig. membranes. Electron micrographs, however, typica lly
11.1lb). Similarly, th e outermost la yer contains some cy- show small amounts of cytoplasm in several locations
toplasm as we ll as the Schwann cell nucleus (Fig. (Figs. 11.1 2 and 11.13 ): the inner collar of Schwann cell
11.1 1c). The apposition of the plasma membrane of th e cytoplasm, between t he axon and the m ye lin; the
last layer to itself as it closes the ring produces the outer Schmidt-Lantermatt clefts, small isl ands within succes-
mesaxon, the narrow intercellular space adjacent to th e sive lamellae of the myelin; perinodal cytoplasm, at the
external lamina. node of Ranvier; and the outer collar of perinuclear cy-
Myelin is rich in lipid because as the Schwann cell toplasm, around the m yelin (Fig. 11 .1 4 ). These areas of
w inds around the axon, its cytoplasm, as noted, is ex- cytoplasm are what light microscopists identified as the
truded from between th e opposing la yers of the plasma Schwann sheath. If one conce ptually unrolls the Schwann
cell, as shown in Figure 11.15, its fu ll extent can be ap-
preciated, and the inner collar of Schwann cell cytoplasm
can be seen to be continuous with the body of the
Schwann cell through the Schmidt-Lanterman clefts and
through the perinodal cytoplasm. Cytoplasm of the clefts
conta ins lysosomes, occasional mitochondria and micro-
tubules, as well as cytoplasmic inclusions, or dense bod-
ies. The number of Schmidt-Lanterman clefts correlates
with the diameter of the axon; larger axons ha ve more
clefts.
inner collar of
Schwann cell
cyto plasm
, :
~ . ..,
... i ... .
\
~
. ... . ...
' '
,;
. ""
\
~. ..,.'
diated diseases affect the myelin sheath.
'1 ., t ~ \. .., GuillainBarre syndrome, known also as acute inflamma-
(\ ' . .' , ~'"'.. : . : ." .; tory demyelinating polyradiculoneuropathy, is one of tile
most common life-threatening diseases of tile PN S. Micro
<t I .. 0, .<oo ..', .I ~ , ... . .
.,' .. . scopic examination of nerve fibers obtained from patients af-
fected by this disease shows a large accumulation of lympho
cytes, macrophages, and plasma cells around nerve fibers
within nerve fascicles. Large segments of the myelin sheath are
damaged, leaving the axons exposed to the extracellular ma-
trix. These findings are consistent with a T cell- mediated im-
(jl' mune response directed against myelin, which causes its de
struction and slows or blocks nerve conduction. Patients
exhibit symptoms of ascending muscle paralysis, loss of mus-
perinodal
cle coordination, and loss of cutaneous sensation.
outer collar of cytoplasm of
Multiple sclerosis (MS) is a disease that attacks myelin in
Schwann cell cytoplasm Schwann cell
the CNS. MS is also characterized by preferential damage to
myelin, which becomes detached from the axon and is even-
. . ...
. ,, ~ .. """""
"~' FIGURE 11.15
' ~
. ~ ~
,. .' . - ......
.
, ...,.,..
........~ Diagrams conceptualizing the relationship of myelin and cytoplasm tu ally destroyed. In addition, destruction of oligodendroglia,
... ~
.
'~. -
.
.. ' ~-
.'l ..
.. . . ~
~
~~~~11-IJii
: - . ,.-.r~~}myelin Schwann cells are not tightly apposed at the
node, and extracellular fluid has free access to
curr en t co ncept s em p hasize t he funct ional i nterdepend ence
of neu roglial cells and neuro ns. The m ost o b vious ex am ple
er at e and becom e acti ve ly phagocyt otic i11 reg io ns of i njury
and disease. T hey are considered p art of the m ononuclear
the neuronal plasma membrane. Also, t11e of ph ys ical support occu rs during development. The brain ph agocytot ic system (see page 144) and are believed t o
~
outer co llar of
node is the site of depolarization of t11e neu-
ronal plasma membra ne during nerve impulse
an d sp inal cord deve lop fr o m th e em b r yon ic neur al tu be. ori ginat e i n the bo ne marrow. M icr ogl ia cells enter the CNS
perinodal cytoplasm l n the head region , th e n eural tu be under goes r em ark abl e par ench ym a fr om the vascular system. Evidence also sug-
Schmidt-Lanterman Schwann transmission. (Courtesy of Dr. Charles P.
of Schwann cell
cleft cell cyto plasm Leblond.)
CHAPTE R 11 NerveTissue 299
gests that they remove debris of cells that die during de- protein (GFAP). The filaments are much more numerous in
velopment of the nervous system. the fibrous astrocytes, however, hence the name. Antibod-
Microglia are the smallest of the neuroglial cells and ies to GFAP are used as specific stains to identify astrocytes
have relatively small, elongated nuclei (Fig. 11.18. ) When in sections and tissue cultures (see Fig. 11.20b). Tumors
stained with heavy metals, microglia exhibit short, twisted arising from fibrous astrocytes, fibrous astmcytomas, ac-
processes . Both the processes and the cell body are covered count for about 80% of adult primary brain tumors. They
with numerous spikes . The spikes may be the equivalent of are also characterized by microscopic examination and
the ruffled border seen on other phagocytotic cells. The GFAP specificity.
TEM reveals numerous lysosomes, inclusions, and vesicles. Astrocyte processes extend between the blood vessels
Howeve1; microglia contain little rER and few micro- and neurons. The ends of the processes expand, forming
tubu les or actin filaments. end feet that cover large areas of the outer surface of the
vessel or of the axolemma. It is now thought that astro-
Astrocytes are of two types, protoplasmic and fibrous cytes play a role in the movement of metabolites and
wastes to and from neurons and regulate ionic concentra-
Astrocytes are the largest of the neuroglial cells. Two tions in the intercellular compartment, thus maintaining
kinds of astrocytes are identified: the microenvironment of the neurons. They also have a
role in maintaining tight junctions of the capillaries that
Protoplasmic astrocytes, wh ich are more prevalent in
form the blood-brain barrier (page 313).
gray matter. These astrocytes ha ve numerous, short,
In additio n, astrocytes provide a covering for the " bare
branching cytoplasmic processes (Fig. 11.19).
areas" of myelinated axons, e.g., at the nodes of Ranvier
Fibrous astrocytes, which are more common in white
FIGURE 11.16 and at synapses. They may confine neurotransmitters to
lamina (BL). In the upper part of the micrograph, myelin (M) of two
matter. These astrocytes have fewer processes, and they
Electron micrograph of unmyelinated nerve fibers. The individual the synaptic cleft and may remove excess neurotransmit-
fibers or axons (A) are engulfed by the cytoplasm of a Scl1wann cell. myelinated nerves is also evident. X27,000. Inset. Schematic diagram are relatively straight (Fig. 11.20).
ters by pinocytosis. Protoplasmic astrocytes at the brain
The arrows indicate the site of mesaxons. In effect, each axon is en- showing the relationship of axons engulfed by the Schwann cell. (Barr Both types of astrocytes contain prominent bundles of and spina l cord surfaces extend their processes (subpial
closed by the Schwann cell cytoplasm, except for the intercellular space ML, Kiernan JA. The Human Nervous System. New York: Harper & Row,
intermediate filaments composed of glial fibrillary acidic feet) to the basal lamina of the pia mater to form the glia
of the mesaxon. Other features evident in the Schwann cell are its nu- 1983.)
cleus (N), the Golgi apparatus (G), and the surrounding basal (external)
\ \
\ \
a b
FIGUI~ : 11.18
Microglial cell in the gray matter of the brain. a. Til is diagram sl1ows ual with diffuse microgliosis. In this condition, tile microglial cells are
tile shape and characteristics of a microglial cell. Note the elongated present in large numbers and are readily visible in a routine H&E
FIGURE 11.17 nucleus and relatively few processes emanating from the body. preparation. X 420. (From Fuller GN, Burger PC. Central nervous sys-
Photomicrograph of a nerve ganglion. a. Pllotomicrograph showing connective tissue capsule (CT) t11at is comparable to, and continuous b. Photomicrograph of microglial cells (arrows) showing their charac- tem. In: Sternberg SS, ed. Histology for Pathologists. Phi ladelphia:
a gangli on stained by the Mallory-Azan method. Note the large nerve witll, the epineurium of the nerve. x 200. b. Higher magnification of teristic elongated nuclei. The specimen was obtained from an individ- Lippincott-Raven, 1997.)
cell bodies (arrows) and nerve fibers (NF) in the ganglion. Satellite cells the ganglion, showing individual axons and a few neuronal cell bod-
are represented by the very small nuclei at the periphery of tile neu- ies w ith their satellite cells (arrows). The nuclei in the region of the ax-
ronal cell bodies. The ganglion is surrounded by a dense irregular ons are mostly Schwann cell nuclei. X 640.
300 C H A PTE R 11 Nrrvr Tissu~ C HA PTER 11 Nervr Tissue 30 1
stem. Sensory ga nglia are located a long the do rsal roots of permit its demonstratio n. At the electron microscope level,
the spinal ner ves and in association w ith crania l nerves V, collagen fibri ls that constitute the endoneur ium are readily
VII, Vlll, IX, and X (see Table 11 .1). apparent (see Figs . 11.12 and 11.13). The fibrils run both
parallel to, and arou nd, the nerve fibers, functiona lly bind-
ing them together into a fascicle, or bundle. Because fi-
Connective Tissue Components of a Peripheral
broblasts are relatively sparse in the interstices of the nerve
Nerve
fibers, it is likely that most of the collagen fibrils are se-
The bulk of a peripheral nerve consists of nerve fibers creted by the Schwann cells. T his conclusion is supported
and their supporting Schwann cells. T he individ ua l nerve by tissue culture studies in which collagen fibrils are FIGURE 11.24
fibers and their associated Schwann cells are held together formed in pure cultures of Schwan n cells and dorsal root Electron micrograph of a peripheral nerve and its surrounding per- dothelial cells of the blood vessel is also apparent (arrow/leads).
by connective tissue organized into three distinctive com- neurons. Other than occasiona l fibroblasts, the only other ineurium. a. Electron micrograph of unmyelinated nerve fibers and a X46,000. b. Electron micrograph showing the perineurium of a nerve.
ponents, each with specific morphologic and Functional connective tissue cell normally fou nd within the en- single myelir.ated fiber (MF). The perineurium (P), consisting of several Four cellular layers of the perineurium are present. Each layer has a
characteristics (Fig. 11.24; also, see Fig. 11.3 ). T hese com- don eur ium is the mast cell. In genera l, most of the nuclei cell layers, is seen at tile left of tile micrograph. Perineurial cell basal (external) lamina (BL) associated with it on both surfaces. Other
ponents are (90%) found in cross sections of peripheral nerves belong processes (arrow/leads) have also extended into the nerve to surround features of the perineurial cell include an extensive population of
to Schwann cells; the rema ining 10% is eq ua ll y distributed a group of axons (A) and their Schwann cell as well as a small blood actin microfilaments (MF), pinocytotic vesicles (arrows), and cytoplas-
E11doneurium, which includes loose connective tissue between the occasional fi broblasts and other cells such as vessel (BV). The enclosure of this group of axons represents the root mic densities (CD). These features are characteristic of smoot11 muscle
surrounding each individual nerve fiber endothelial cells of capillaries and mast cells. of a small nerve branch that is joining or leaving the larger fascicle. cells. The innermost perineurial cell layer (righ t) exhibits tight junc-
Perineurium, which includes specialized connecti ve tis- XlO,OOO. The area within the circle encompassing the endothelium of tions (asterisks) where one cell is overlapping a second cell In forming
sue smround ing each nerve fascicle the vessel and tile adjacent perineurial cytoplasm Is shown In the in- the sheath. Other features seen In the cytoplasm are mitochondria
Perineurium is the specialized connective tissue surrounding a set at higher magnification. Note the basal (external) laminae of the
Epineurium., wh ich includes dense irregular connective (M), rough endoplasmic reticulum (rER), and free ribosomes (R).
nerve fascicle vessel and the perineurial cell (arrows). The junction between en- xz?,OOO.
tissue that surrounds a peripheral nerve and fi lls the
spaces between nerve fascicles Surrounding the nerve bundle is a sheath of uniq ue con-
nective tissue cells that constitute the perineurium. The ing the brai n- blood barrier (see page 313), perin eurial cells nal (basal) lamina on both surfaces (Fig. 11.24b). The cells
Endoneurium constitutes the loose connective tissue perineurium serves as a metabolica ll y active diffusion bar- possess receptors, tra nsporters, a nd enzymes tha t provide are contractile and contain a n appreciable number of actin
associated with individual nerve fibers rier tha t contribu tes to the for mation of a blood- nerve for the active transport of substances across the perineur- filaments, a characteristic of smooth muscle cells and other
barrier. This ba rrier mai ntains the ionic milieu of the en- ial cells. The perineurium may be one or more cell layers contractile cells. Moreover, when there are two or more
The endoneurium is not conspicuous in routine light mi- sheathed nerve fibers. In a manner similar to the p roperties thick, depending on the ner ve diameter. The cells that com- perineurial cell layers (as man y as five of six layers may be
croscope preparations, but specia l connective tissue stains exhibited by the endothelia l cells of brain capillaries fo rm- pose th is layer are sq uamous; each layer exhibits an exter- present in la rger nerves), collagen fibri ls are present be-
~06 CHA PTE R 11 Nrwr Timt e CHAPTER 1 1 Nrmc Tiss 11r 30 7
tween the pe rine urial cell layers, but fi broblasts are absent. Enteroceptors, wh ic h react to stimuii fr om w ithin th e
Tight ju nctions, p rovid ing the basis for the blood-nerve body, e.g., the degree of fill ing or stretch of the alimen-
barrier, a re present between t he cells located w ith in th e dorsal roots of ta ry canal, bladder, and blood vessels
sa me layer of the perineurium. In effect, th e arra ngement spinal nerve P1-oprioceptors, w h ic h also react to stimu li from with in
of these cells as a barrier-the p resence of tight junctions the bod y, provid ing sensatio n of body p ositio n and mus-
and basa l (external) la mina material- liken th em to a n ep- s pinal nerve cle tone and movemen t
ithelioid tissue. O n th e other h and, their co ntractile nature T he simplest receptor is a bare axon, called a nonencap-
a nd t heir apparent a bility to produce col lagen fibri ls also sulated (free) ending. T h is ending is fo und in epithelia, in
Liken them to smooth muscle cells a nd fibro blasts. The lim- connective tissue, a nd in close association with hair follicles.
ited n umber of connective tissue cell types withi n the en-
doneurium undoubtedly reflects t he protective role that the Most sensory nerve endings acquire connective tissue capsules
perine urium p lays. Typical imm une system cells (i.e., lym- or sheaths of varying complexity
p hocytes, plasma cells) are not found withi n th e en-
d oneuria! a nd perineurial com partments. This a bsence of Sensory n erve endings with connective tiss ue sheaths are
immune cells (other t han the mast cell) is accou nted for by denticulate
ligament called encapsulated endings. Many enca psu la ted endings
the protective barrier created by the perine ur ia l cells. Typ- are mechanoreceptor s loca ted in the skin and joint cap-
icall y only fibroblasts a nd occasional mast cells a re present sules (Kra use's end b ulb, Ruffini's corpuscles, M eissne r's
w ith in t he nerve compartment. corpu scles, and Pacinian corpuscles) a nd a re described in
ventral roots of
spinal nerve FIGURE 11.26 Ch apter J 4 , " In tegu mentary System" (page 400).
Epineurium consists of dense irregular connective tissue that Cross section of the human spinal cord. The photomicrograph shows M uscle sp indles are encaps ul ated sensory endings lo-
surrounds and binds nerve fascicles into a common bundle FIGURE 11.25 a cross section through the lower lumbar (most likely L4-LS) level of cated in skeletal muscle; they a re described in C hapter 10,
Posterior view of exposed spinal cord. Note that each spinal nerve the spinal cord stained by the Bielschowsky silver method. The spinal " Muscle Tissue" (page 260). Fu nctionally related Golgi
The epine urium fo rms the outermost tissue o f the pe- emerges from the cord by a number of dorsal (posterior) and ventral cord is organized into an outer part, the white matter, and an inner
(anterior) roots. Note the dura mater (the outer layer of the meninges) tendon organs a re encapsu la ted tensio n receptors found a t
riphera l nerve. It is a typical dense connective tiss ue that pa rt, the gray matter that contains nerve cell bodies and associated musculotendi no us junctio ns.
surro unds the fascicles formed by the p erineurium . Adi- and the denticulate ligaments of the pia mater, which anchor the nerve fibers. The gray matter of the spinal cord appears roughly in the
spinal cord to the wall of the spinal canal. (From Barr ML, Kiernan JA. form of a butterfly. The anterior and posterior prongs are referred to
pose tiss ue is often associated with t he epineurium in
The Human Nervous System. New York: Harper & Row, 1983 .)
larger nerves . as ventral horns (VH) and dorsa l horns (DH), respectively. They are Autonomic Nervous System
T he b lood vessels that supply th e nerves travel in th e connected by the gray commissure (GC). Tl1e wh ite matter contains
nerve fibers that form ascending and descending tracts. The outer sur- Although the ANS was intro duced ea rl y in this ch apter; it
epineurium, a nd t heir branches penetrate into the nerve called nuclei. In t his context, t he term nucleus means a
face of the spinal cord is surrounded by the pia mater. Blood vessels is useful h ere to d escribe so me of th e sa lient features of its
and t ravel w it hin the perinemium. Tissue at the level of the cluster o r group o f ne uronal cell bodies p lus fibers and
of the pia mater, ventral fissure (VF), and some dorsal roots of the organization and distribution. The ANS is classified into
e ndo neurium is poorly vasculari zed; metabolic exc hange neuroglia. N uclei of t he CNS a re the morphologic a nd spinal nerves are visible in the section. x s. three di visions:
of substra tes a nd wastes in this tissue d epends o n d iffusio n func tional equivalents of t he ganglia o f the PNS. Synapses
from a nd to the blood vessels thl'Ough the pe rineurial occur on ly in th e gray matter. Sympathetic division
sheath (see Fig. 11 .24 ). Parasympathetic division
The cell bodies of motor neurons that innervate striated Enteric division
muscle are located in the ventral (anterior) horn of the gray ripheral segmen t that brings infor ma tio n fro m t he perip h-
Organization of the Spinal Cord T he ANS is th at portion of th e PNS that conducts im-
matter ery to the cell bod y a nd a central segme nt th at carries in-
The spinal cord is a fla ttened cylin drica l structu re that is fo rma ti on from t he cell body into the gray matter of the pulses to smooth m uscle, ca rdia c muscle, and glandular
directly continuous w ith the brain . It is di vided in to 3 1 seg- Ventral motor neu1'ons, also ca lled anterior hom cells, sp inal cord. Beca use the sensor y n euron conduc ts impu lses epit helium . T hese effectors are the fu nction al uni ts in t he
ments (8 cervical, 12 t horacic, 5 lumbar, 5 sac ral, a nd a re la rge basophilic cells a nd a re easily recognized in ro u- to the CNS, it is called an a ffereltt 1teumn. Impulses a re orga ns that r espond to regula tion by nerve tissue. The
1 coccygea l), a nd each segmen t is connected to a pai r of tine histologic prepa ratio ns (Fig. 11.26). Beca use the mo- genera ted in t he term inal receptor arboriza tion o f the pe- term visceral is sometimes used to refer to the ANS or its
spina l n erves. Each spinal nerve is joined to its segment o f tor ne uron co nd ucts impulses away from t he CNS, it is riph era l segme nt. n eurons, w hic h a re, the refo re, ca lled visceral efferent
the co rd by a numbe r o f roots or ro otlets gro uped as d o r- called a n efferent neuron. neu1ons.
sa l (posterior) o r ventra l (anterior) roots (Fig. 11.25; see T he axon of a moto r neu ron leaves t he spina l cord, Sensory neurons also lea ve t he o rgan s to con vey im-
Afferent (Sensory) Receptors
a lso Fig. 11.3 ). passes thr o ugh the ventral (anterior) root, becomes a com- p ulses to t he CNS. These visceral afferent neurons have
In c ro ss sectio n, the spinal cor d exhibits a butterfl y- pone nt o f the spi nal nerve of that segmen t, and, as such, is th e same a rrangeme n t as o the r se nso ry ne uro ns; i.e., their
Afferent receptors are specialized structures located at the
shaped grayish ta n inner su bsta nce, the gray matter su r- conveyed to t he muscle. T he axon is m yelinated except at cell bodi es are loca ted in senso ry ganglia, and t hey pos-
distal tips of the peripheral processes of sensory neurons
ro und ing t he centra l ca n al, and a wh itish perip heral sub- its origi n a nd term ina tion . Nea r th e muscle cell, the axo n sess long periphe ral a nd central ax ons, as d esc ribed
sta nce, the white matte1: The w hi te ma tte r (see Fig. 11.3) di vides into numero us terminal branches that form neuro- above.
Alt ho ugh recepto1'S may ha ve many different struct ures,
contains on ly myelinated a nd un myelinated axons travel- muscular synapses w ith t he muscle cell (see page 257). T he main orga nizationa l difference between th e efferent
they have o ne basic cha racteristic in common: T hey ca n
ing to a nd from o th er p a rts of the spina l cord a nd to a nd flow of imp u lses to skeleta l muscle (somatic effectors) and
initiate a ne rve impu lse in response to a stimu lus. Recep-
fro m the brain. Functio nally rela ted bund les of axons in The cell bodies of sensory neurons are located in ganglia that tors ma y be classified as the effere nt flow to smooth m uscle, ca rdiac muscle, a nd
the white matte r are called tracts. lie on the dorsal root of the spinal nerve g la nd ula r epitheliu m (visceral effectors) is that one neuron
The gray matter contains n euronal cell bodies a nd their Exteroceptors, which react to stimuli fro m t he external conveys the impulses fro m the CNS to t he soma tic effector
dendrites, alon g w ith axons a nd n eurog.lia. Functio nall y Sensory neurons in the do rsal root ga ng lia are pseudo- envi ronme nt, e.g ., temperatm e, to uch, smell, so und, or (Fig. 11.27a), whereas a chai n of t wo neurons conveys
related groups o f nerve cell bodies in th e gr ay matter are unip olar. T hey h ave a single process tha t di vides into a pe- vision the impulses from the CNS to the viscera l effectors
308 C H APTER 11 Nerve Tissue C HAPTER 11 Nerl! e Tissue 3 09
Innervation via
cranial oulllow
lacrimal gland
nasal, palatine,
and pharyngeal
glands
a
8
ganglion supply organs of the abdomen reach I sacral
parasympathetic
these organs by way of the splanchnic \ ,.
\ I
oulflow (via pelvic ~
The presynaptic neurons send axo ns from the tho racic The presynaptic parasympathetic neurons send axons
a nd upper lu mbar spinal cord to the vertebra l a nd pa r- from the brain stem , i.e., the midbra in, pons, and medulla,
3 JQ CHAPTER 11 Nro-iJe Tissue C H APTE R 1 1 Nrwr Tissue 3I 1
and the sacral segments of the spin al cord (S2 t hro ug h S4) HEAD the body wa ll is only sympathetic (see Fig. 11.27b). Each
to viscera l ga nglia. The ganglia in or near the wa ll of ab- sp inal ner ve contains postsyn aptic sympa thetic fiber s, i.e.,
do minal and pel vic o rgans and the viscera l motor ganglia
Parasympathetic presynaptic o utfl ow to the head leaves unmyelina ted visceral effer ents, of ne uron s whose cell bod- molecular
the br ain with th e crania l ner ves, as indicated in Figure ies a re in pa ravertebra l ganglia of th e sympa thetic trunk. layer
o f cra nial nerves III, VII, IX, a nd X contain cell bodies of
11.28, but the r o utes a re q uite complex. Cell bodies may For sweat glands, the n eurotransmitter released by the
the postsynaptic effector neur ons of th e parasympathetic
also be found in structures othe r than head ganglia listed "sympat hetic" neurons is ACh instead of th e usual NE.
division (Figs . 11.27c and 11.28).
in Table 11.1 a nd Figure 11.28, e.g., in th e tongue. II external
The sympa th etic and parasympathetic divis io ns o f the granular layer
These are " terminal" ganglion cells of the parasympa-
ANS often supply the same o rga ns . In these cases, t he
actions of th e t wo are us uall y antagonistic. An obvio us
thetic system. 9 ORGANIZATION OF THE CENTRAL
example of this a ntagonistic action is that sympa thetic
Sympathetic P1'esynaptic o utflow to the head comes NERVOUS SYSTEM
from the thoracic reg.ion of th e spinal cord. The postsy- Ill external
stimula tion increases the rate o f card iac muscl e contrac- pyramidal
naptic neurons have their cell bodies in the superior cer- In the brain, the gray matter forms an outer covering or cortex; cell layer
tions, whereas parasympa thetic stimula tion reduces th e
vical ganglion; the axons leave the ganglion in a nerve the white matter forms an inner core or medulla
ra te.
network that hugs the wal l of the intern al carotid arte ry.
Many functions of th e SNS are similar to those of the
The nerve is called the internal carotid nerve, o r th e in- IV internal
adrena l medulla , an endocrine g land. This fun ctio nal The cortex of g ray matter in the brai n conta ins nerve ceU granular layer
s imila rity is pa rtl y expla ined by the d evelopmental rela-
ternal carotid plexus. Some postsynaptic fibers also bodies, axons, dendrites, a nd glia l cells and is th e site of
reac h the head by a much smalle r external camtid nerve synapses. In addition to the gray m atter of th e cortex, is-
tionsh ips between the cells of the adrenal medull a and
and plexus. la nds of gray matter, called nuclei (see page 306), are fo und V ganglionic
p ostsy nap ti c sympathetic n e urons. Both a re deri ved layer (internal
fro m th e n e ura l crest, are inne rvated by presynaptic in the deep portions of the cerebrum a nd cerebellum. pyramidal
symp a th etic n e urons, a nd produce closely re late d phys- THORAX The w hite ma tter co ntains o nl y axons of nerve cells cells)
io logically ac ti ve agents, EPI and NE. The diffe rence is plus the associated glia l cells a nd blood vessels. These ax-
that th e sy mpa th etic neurons deliver th e agent d irectly
Parasympathetic presynaptic o utflow to the thoracic o ns travel from one part o f th e nervous system to an-
viscera is via the vagus nerve (X). The postsynaptic neu- other. Whereas many of the axons going to, or coming VI multiform
to the effector, whereas the cells of th e adrena l medulla
mns have their cell bodies in the walls or in the sub- (polymorphic)
d elive r the agent indirectly throug h the bloodstream. fro m, a specific location a re gr o uped into bundles ca lled
stance of the o rgans of t be thorax. cell layer
The inne rvation of the adrena l medulla may co nstitu te tracts, th e tracts themsel ves do not stand out as d elin-
a n exception to the ru le that a uto nomic innerv a ti o n Sympathetic presynaptic o utflow to the thoracic o rgans is eated bundles. The demonstration of a tra ct in w hite mat-
consists of a two-ne uron chain from CNS to an effector; fro m the upper thoracic segm ents of the spina l cord. Sym- ter of th e CNS requires a special procedure, such as the
fo r th e adrena l m edulla, it is o nl y o ne ne uron , un less the pathetic postsynaptic neumns fo r the hea rt are mostl y in destruction of ceU bodies th a t contribute fibe rs to the
adrenal medul lar y cell is con sidered the functi o n al the cervical ganglia; th eir axons m a ke up the cardiac tract. Th e damaged fibe rs can be displayed by the use of FIG URE 11.29
equi va lent o f th e second neuron , in effect, a n e urosecre- nerves. Postsynaptic neumns for the o ther th oracic vis- appropriate staining or labeling me th ods a n d the n traced. Nerve cells in intracortical circuits. This simple diagram shows the or-
tory ne uro n. cera ar e in ganglia of the th oracic part of the sympathetic Even in t he spinal cord, w he re the grouping of tracts is ganization and connections between cells in different layers of the
trunk. T he axons are in sma ll splanchnic nerves that m os t pro nounced, t here are no s harp bou ndar ies between cortex contributing to cortical afferent fibers (arrows pointing up) and
The enteric division of the ANS consists of the ganglia and travel from the sympa thetic trun k to the o rga ns. adjacent t racts. cortical efferent fibe rs (arrows pointing down). The small interneurons
postsynaptic neuronal networks of the alimentary canal are indicated in yellow.
ABDOMEN AND PELVIS Cells of the Gray Matter
Gangli a a nd postsynaptic neurons of the en teric divi-
sio n are located in the lamina propria, muscularis m u- Parasympathetic p1'esynaptic outflow to the a bdo minal T he types of cell bodies found in th e gray ma t ter vary ac- The b1'aiu stem is not clea rl y sepa ra ted into regio ns of
cosae, submucosa, muscu la ris externa, a nd subse rosa o f viscera is via the vagus (X) a nd pelvic n erves. Post- co rding to wh ich part of the brain or spina l cord is being gray matter an d white matter. The nuclei of the cran ial
the a lime nta ry canal from th e esop hagus to the anus (see synatJtic neurons of the parasympathetic system to ab- exa mined.
nerves located in the brain stem, however, appear as is-
page 4 76). The e nte ric division can functio n independ - do minopelvic orga ns a re in term ina l ga nglia that gener-
la nds surrou nded by more o r less di stinct tracts of w hite
entl y o f presynaptic inp ut fro m th e vagus nerve a nd sacra l all y are in the wa lls of th e orga ns, such as the ganglia o f Each functional region of the gray matter has a characteristic
m a tter. T he nuclei conta in the cell bodies of the motor neu-
o utflow; e.g., t he intestin e w ill continue perista ltic move- the submucosa l (Meissne r's) plexus a nd the myenteric variety of cell bodies associated with a meshwork of axonal,
rons of th e c ra ni a l ne rves a nd a re both the morph ologic
ments even after th e vagus n erve is cut. T he re a re many (Auerbac h's) plexus in the a limenta ry ca nal. dendritic, and glial processes
and functi onal co unterpa rts o f the anteri or ho rn s of the
mi llions more gan g lion cells in the e nteric division tha n Sympathetic presyttaptic ou tflow to t he abclomino pelvic
spinal cord. ln oth er sites in th e brain stem, as in th e retic-
could be suppl ied by the presyna ptic n eurons o f th e vaga l organs is from th e th o racic and upper lumba r segments T he meshwork of axona l, de ndritic, a nd glia l processes
ular formation, the distinction be tween white matter a nd
and sacra I ou tflows. of the spinal cord. Postsynaptic neurons have th eir cell associated w ith the gray matte r is ca lled the neuropil. The
gray matter is even less evide nt.
bodies mostly in the prevertebra l ga nglia (see Fig. organ ization of the neuropil is not demo nstra ble in
11.27c), a lthough some ar e in paravertebral ga ngl ia of H&E-stained sectio ns. Tt is n ecessary to use methods othe r
A Summarized View of Autonomic Distribution the sympathetic t run k, a nd their ne urons ente r th e tha n H &E h istology to d ecipher the cytoa rc hitecture o f Connective Tissue of the Central Nervous System
Figures 11 .27 an d 1 1.28 summa rize d iagrammatica ll y t he splanchnic n erves. the gray matter.
Three seque ntia I connective tiss ue membran es, the
origi ns a nd di str ibution of t he ANS. Refer to t hese figu res Although general histology programs usua ll y d o not deal
meninges, cover the bra in a nd spina l cord:
as you r ead t he descriptive sectio ns. Note that t he dia - with t he actua l a rra ngements of the neurons in th e CNS, the
EXTREMITIES AND BODY WALL
gra ms indicate both the paired innervation (parasympa- presentation of two examples will add to the appreciation of The dura mater is the outerm ost layer.
thetic and sympa thetic) common to the ANS as well as the There is no parasympathetic o utflow to the body wa ll a nd H&E sectio ns that students usually exa mine. These exa m- The arachnoid layer lies benea th the dura .
important exceptio ns to this genera l cha racteristic. extremities. Anatomicall y, the autono mi c innerva tion in ples present a region o f the cerebra l cortex (Fig. 11.29) a nd The pia mater is a d elicate layer resting directl y on the
the cerebellar cortex (Fig. 1 1.30), respectively. surface o f t he brai n and spina l co rd .
3 I '2 CHAPTER 11 Nerar Tissue C HAPTER 11 Neme 1i'ss11e 3 I3
} molecular (') The arachnoid is a delicate sheet of connective tissue adjacent Blood-Brain Barrier lamina (Fig. 11.32 ). The tight junctio ns eliminate gaps be-
(1)
layer ro to the inner surface of the dura tween endothelia l cells and prevent simple diffusion of
CY
} Purkinje ~ The blood- brain barrier restricts passage of certain substances solutes and fluid into the neural tissue.
} celllaym ~ The arachnoid abuts o n the inner sur face of the dura from the bloodstream to tissues ofthe CNS Evidence suggests that the tight junctio n depends on the
(')
granule s; and extends delicate arachnoid trabeculae to the pia m ater no rma l functioning of the astrocyte. In several brain dis-
cell layer roX o n the surface of the brain and spinal cord. T he web-like T he observation o ver 100 years ago that vital d yes in- eases, the blood-brain barrier loses effectiveness . Examina-
trabeculae of the arachnoid give this tissue its na me (Gr, re- jected into the bloodstream can penetrate and stain nearl y tion of brain tissue in these conditions by TEM r eveals loss
sembling a spider's web). Trabeculae are composed of loose all organs except the brain provided the first description of of the tig ht junctions as well as alterations in the morphol-
white
matter connective tiss ue fibers containing elongated fibroblasts. the blood-brain barrier. More recently, advances in mi- ogy of the astrocytes. Other experimental evidence has r e-
The space bridged by these trabeculae is the subarachnoid croscopy and molecular biology techniques ha ve revealed vealed that astrocytes release soluble factors that increase
space; it contains cerebrospinal fluid (Fig. 11.31). the precise location of this unique barrier and the role of barrier pro perties and tight junction protein content.
The pia mater (L., tender motl7er) is also a delicate connec- endothelial cells in transporting essential substances to the The presence of only a few small vesicles indicates tha t
tive tissue layer. It lies directly on the surface of the brain brain tissue. pinocytosis across the brain endo thelial cells is severely re-
a nd spinal cord and is continuous with the perivascular The blood-bra in barrier develops early in the embryo stricted . The substances that do cross the capillary wall are
connective tissue sheath of the blood vessels of the brain thro ugh an interaction between glia l astrocytes and capil- actively transported by specific recepto r-media ted endocy-
FIGURE 11.30
and spinal cord. Both surfaces of the arachnoid, the inner lar y endothe li al cells. The barrier is created largely by the tosis. Thus, the low permeability of the blood-bra in bar-
Cytoarchitecture of the cerebellar cortex. This diagram shows a sec-
smface of the pia mater, and the trabeculae ar e covered elaborate tig ht junctions between th e endo thelial cells, rier to mac romolecules is due to a low level of expression
tion of the folium, a narrow, leaf-like gyrus of the cerebellar cortex.
Note that the cerebellar cortex contains white matter and gray mat- with a thin sq uamous epithelial layer. Both the arachnoid which form continuous-type capillaries. Studies with the of specific receptors on the endothelial cell surface.
ter. Three distinct layers of gray matter are identified on this diagram. and pia mater fuse aro und the opening for the cranial and TEM, using electron-opaque tracers, show complex tight Substances that are required for neuronal integrity must
They are (1) superficially located molecular layer, (2) the middle Pur- spinal nerves as they exit the dura mater. junctions between the endothelial cells . Morphologically, leave and enter the blood capillaries through the endothelial
kinje cell layer, and (3) the granule cell layer adj acent to the white these junctions are more similar to epithelial tight junc- cells. Thus, certain lipid-soluble molecules as we ll as 0 2 and
matter. a, granule cell; b, Purkin)e cell; c, basket cell; d, stellate cell; e, tions than to those found in other endothelial cells. In ad- C0 2 easily penetrate the endothelial cell. Other substances
arachnoid
Golgi cell; f, mossy fiber; and g, climbing fiber. (Based on Barr ML, dition, TEM studies revea l a close association of astrocytes such as glucose (which the neuron depends o n almost ex-
trabeculae blood vessel
Kiernan JA. Tl1e Human Nervous System. New York: Harper & Row, and their end foot processes with the endothelia l basal clusively for energy), amino acids, nucleosides, and vitamins
1983.) are actively transported by specific transmern brane carrier
proteins. In addi tion, several other proteins that reside
dura mater[
within the plasma membrane of the endothelial cells protect
Because arachnoid and pia m ater develope from the single arachnoid C the brain by rejecting drugs, foreign proteins, and other dis-
layer of mesenchyme surrounding the developing brain, ruptive molecules from crossing the barrier.
they are commonly r eferred as the pia-arachtwid. In subarachnoid [ Recent studies indicate that the end fee t of astrocytes
space
adul ts, pia mater represents the visceral portion and arach- a lso play an important role in mainta ining water home-
p-.:..;:;~....k:::,,Y
noid r epr esents the parietal portion of the same layer. This ostasis in brain tissue. Water channels (aquaporin AQP4 )
common origin of pia-arachnoid is evident in gross dissec- pia mater -1---Jf-./ are found in end feet processes where wa ter crosses the
tion of adult meninges in which numerous strands of con- blood-brain barrier. In pathologic cond ition s such as brain
nective tissue (arachnoid trabeculae) pass between pia edema, these cham1els play a key role in reesta blishi ng os-
mater and arac hnoid. motic eq uilibrium in the brain.
cerebral Some parts of the CNS, however, are not isoJated from
The dura mater is a relatively thick sheet of dense connective cortex substances carri ed in the bloodstream. T he barrier is inef-
tissue fective or absent in the neurohypophysis (posterior pitu-
itary), substantia nigra, and locus ceru leus. In these areas
In the cranial cavity, the thick layer of connective tissue of the bra in , sa mpling of materials circ ulating in the blood
that forms the dura mater [L., toug/1 mot11er) is continuo us at may be necessary to r egu late neurosecretory control of
its outer surface with the periosteum of the sk ull. Within parts of the nervou s system and of the endocrine system.
the dura mater ar e spaces lined by endothelium (a nd '-'!'d -11+---J~ tigh t
neuron cell body junction
backed by periosteum and dura mater, respectively) that
serve as the principal channels for blood re turning from FIGURE 11.31 '\1 RESPONSE OF NEURONS TO
the bra in. These venous sinuses receive blood from the Schematic diagram of the cerebral meninges. The outer layer, tile INJURY
principal cerebra l veins and carry it to the internal jugular dura mater, Is joined to adjacent bone of the cranial cavity (not
shown). Tile inner layer, the pia mater, adheres to the brain surface Degeneration
vems.
and follows all its contours. Note that the pia mater follows the
Sheet-like extensions of the inner smface of the du ra
branches of tl1e cerebral arteries as they enter cerebral cortex. The in-
mater form partitions between parts of the brain, support- The portion of a nerve fiber distal to a site of injury
tervening layer, the aract111oid, is adjacent but not attached to the
ing those parts within the cranial cavity and carrying the FIGURE 11.32 degenerates because of interrupted axonal transport
dura mater. The arachnoid sends numerous, web-like arachnoid tra-
arac hnoid to some of the deeper parts of the brain . In the beculae to the pia mater. Located between tile arachnoid and the pia Schematic drawing of blood-brain barrier. This drawing shows the
spinal canal, the vertebrae have their own periosteum, a nd mater is the subarachnoid space; it contains cerebrospinal fluid. The blood-brain barrier, which m nsists of end otllelial cells j oined to- Degeneration of an axon distal to a site of in jmy is
the dura mater forms a separate tube surrounding the space also contains the larger blood vessels (cerebral arteries) that gether by elaborate, complex tight junctions, endothelial basement ca lled anterograde (Wallerian) degeneration. In the PNS,
spinal cord (see Fig. 11.25). send branches into the substance of the brain. membrane, and the end foot processes of astrocytes. th e axon distal to the injury becomes beaded and frag-
3 14 CHAPTER 11 Nrrve Tissur CHAPTER 11 Nm>e Tissu r 1 I5
ments into discontinuous segments within a few da ys (Fig. ser ved within 1 to 2 days after injury and reaches a peak gical appos ition of the cut ends of the nerve is possible, the ing sensory and motor connections. Successful sprouts
11.33, a and b). In the CNS, breakdown of the isolated at about 2 weeks (Fig. 11.33b). The changes in the cell severed nerve will probably regenerate. grow at about 3 mm/da y. After crossing the scar, neurites
axon segments takes several weeks. body are proportional to the amount of axoplasm lost by In the CNS, scar tissue derived from proliferating glial enter the su rvivi.ng Schwann tubes in the distal stttmp.
The myelin sheath a lso fragments, and the m yeli n frag- the injury; extensive loss of axoplasm can lead to death of cells appears to prevent regeneration. Current research on T hese tubes wi ll then guide the neurites to their desti na ti o n
ments enclose the axon fragments. Phagocytotic cells, de- the cell. When a motor fiber is cut, the m uscle innervated CNS regeneration is, therefore, focused on preventing or as well as provide the microenvironment for continued
rived from the Schwann cells in the PNS, microglia in the by that fi ber undergoes atroph y (Fig. ll.33c). inh ibiting glial scar formation. growth (Fig. 11.33d).
CNS, and blood monocytes that migrate to the site of in- Before the development of modern dye and radioisotope
jury, remove the myelin and axon fragm ents. Some r etro- tracer techniq ues, Wallerian degener ation and chromato ly- If physical contact is reestablished between a motor n euron
Regeneration
grade degeneration also occurs but extends for only a few sis were used as research tools. These tools allowed re- and its muscle, function is usually reestablished
internodal segments. In the PNS, the Schwann cells and searchers to trace the pathways and destination of axons
In the PNS, Schwann cells divide and develop cellular bands
their external laminae remain as tubular structures distal and the localization of th e cell bod ies of experimenta ll y in- Microsurgical techniques that rapid ly reestablish inti-
that bridge a newly formed scar
to the injury (Fig. 11.33c). jured nerves. mate apposition of severed nerve and vessel ends have
Division of Schwa nn cells is the first step in the regener- made reattachmen t of severed limbs and digits, w ith sub-
The cell body of an injured nerve swells, its nucleus moves sequent reesta bl ishment of function, a relatively common
Scar Formation ation of a severed or crushed peripheral nerve. The
peripherally, and there is loss of Nissl substance procedure.
Schwann cells then bridge the scar. ln the second step in re-
In the PNS, connective tissue and Schwan11 cells fo rm scar If the axonal sprouts do not reestablish contact with
generation, large numbers of new nerve processes (neu-
Nerve injury leads to a loss of N iss l substance from the tiss ue in the gap between the ends of a severed or crushed the bridge of Schwann cells, the sprouts grow in a disor-
rites) sprout from the proximal stump (Fig. 11.33c). The
cell body, called chromatolysis. Chromatolys is is first ob- nerve. If the amount of scar tissue is not too great or if sur- ganized manner, and the muscle remains atrophic
Schwann cell bridges the n serve as guides for the regener-
(Fig. 11.33e).
ating axons to grow across the scar, thus maintaining the
norma l pathways of the growing axons.
Although many of the new nerve processes degenerate,
their la rge number increases the probability of reestablish-
1 .'
-:.
a d . ; ( e e.. :.
; :.:-
. :
: I
.;:
.::'
the viscera. Parasympathetic gang li a are located in, or close to, the organs innervated by thei r postsynaptic neurons. The e n-
teric ganglia are located in the submucosal plexus and the myenteric plexus of the a li mentary canal. They receive parasympa-
thetic presynaptic input as well as intrinsic input from other enteric gang lia and innervate smooth muscle of the gut wall.
Figure 1, ganglion, human, silver and H&E stains shows that some d isplay several processes joined to them.
EB x 160.
A sympathetic ganglion stained with silver and counter-
stained with H&E is illustrated here. Shown to advantage are
several discrete bundles of nerve fibers (NF) and numerous
Thus, these are multipolar neurons (one contained with in the
rectangle is shown at higher magnification in Figure 2). Gen-
erally, the connective tissue is not conspicuous in a silver
preparation, although it can be identified by viJt ue of its loca-
large circ ular structures, namely, the cell bod ies (CB) of the tion about the larger blood vessels (BV), particularly in the
postsynaptic neurons. Random patterns of nerve fibers are upper part of this figure.
also seen. Moreover, careful examination of the cell bodies
Figure 2, ganglion, human, silver and H&E stains large pale-staining nucleus (i ndicating much-extended
EB xsoo.
The cell bod ies of the sympathetic ganglio n are typically
large, and the o ne labeled here shows severa l processes ( P).
In add ition, the cell body contains a large, pale-sta ining
chromatin) and a large nucleolus, re flect a cell active in pro-
tein synthesis. Also shown in the cell body are accum ula-
tions of lipofuscin (L), a yellow pi g ment that is darkened by
the si lver. Because of the large size of the cell body, the nu-
spherical nucleus (N); th is, in turn , co ntains a s pheri cal, in- cleus is not always included in the section; in that case, the
tensely staini ng nucleol us (NI). T hese features, name ly, a cell body appears as a rounded cytoplasmic mass.
Figure 3, ganglion, cat, H&E x 160. ganglion, where it is covered wi th connective tissue (CT).
KEY
A, axon L, lipofuscin P, processes of nerve cell body
BV, blood vessels N, nucleus of nerve cell Sat C, satellite cells
en, cell body of neuron NF, nerve fibers arrowheads, neuri lemma
CT, connective tissue Nl, nucleolus asterisks, clusters of satellite cells
316
CHAPTER 11 Neme Tis5ue 3l9
tB
epineurium (Epn) are readil y distinguished in the triangul ar
This c ross secti on (Fig. I) shows several bundles of area formed by the diverging perineurium of the two adja-
nerve fibe rs (BNF). T he external cover for the entire nerve cent nerve bundles.
is the epi neurium (Epn), the layer of dense connecti ve tis- The nerve fibers inc luded in Figure 2 are mostly myeli-
sue that one touches when a nerve has been exposed during nated, and because the ne rve is cross-sectioned, the nerve
a dissection. The epineurium may al so serve as part of the fibers are also seen in thi s plane. They have a characteri stic
outermost cover of individual bundles. It contai ns blood cross-sectional profile. Each nerve fiber shows a centrally
vessels (BV) and may contain some fat cells. Typically, adi- placed axon (A); tllis is suJTounded by a myelin space (M )
pose ti ssue (AT) is found about the nerve. in which some rad iall y di sposed prec ipitate may be re-
Figure 2 shows, at higher magnification, an area ti'om tained , as in th is specimen. External to the myelin space is
~ I;
the upper left of Figure 1. T he illustration has been rotated, a thin cytoplasnlic rim representing the neurilemma. On oc-
and the septum (marked with arrows in Fig. I) is now ver- casion, a Schwann cell nucleus (SS) appears to be perched
tically disposed (arrows).
The layer under the epineurium that directly surround s
on the neurile mma. As show n in the illustration, the upper
edge of the nuclear crescent appears to occupy the same
-M
the bundl e of nerve fibers is the perineurium ( Pn). As seen plane as that occupied by the neurilemma (N). T hese fea-
in the cross secti on through the nerve, the nuclei of the per- tures enable one to identify the nucleus as belonging to a
ine urial cells appear flat and elongate; they are actually be- Schwann (neurile mma) cell. Other nuclei are not related to 2
ing viewed on edge and belong to flat cell s that are also be- the neurilemma but, rathe r, appear to be between the nerve
ing viewed on edge. Again, as noted by the di stribution of fibers. Such nuclei belong to the rare fibroblasts (F) of the
nuclei , it can be ascertained that the perineurium is onl y a e ndoneurium . The latter is the de licate connective ti ssue
few cells thick. The perineurium is a specialized layer of between the indi vidual nerve fibers; it is extremely sparse
cells and extracellular materia l whose arrangement is not and contains the capillaries (C) of the nerve bundle.
evident in H&E sections. The perine urium (Pn) and
Figures 3 and 4, femoral nerve, H&E. positioned axo n (A ) surrounded by a myelin space (M),
KEY
A, axon F, fi broblast NR, node of Ranvier
AT, adipose tissue M , myelin Pn, perineu rium
BNF, bundle of nerve fib ers N: Fig . 2, neurilemma; Fig. 4, nucleus o f SS, Schwann cell nucleus
BV, blood vessels Schwann cell ari'Ows (Figs. l and 2), septum formed by
C , capillary NF, nerve fiber perineuri um .4 '
Epn, epineurium Nl, neurilemma
318
C HAPTER 11 Ncwc Tiss11e 32 I
PLATE 25. CEREBRUM
The cerebrum is the principal portion of the brai n and contains the cell bodies of nerves that receive and store sensory in-
formation, nerves that control voluntary motor activity, and nerves that integrate and coordinate the activity of other nerves,
as well as the nerves and neural pathways that constitute memory.
III:
tively few cells, mostly neuroglial cells and occasional hori -
zontal cell s of Cajal.
The small pyramidal cell layer (or outer granular layer) con-
sists mainly of small pyramidal cells, and granule cell s, also
called stellate cells.
The layer of medium pyramid al cells (or layer of outer py-
ramidal cells) is not sharply demarcated from layer II. How-
cells rather than nerve cell bodies that are present in the ever, the pyramidal cells are somewhat larger and possess a
cortex. Covering the cortex is the pia mater (PM) . A vein typical pyramidal shape.
(V) can be seen enclosed by the pia mater. Also, a smaller IV: The granular layer (or inner granu lar layer) is characterized
blood vessel (BV) can be seen entering the substance of the by the presence of many small granule cells (stellate cells).
cortex. The six layers of the cortex are marked by dashed V: The layer of large pyramidal cells (or inner layer of pyramidal
cell s) contains pyramidal cells that, in many parts of the cere-
lines, whic h represent onl y an approximation of the bound-
brum, are smaller than the pyramidal cells o f layer ill but in
ari es. Each layer is distingui shed on the basis of predomi-
the motor area are extremely large and are called Betz cells.
nant cell types and fiber (axon and dendrite) arrangement. VI: The layer of polymorphic cells contains cells with diverse
Unless the fibers are specifically stai ned, they cannot be uti- shapes, many of which have a spindle of fus iform shape.
lized to further aiel in identification of the layers. Rather, the These cells are called fusiform cell s.
delineation of the layers, as they are identified here, is In addition to pyramidal cells, granule cells, and
based on cell types, and more specifically, the shape and ap- fusiform cells, two other cell types are also present in the
pearance of the cells. cerebral cortex but are not recogn izable in this pre paration:
The six layers of the cortex are named and described as the horizontal cells of Cajal, whi ch are present onl y in layer
follows: I and send their processes latera lly, and the cells of Mar-
/: The plex iform layer (or molecular layer) consists largely of tinotti, which send their axons toward the surface (opposite
fibers, most of which travel parallel to the slllt'ace, and re la-
to that of pyramidal cell s).
Figure 3, brain, human, Luxol fast blue-PAS ule cells (GC) are also numerous, though difficult to iden-
x350. tify here.
[] This micrograph shows layer II, the small pyramidal cell
layer. Many small pyramidal cells (PC) are present. Gran-
Figure 4, brain, human, Luxol fast blue- PAS are also prominent. The micrograph also reveals a numbe r
x350. of capillaries. Note how they travel in various di rections.
[] This mic rograph shows layer IV, the granular layer.
Many of the cells here are granul e cells, but ne uroglial cells
rn
KEY
Figure 6, brain, human, Luxol fast blue-PAS
x 350.
This mkrograph shows the outer portion of the whi te
matter. The small round nuclei (NN) be long to neuroglial
cells. As in the cortex, the cytoplasm of the ce ll is not di s-
tinguishable. Thus, they appear as naked nuclei in the bed
of nerve processes. The neuropil is essentially a densely
packed aggregation of nerve fi bers and ne uroglial cells.
tE
Figure 1, cerebellum, human, H&E x40. no distinctive histologic featu res. Thjs is the white matte r
The cerebe llar cortex has the same appearance regard- (WM). As in the cerebrum , it contains ne rve fi bers, sup-
less of which regi on is examined. In thi s low-magnification porti ng neurogl ia l cells, and smal l blood vessels, but no
view of the cerebellum, the o utermost layer, the molecular neuronal ce ll bodies. The fi brous cover o n the cerebellar
layer (Mol), is lightly stained with eosin. Under this is the surface is the pia mater (Pia). Cerebe llar blood vessels ( BV)
g ranular layer (Gr), which stains inte nsely with he ma- travel in this layer. (Shrinkage artifact has separated the pia
toxylin. Together, these two layers co nstitute the cortex of mate r from the cerebe ll ar s urface.) The rectangular area is
the cerebellum. Deep in the granular layer is another region shown at higher magnification in Figure 2.
that stains lig htly with H&E and, except fo r location, shows
,
tE
Figure 2, cerebellum, human, H&E x400. contrast, the granu lar layer presents an overall spotted-bl ue
At the junction between the molecular and gra nular layers appearance due to the staining of numerous small nuclei
,
are the extremely large flask-shaped cell bodies of the Purk-
inje cells ( Pkj). These cells are characteristic of the cerebel-
with hematoxylin. T hese small neurons, called granule
cells, receive incoming impulses from other parts of the
lum. Each possesses numerous dendrites (D) that arborize in CNS and send axons into the molecular layer, where they t" BC ~
the molecular layer. The Purkinje cell has a sing le axon that
is not usually evident in H&E sections. This nerve fi ber rep-
resents the beginning of the outflow from the cerebe llum.
The figure shows relativel y few ne uron cell bod ies, those
bra nch in the form of a T, so that the axons contact the den-
drites of several Purkinje cells and baske t cells. Incomi ng
(mossy) fi bers contact gra nule cells in the lightly stained ar-
eas called glomeruli (a rrows). Carefu l examination of the BV/
.4\
.. ..
4
of the basket cells (BC), in the molecul ar laye r; they are granular layer where it meets the molecular layer will re- ~
widely removed from each other and , at best, show only a ve al a group of nuclei (G) that are larger than the nuclei of
small amount of cytoplasm surrounding the nucleus. In granule cells. These belong to Golg i type II cells.
11 ~ _2,
tE
Figure 3, cerebellum, human, silver stain x40. Purki nje cells can be recognized in the silver preparation
The specimen in thi s fi gure has been stai ned with a sil- because of their large size, characteristic shape, and loca-
ver procedure. Such procedures do not always color the tion between an outer molecular layer (Mol) and an inner
specimen evenly, as do H&E. Note that the part of the mo- granular layer (Gr). The main advantage of this silver
lecula r layer on the ri ght is much darker than that on the preparation is that the wh ite matter (WM) can be recogn ized
le ft. A rectangular area on the left has been selected for ex- as being composed of fibers; they have been blackened by
amination at hi gher mag nification in Figure 4. Even at the the silver-stai ning procedure. T he pia mater (Pia) and cere-
re latively low magnification shown here, however, the bellar blood vessels are also evident in the preparation.
tE
Figure 4, cerebellum, human, silver stain x400. ies, and in the molecula r layer (Mol) disposed in a horizon-
At hig her magnification, the Purkinje cell bod ies (Pkj) tal direction (re lative to the cerebellar surface) . The anvw
stand out as the most distinctive and conspicuous neuronal indicates a T turn characteristic of the turn made by axons
cell type of the cerebellum, and numero us dendritic of granule cel ls. As these axonal branches travel horizon-
branches (D) can be seen. Note, also, the blackened fibers tall y, they make sy naptic contact wi th numerous Purkinje
within the granular laye r (Gr), abo ut the Purkinje cell bod- cells.
KEY
BC, basket cells Gr, granul ar layer anows: Fig. 2, glomeruli; Fig. 4, T branch-
nv, blood vessels Mol, molecular layer ing of axon in molecular layer
D, dendri tes Pia, pia mater rectang ular area (Figs. 1 and 3), areas
l~ ~bcr~ Pkj, Purkinje cells shown at higher magnification in Figures
G, Golgi type 11 cells WM, whi te matter 2 and 4, respectively
322
...... ,...
Figure 1, spinal cord, human, silver stain x16. ferred to as ventral horns ( VH) and dorsal horns (DH), re-
W
Figure 2, spinal cord, human, silver stain x640. ber of other nuclei (NN) belong to ne uroglial cells. The cy-
This preparation shows a reg ion of a ventral horn. The toplasm of these cells is not evident. The remainder of the
nucleus (N) of the ventral horn cell is the large, spherical, field consists of nerve fibers and neuroglial cells whose or-
pale-staining structure within the cell body. It contains a gani zatio n is hard to inte rpret. This is called the neuropil
spherical, intensely staining nucleolus. The ventral horn (Np). A capillary crosses throug h the field below the cell
cell has many processes, two of which are obvious. Anum- body.
Figure 3, spinal cord, human, toluidine blue bodies in the cytoplasm. Nissl bodies do not extend i11to the
Ed x640.
This preparation of the spinal cord is from an area com-
parable to that of Fig ure 2. The toluidine blue reveals the
Nissl bodies (NB) that appear as the large, dark-staining
axon hillock. The axon leaves the cell body at the axon
hillock. The nuclei of neuroglial cells (NN) are also evident
here, but the ir cytoplasm is not. The neuropil stains very
faintly.
KEY
BV, blood vessels NB, Nissl bodies VH, ventral (anterior) horn
DH, dorsal (posterior) horn NN, nucleus of neuroglial cell a1-rows (Fig. 1), cell body of anterior (ven-
DR, dorsal root Np, neuropil tral) horn cell
GC, gray commissure Pia, pia mater
N, nucleus of ventral horn cell VF, ventral fissure
324
with the assistance of negative pressure in the thoracic VEINS ARTERIES
cavity during inspiration and compression of the veins by large vein large or elastic artery
skeletal muscle. The blood vessels are arranged so that
blood de livered from the heart quickly reaches a network
of narrow, thin-walled vessels, the blood capillaries,
within or in proximity to the tissues in eve ry part of the
BOX 12.2. Clinical Correlations: Atherosclerosis 337 Two pathways of circulation are formed by the blood
vessels and the heart:
BOX 12.3. Clinical Correlations: Ischemic Heart Disease 346
9 GENERAL FEATURES OF ARTERIES
Pulmonary circulation con veys blood from the heart to AND VEINS
the lungs and from the lungs to the heart (Fig. 12.2) .
Systemic circulation conveys blood from the heart to The walls of arteries and veins are composed of three layers
other tissues of the body and from other tissues of the called t unics
body to the heart.
Although the general arrangement of blood vessels in both The three layers of the vascular wa ll, from the lumen
9 OVERVIEW OF THE The cardiovascular system includes the heart, blood vessels, circulations is from arteries to capillaries to veins, in some
outward (see Fig. 12.1 ), are
CARDIOVASCULAR SYSTEM and lymphatic vessels parts of the systemic circulation it is modified so that a vein Tunica intima, the innermost layer of the vessel. It con-
or an arterio le is in terposed between two capillary networks; sists of three components: (a) a single layer of squamous
The cardiovascular system is a transport system that car- Blood vessels provide the route by w hich blood circu- these vessels constitute p011al systems. Venous portal sys- epithelial cells, the endothelium; (b) the basal lamina of
r ies blood and lymph to and from the tissues of th e body. lates to and from all parts of the body. The heart pumps tems occur in vessels carryU;lg blood to the liver, namely, the the endothelial cells; and (c) the subendothelial layer,
The constitutive elements of these flu ids include cells, nu- the blood through the arteria l system under significant hepatic p011al system (portal vein) and, in vessels leading to consisting of loose connective tissue. Occasional smooth
trients, waste products, hormones, and antibodies. pressure; blood is returned to the heart under low pressure the pituitary, the hypothalamic-hypophyseal portal system. muscle cells are found in the loose connective tissue. The
3'26 32 7
328 CHAPTER 12 Cnrdio1wsclllnr System C HAPTER 12 CnrdiovnsCIIInr Syslrm 32 9
Histologically, the various types of arter ies and veins Muscular artery 2-10 mm Endothelium Smooth muscle Connective tissue
- Large Connective tissue Collagen fibers Some elastic fibers
are distinguished from each other on the basis of the Smooth muscle Relatively little elastic tissue Thinner than tunica media
thickness of the vascula r wa ll a nd differences in the com- Prominent internal elastic
position of the layers. Table 12.1 summarizes the features membrane
of the various types of blood vessels. -Small 0.1-2 mm Endothelium Smooth muscle (8-1 0 cell Con nective tissue
Connective tissue layers) Some elastic fibers
Contraction and relaxation of smooth muscle cells in the tunica Smooth muscle Collagen fibers Thinner than tunica media
media influence blood flow and pressure Internal elastic membrane
Arteriole 10- 100 fLm Endothelium Smooth muscle (1-2 cell Thin, ill-defined sheath
Contraction of smoo th muscle in the tun ica media of Connective tissue layers) of connective tissue
Smooth muscle
small arteries and arterioles reduces the luminal diameter
Capillary Endothelium None None
of these vessels (vasoconstriction), increasing the vascula1'
resistance. Vasoconstriction leads to an increase in the
systentic blood pressure. Genera lly, vasoconstriction is in- Veins
FIGURE 12.2
Diagram depicting circulation of blood through the heart. Blood re- duced by nerve impulses or circu lating hormones. The re- Inner Layer Middle Layer Outer Layer
turns from the tissues of the body via the superior vena cava and in- laxa tion of smooth muscle cells increases the lumina l di- Vessel Diameter (Tunica Intima) (Tunica Media) (Tunica Adventitia)
ferior vena cava. These two major venous vessels carry the blood to ameter of the vessels (vasodilation), decreasing vascular Postcapillary 10-50 ~-tm Endothelium None None
the right atrium. Blood then passes into the right ventricle and is resistance and systemic blood pressure. Vasodilation oc- venule Pericytes
pumped into the pulmonary trunk and next flows into pulmonary ar
curs in response to substances produced by the endothe- Muscular venule 50-100 ~-t111 Endothelium Smooth muscle (1 -2 cell Connective tissue
terles that convey the blood to the lungs. The blood is oxygenated in
lia l cells, ca lled endothelial-derived relax ing factors Perlcytes layers) Some elastic fibers
the lungs and Is then returned to the left atrium via the pulmonary Thicker than tunica media
veins. Blood then passes to the left ventricle and is pumped into the
(EDRFs). The most important EDRFs are nitric oxide (NO)
and its r elated compounds, which a re released by epithe- Small vein 0.1-1 mm Endothelium Smooth muscle (2-3 layers Connective tissue
aorta, which conveys the blood to the tissues of the body. From the continuous with tunica in-
Connective issue Some elastic fibers
heart to the lungs and from the lungs to the heart constitutes the pul- lial cells in arteries, blood capillaries, and even lymphatic
Smooth muscle (2-3 lay- tima) Thicker than tunica media
monary circulation from the heart to the tissues and from the tissues capillaries. ers)
to the heart constitutes the systemic circulation. Medium vein Endothelium Smooth muscle Connective tissue
1-10mm
Connective tissue Collagen fibers Some elastic fibers
su bendothelial layer of the intima in arteries and arter i-
9 ARTERIES Smooth muscle Thicker than tunica media
Internal elastic membrane
oles contains a sheet-like layer or lamella of fenestrated Traditionally, arteries are classified into th ree types on the in some cases
elastic material called the internal elastic memb1'ane. Fen- basis of size and the characteristics of the tunica media: Large vein > lmm Endothelium Smooth muscle (2-15 Connective tissue
estrations enable substances to diffuse readily through the Connective tissue layers) Some elastic fibers
layer and reach cells deep within the wa ll of the vessel. Large or elastic arteries Smooth muscle Cardiac muscle near heart Much thicker than tunica
Tunica media, the middle layer. This layer consists pri- Medium or musculm' arteries (most of the "named " ar- Collagen fibers media
ma ril y of circumferential ly arranged layers of smooth ter ies of the body)
muscle cells. In arteries, it is relatively thick and extends Small arteries and m'terioles
from the intemal elastic membrane to the external elas- the con tinu o us a nd uniform movement of blood a long the away from, and back toward, the heart. The flow of blood
tic membrane. The external elastic membrane is a layer of Elastic Arteries tube. Blood flow occurs as fo llows: The ventricles of the toward the heart ca uses the aortic and pulmonary valves to
elastin that separates the tunica m edia from the tunica heart pump blood into the elastic arteries during the con- close. Continued elastic recoil then maintains contin uous
adventitia. Varia ble amounts of elastin, reticula r fibers, Elastic arteries have multiple sheets of elastic lamellae in their traction phase (systole) of the cardiac cycle. The pressure flo w of blood away from the heart.
and proteoglycans are interposed between the smooth walls generated by contraction of the ventricles moves the blood
muscle cells of the tunica media. T he sheets or lamellae of th rough the elastic arteries and along the arteri al tree. Si- The tunica intima of the elastic artery consists of endothelium,
elasti n are fenest rated and are arranged in circular con- The largest elastic arteries, the aorta and pulmonary ar- multaneously, it a lso causes the wa ll of the large elastic ar- subendothelial connective tissue, and an inconspicuous
centric layers. All of the extracellular components of the teries, convey blood from th e heart to the systemic and teri es to distend. The distension is limited by the network internal elastic membrane
tunica media are produced by the smooth muscle cells. pulmonary circulations, respectively (see Fig. 12.2). These of collagenous fibers in the tunica media and tunica ad-
Tunica adventitia, the outermost connective tissue layer. arteries, as well as their main branches, the brachia- ventitia (Fig. 12.3). During the relaxation phase (diastole) The tunica intima of elastic arteries is relatively thick
It is composed primarily of longitudina ll y arranged co l- cephal ic, common carotid, subclavian, and common iliac of the cardi ac cycle, when .n o pressure is generated by tbe and consists of
lagenous tissue and a few elastic fibers. These connective arteries, are classified as elastic arter ies. heart, the recoil of the distended elastic arteries serves to
tissue elements grad ua lly merge with the loose con nec- From a functional standpoint, elastic arteries serve pri- mainta in arterial blood pressure and the flow of blood Endotheliallini1~g wit h its basal lamina. The cells are
tive tiss ue surro unding the vessels. The tunica adventitia marily as conduction tu bes; however, they also facilitate within the vessels. Initial elastic recoil forces blood both typica ll y flat and elongate, with their lo ng axes o ri-
330 CHAPTER 12 Cn ,Aiollnsctdnr Syslem C H A PTE R 12 Cardiovascular Syslem 33I
unmyelinated nerve macrophage fibrob last blood vessel myelinated nerve ented parallel to the direction of blood flow in the ar- Endothelial cells participate in the structural and functional
tery (Fig. 12.4). In forming th e epithelial sheet, the integrity of the vascular wall
cells are joined by tight junc ti ons (zo nulae occlu-
Endothelial cells play an important role in blood home-
dentes) and gap junctions (Fig. 12.5) . Endothelial cells
ostasis. The functional properties of these cells change in
possess rod -like inclusions, called Weibel-Palade bod-
r esponse to va rio us stimuli. T his process, known as an en-
ies, which are present in the cytoplasm. These specific
dothelial activation, is a lso respo nsible for the pathogene-
e ndothelial orga nelles are electron-dense structures
sis of many vascular diseases (e.g., a therosclerosis) . Induc-
a nd contain von Willebrand factor (a lso ca lled coagu-
ers of endothelial activatio n include bact erial and vira l
lating factor VIII). Studies indicate that most von
antigens, cytotoxins, complem ent products, lipid products,
Willebrand facto r is synth esized by a rterial endothelial
and hypox ia . Activated e ndothelial cells exhibit new sur-
cells and secreted into the blood. The a ntibody to von
face adhesion molecules a nd produce different classes of
Willebrand factor is conunonl y used as an immunohis-
cytokines, lymphokines, growth fa ct ors, vasoconstrictor
toc hemical marker for identificati on of end othelium-
and vasodil a tor molecules as well molecules controlling
derived tumors.
blood coagulation. Therefore, endothelial cells are active
Subendothelial layer of connective tissue, w hich in larger
participants in a variety of interactions between the blood
e lastic arteries con sists of connective tissue with both col-
and und erlying connective tissue and are responsible for
lagen and elastic fibers. The main cell type in t his layer is
many properties o f the vessels (Ta ble 12.2). These proper-
the smooth muscle cell. It is contractile and secretes ex-
ties include
tracellula r ground substance as well as collagen and elas-
tic fibers. Occasional macrophages may a lso be present. Mai1-ztenance of a selective permeability barrier, which
The internal elastic membrane (lamina), which in elas- allows selective mo ve ment of small and large molecules
ELASTIC ARTERY t ic arteries is not conspicuous beca use it is one of many from the blood to the tissues and from the tissues to the
elastic layers in the wa ll of the vessel. It is usuall y iden- blood. This moveme nt is related to the size and charge
FIG URE 12.3
and the distribution of elastic lamellae. t., tunica. (Based on Rhodin tified only because it is th e innermost elastic layer of t he of the molecules. Sma ll hydrophilic a nd hydropho bic
Schematic diagram of an elastic artery showing its cellular and ex-
tracellular components. This diagram shows a section of the wall of JAG. Handbook of Physiology. New York: Oxford University Press, arterial wa ll. molecules (e.g ., oxygen, carbon diox ide, glucose, amino
a typical elastic artery. Note the organization of smooth muscle cells 1980.)
microvilli junctional
endothelial cells comp lex
tw
J
.
FIGURE 12.5
::':/'. ':
-~. Diagram depicting segments of two
junctional ~: "* adjacent endothelial cells. This dia-
complex gram shows cell-to-cell and cell-to-
extracellular matrix junctions repre-
sented here by the junctional complex
and hemidesmosomes, respectively.
Observe tile organization of the cyto-
plasm and cytoplasmic inclusion, the
Weibei-Palade bodies that are charac-
teristic of endothelial cells. Pinocytotic
vesicles in the cell on the left have been
positioned to suggest the pathway of
basal lamina vesicles from the lumen of the blood
cytop lasm of nuclei of vessel to the basal cell membrane or to
endothelial cells endothelial cells
the lateral cell membrane as indicated
FIGURE 12.4 by tile dashed arrows. Various markers
Diagram and scanning electron micrograph of the endothelium. This 12.5. (Based on Rhodin JAG. Handbook of Physiology. New York: Ox- have been traced through pinocytotic
schematic drawing shows the luminal surface and cut edge of the en- ford University Press, 1980.) Inset. Scanning electron microgra ph of a pathways across the endothelial cell .
dothelium. Th e cells are elongated with their long axis parallel to t11e small vein, showing the cells of the endothelial lining. Note tile spin- \-
.,.,~=~"
~'-~
(Modified from Rhodin JAG. Handbook
direction of blood flow. Nuclei of endothelial cells are also elongated dle shape with the long axis of the cells running parallel to the vessel. hemidesmosomes connective of Pl1ysiology. New York: Oxford Univer-
lamina
in the direction of blood flow. The rectangular area is shown in Figure X1,100. tissue sity Press, 1980.)
332 C HAPTER 1 2 Cnrtlio11nscrdnr System C HAPTER 12 Cardiovnsc:dn: Systew 333
acids, and electrolytes) can diffuse or are actively trans- converting enzyme) and vasodilators (EDRF/NO,
tenstlc fea ture m the formation of atherosclerotic the extracellular m atrix. In addition, in response to
ported across the plasma membrane and released into prostacyclin).
plaques. growth factors (i.e., PDGF, FGF) produced by endothe-
the extracellular space. Small molecules, water, and sol- Regulation and modulation of immune responses by
lial cells they may proliferate and migrate to the adjacent
uble pwteins are transported by pinocytotic vesicles (a controlling interaction of lymphocytes with the endothe-
The tunica media of elastic arteries consists of multiple layers intima. This characteristic is important in norma l repair
clathrin-independent form of endocytosis). Small but lial surface, which is mainly achieved by the expression
of smooth muscle cells separated by elastic lamellae of the vascular wa.ll as well in pathologic processes sim-
numerous, pinocytotic vesicles transport bulk material of adhesion molecules and their receptors on the en-
ilar to those occurring in atherosclerosis.
from the blood into the cell. Larger molecules are trans- dothelial free surface as well by secretion of three classes
The tunica media is the thickest of the three layers of Collagen fibers and ground substance (proteoglycans),
ported through fenestrations within the endothelial cells of interleukins (IL-l, IL-6, and IL-8).
elastic arteries and consists of which are synthesized and secreted by the smooth mus-
visible in transmission electron microscope (T EM) Hormonal synthesis and other metabolic activities by
cle cells.
preparations. These fenestrations are believed to be the synthesis and secretion of various growth factors (he- Elastin in the forrn of fenestrated sheets or lamellae be-
morphologic equivalents of the "large pores" described mopoietic colony-stimulating factors [CSFs], such as tween the muscle cell layers. These lamellae are arranged
The tunica adventitia in the elastic artery is a relatively thin
by physiologists. In addition, some specific molecules granulocyte-macrophage CSF [GM-CSFl, G-CSF, and in concentr ic layers (Fig. 12.7a). As noted, fenestrations
connective t issue layer
(e.g., low-density lipoprotein (LDL), cholesterol, trans- M-CSF; fibroblast grow th factor (FGF); and platelet- in the lamellae facilitate the diffusion of substances
ferrin) are transported via receptor-mediated endocyto- derived growth factor (PDGF)]. Endothelial cells also within the a rterial wa ll. The number and thickness of
In elastic arteries, the tunica adventitia is usually less
sis (a clathrin-dependent process), which uses endothe- synthesize growth inhibitors such as heparin and trans- these lamell ae are related to blood pressure and age. At
than half the thickness of the tunica media. It consists of
lial specific surface receptors. forming growth factor {3 (TGF-{3). Endothelial cells birth , the aorta is almost devoid of lamellae; in the adult,
Maintenance of a nonthrombogenic barrier between fu nction in the conversion of angiotensin I to an- the aorta has 40 to 70 lameLlae. In individuals with hy- Collagen and elastic fibers in the form of a loose net-
blood platelets and subendothelial tissue by producing giotensin II in the renin-angiotensin system that controls pertension, both the number and the thickness of the work of elastic fibers (not lamellae) that are less organ-
anticoagulants (thrombomodulin and others) and an- blood pressure, as well as in the inactivation or conver- lamel lae are increased . ized than those in the tunica media. The collagen fibers
tithrombogenic substances (prostacycl in [PGI2 ] and tis- sion of a number of compo unds conveyed in the blood Smooth muscle cells arra nged in layers. The smooth help prevent the expansion of the arterial wall beyond
sue plasminogen activator). Damage to endothelial cells (norepinephrine, thromb in, prostaglandins, bradykinin, muscle cells are arranged in a low-pitch spiral relative to physiologic lim.its during systole of the cardiac cycle.
causes them to release protbrombogenic agents (von and serotonin) to inactive forms. the long axis of the vessel; thus, in cross sections of the Fibroblasts and macrophages, the principal cells of the
Willebrand factor, plasminogen activator inhibitor ). Modification of the lipoproteins by oxidation. Lipopro- artery they appear .in a circular array. The smooth mus- tunica adventitia.
These agents cause platelets to aggregate and release fac- teins, mainly LDLs with a high cholesterol content and cle cells are spind le shaped with an elongated nucleus. Blood vessels (vasa vasorum) and nerves (nervi vascu-
tors that result in the formation of clots or masses, very low density lipoproteins (VLDLs), are oxid ized by They are invested with an external (basal) lamina except laris). Branches of the vasa vasorum partially enter the
call ed thrombi, that potentially prevent blood loss. free radicals produced by endothelial cells. Modified where they are joined by gap junctions. Fibroblasts are tunica media and provide nutrients to the outer portion
Modulation of blood flow and vascular 1'esistance by LDLs, in turn, are rapidly endocytosed by macrophages, not present in the tunica media. Smooth muscle cells of the arterial wall. The inner part of the wall is supplied
secretion of vasoconstrictors (endotheJin, angiotensin- forming foam cells (Fig. 12.6). Foam cells are a charac- synthesize the collagen, elastin, and other molecules of by nutrients from the lumen of the vessel.
334 CHAPTER 12 Cnrdiovnsc11lnr Sy slelll CHA PTE R 12 Cnrdiovnsc11IM Syste111 335
In histologic sections, the internal elastic membrane usually scattered adipose cells. Compared with elastic arteries, the
appears as a well-defined, undulating or wavy structure be- tunica adventitia of muscular arteries is relatively thick,
cause of contraction of the smooth muscle (Fig. 12. 7b). about the same th ickness as the tu nica media. Collagen
The thickness of the tunica intima varies with age and fibers are the principal ex tracellular component. However,
oth er factors. In young children, it is very thin. In muscu- a concentration of elastic material immediately adjacent to
lar arteries of young adults, the tunica intima accounts for the tunica media is often present and as such constitutes
about one six th of the total wall thickness. In older adults, the external elastic membrane. Nerves and small vessels
the tunica intima may be expa nded by lipid deposits, often travel in the adventitia and give off branches tha t penetrate
in the form of irregular " fatty streaks. " into the tunica media in the large muscular arteries as the
vasa vasonun.
The tunica media of muscular arteries is composed almost
entirely of smooth muscle, with little elastic material
Small Arteries and Arterioles
The tunica media of muscular arteries consists of
smooth muscle cells amid collagen fibers and r elatively lit- Small arteries and arterioles are distinguished from one another
tle elastic material. The smooth muscle cells are arranged by the number of smooth muscle cell layers in the tunica media
in a spiral fas hion in the arte ri al wall. T heir contraction
helps maintain blood pressure. As in elastic arteries, there By definition, arterioles have only one or two layers of
are no fibroblasts in this layer. The smooth muscle cells smooth m uscle in their tunica m edia (Fig. 12.9); a small ar-
possess an external (basal) lamina except at the sites of gap tery may have up to about eight layers. Typically, the tu-
junctions and produce ex tracellular collagen, elastin, and nica intima of a sma ll artery has an internal elastic mem-
ground substance. brane, whereas this layer may or may not be present in the
arteriole. The endothelium in both is essentiall y similar to
T ~ --+ The tunica adventitia of muscular arteries is relatively thick endothelium in other arteries, except that at the EM level,
r
+ .
tunica adventi.tia
b
and is often separated from the tunica media by a recognizable
external elastic membrane
gap junctions may be found between endothelial cells and
the smooth muscle cells of the tunica media. Lastly, the tu-
nica adventitia is a thin, ill-defined sheath of connective tis-
FIGURE 12.7 The tunica adventitia of muscular arteri es consists of fi- sue that blends w ith the connective tissue in which these
Photomicrographs of the wall of elastic and muscular types of ar- through a muscular artery in a routine H&E preparation shows that broblasts, collagen fibers, elastic fibers, and in some vessels vessels travel.
teries. a. T11is photomicrograph shows a cross section of the 11uman the wall of the muscular artery is also divided into the same three lay-
aorta stained with resorcin-fucllsin to demonstrate elastic material. ers as in the elastic artery. The tunica intima consists of an endothe-
Three layers can be recognized: the tunica intima, tunica media, and lial lining, a small amount of connective tissue, and the internal elas-
tunica adventitia. The tunica intima consists of a lining of endothelial tic membrane. This structure has a scalloped appearance when the
cells that rest on a thin layer of connective tissue containing smooth vessel is constricted and is highly refractile. Constriction also causes
muscle cells, occasional macrophages, and collagen and elastic the endothelial cell nuclei to appear rounded. The tunica media con-
fibers. The boundary between it and the tissue below, the tunica me- sists mainly of circularly arranged smooth muscle cells and collagen
dia, is not sharply defined. The tunica media contains an abundance and elastic fibers. The nuclei of the smooth muscle cells, when con-
of smooth muscle cells (note the blue staining nuclei) and numerous tracted, have a corkscrew appearance. The tunica adventitia consists
elastic fenestrated membranes (the red, wavy lamellae). The tunica mostly of connective tissue. A well-defined external elastic mem-
adventitia, the outermost part, lacks elastic laminae, consists mainly brane is not apparent in this vessel, but profiles of elastic material (ar-
of connective tissue, and contains the blood vessels and nerves that rows) are present. x 360.
supply the aortic wall. x 300. b. Photomicrograph of a cross section
Muscular Arteries muscular arteries from elastic arteries. In many instances, a t. media
recognizable external elastic membrane is also evident.
Muscular arteries have more smooth muscle and less elastin in
the tunica media than do elastic arteries The tunica intima is thinner in muscular arteries and contains a
prominent internal elastic membrane
There is no sharp dividing line between elastic arteries internal
and large muscular arteries (Fig. 12.8). Some of these ar- The tunica intima is relatively thinner in muscular arter- elcrstic,lll
teries are difficult to classify because they have features that ies than in elastic arteries and consists of an endothelial lin- memt;>rane
are intermediate between the two types. Genera lly, in the ing with its basal lamina, a sparse subendothelial layer of MUSCULAR ARTERY
region of transition, the amount of elastic material de- connective tissue, and a prominent internal elastic mem- FIG URE 12.8
creases, and smooth muscle cells become the predominant brane. In some muscular arteries, the subendothelia l layer Schematic diagram of a muscular artery. The cellular and extracellu- nica media are shown in contact to represent the presence of gap
constituent of the tunica media. Also, a prominent internal is so scanty that the basal lamina of the endothelium ap- lar components are labeled. Note the locations of external and inter- junctions between cells. t., tunica. (Based on Rhodin JAG. Handbook of
elastic membrane becomes apparent, helping to distinguish pears to make contact with the internal elastic membrane. nal elastic membranes. In certain locations, the muscle cells in the tu- Physiology. New York: Oxford University Press, 1980.)
336 C HAPTER 12 Cnrdioonmdnr System CHAPTER 12 Cnrdioon sculnr System 3 37
Arterioles control blood flow to capillary networks by late 60 to 100% from their resting diameter, and they
contraction of the smooth muscle cells can maintain up to 40% constriction for a long rime .
Therefore, a large decrease o r increase in vascu l ar resist-
Arterioles serve as flow regulators for the capillary ance has a direct effect on blood flow and systemic arte-
beds. In the normal relationship between an arteriole rial piessLue. This regulation directs b lood to where it
and a capillar y network, contraction of the smooth may be most needed. F or instance, duri ng strenuous
muscle in the wall of an arteriole increases the vascular physical exerti on, such as running, blood flo w t o ske le-
res i stance and reduces or shuts off the blood going to tal muscle .is increased by dilation of arterioles, an d
the capillari es. The slight thickening of the smooth m us- blood flow to the i ntestine is reduced by arteriole con -
cle at the orig in of a capillary bed f rom an arteriole is striction . After ingestion of a la r ge meal , h owever, the
ca lled the precapillary sphincte1: Most a rterioles can di- reverse is true .
Atherosclerotic lesions are the most common acquired abnormal- ticularly LDL (Fig. 12.10). Progression of the lesion is marked by ac
ity of blood vessels. More than half of the annual deaths in the cumulation of lipid and loss of integrity of the endothelium. In ad-
United States are related to complications of atherosclerotic dis- vanced lesions, blood stasis and clotting (thrombosis) may lead to
ease, which includes ischemic heart disease, myocardial infarction, occlusion of the vessel. Other changes seen in advanced lesions in-
stroke, and gangrene of the limbs. The lesions develop in the in- clude thinning of the tunica media, calcifications, and a necrotic
tima and consist of a thick layer of fibrous connective tissue con- mass within the lesion. Progression from simple to complicated le
taining scattered smooth muscle cells, macrophages, foam cells, sions can be found in some people in their 20s and in most indi-
lymphocytes, cholesterol crystals, and cell debris. It Is believed that viduals by age 50 or 60 years.
FIGURE 12.9 both macrophages and smooth muscle cells accumu late lipid, par-
Electron micrograph and photomicrograph of arterioles. a. Th is elec- seen in longitudinal section, while anoth er is seen in cross section. The
tron micrograph shows a cross section of an arteriole. The tunica in- round and ovoid nuclei in the wall of the longitudinally sectioned arte-
tima of the vessel is composed of an endothelium and a very thin layer riole belong to the smooth muscle cells of the tunica media. Their
of subendothel ial connective tissue (collagen fibrils and ground sub- round to ovoid shape indicates that these cells have been cut in cross
stance). The arrows indicate tl1e site of junction between adjoining en- section. The elongated nuclei (arrows) belong to endothelial cells.
dothelial cells. The tunica media consists of a single layer of smooth X320. Inset. The cross-sectioned arteriole is shown here at higher
muscle cells {SM). The tunica adventitia is composed of collagen fibrils magnification and reveals the endothelial cell nuclei bulging into the
and several layers of fibroblasts (F) with extremely attenuated lumen (arrows). Tiley reflect a cross-sectional cut. The nuclei of the
processes. Red blood cells are visible in the lumen. x6,000. b. Pho- smooth muscle cells in the tunica media appear as elongate profiles re-
tomicrograph of arteriole and venule in the dermis. One arteriole is flecting their circular pattern around the vessel. X 600.
Hypertension, or high blood pressure, occurs in about 25% of the muscle cells accumulate lipid. This is one reason why hypertension
population and is defined by a sustained diastolic pressure greater is a major risk factor for atherosclerosis. In fat-fed animals, hyper-
than 90 mm Hg or a sustained systolic pressure in excess of 140 tension accelerates the rate of lipid accumulation in the vessel wall.
mm Hg. Hypertension is often associated with atherosclerotic vas- In the absence of a fatty diet, hypertension increases the rate of in-
cular disease and with an increased risk of cardiovascular disorders timal thickening that occurs naturally with age.
such as stroke and angina pectoris. In most cases of hypertension, Cardiac muscle is also affected by chronic hypertension. Ven FIGURE 12.10
the size of the lumen of the small muscular arteries and arterioles tricular hypertrophy, caused by an increase in number and size of Photomicrographs of an atherosclerotic lesion. a. This specimen sue of the plaque is evident. The arrows point to smooth muscle
is reduced, which leads to increased vascular resistance. Restriction cardiac muscle cells, is a common manifestation of hypertension. is from a human aorta stained by the Masson trichrome method. cell nuclei that have produced the collagen fibers of the fibrous
in the luminal size may also result from active contraction of the Ventricular hypertrophy makes the wall Jess elastic and the heart The lesion, referred to as a fibrous plaque, consists of connective plaque. Also evident are the foam cells (FC) and the characteristic
smooth muscle in the vessel wall, an increase in the amount of must then work harder to pump blood. Recent studies have shown, tissue fibers, smooth muscle cells, fat-containing macrophages cholesterol clefts (CC). The latter are spaces occupied previously by
smooth muscle in the wall, or both. however, that prolonged reduction of blood pressure in patients (foam cells), and a necrotic material. It occupies the site of the tu- cholesterol crystals that have been dissolved during specimen
In individuals with hypertension, multiplication of smooth mus with ventricular hypertrophy due to chronic hypertension can ac nica Intima {TI), which is greatly expanded in thickness. TM, tunica preparation. The remainder of the plaque consists of necrotic ma-
cle cells occurs. The additional smooth muscle then adds to the tually reduce the degree of hypertrophy. media; TA. tunica adventitia. x 40. b. A higher power of the area in terial and lipid. x 240.
thickness of the tunica media. Concomitantly, some of the smooth the rectangle in a. On the right, some of the fibrous connective tis
338 CHAPTER 12 Cnrdiovmcular Sy slf111 CHAPTER 12 Canliovascular System j 39
capillary lumen, m inimizing the diffusion pa th for gases described: conti nuo us capillaries, fen estrated ca pillaries, large nucle us ric h in he te rochromatin. It is d erived from
\1 CAPillARIES a nd nutrients between the ca pilla ry and t he extravascular and d iscontinuous capillaries. the sam e precursor cell t hat forms endothelia l cells in n ew
tissue. In cross sections a nd with t he TEM, the tube ap- Continuous capillaries are typically fou nd in muscle, vessels. It can also give ri se to smooth muscle cells during
Capillaries are the smallest diameter blood vessels, often pears to be formed by o nly one cell o r portions of several lung, a nd the centra l nervous system (CNS). Wi t h the vessel growth (as in development and wound healing).
smaller than the diameter of an erythrocyte cells. Because of their thin walls and close physical associ- TEM, they appear in cross sectio ns as two plasma mem - Fenestrated capillaries a re typicall y found in endocrine
ation w ith metabolically active cells and tissues, capillar- branes encl osing a rib bon of cytop lasm tha t may include glands and sites of fluid a nd metabolite absorption, such as
Capillaries form blood vascular networks th at allow ies are particula rly well suited for the exchange of gases the nucleus (Fig. 12.11 ). Occluding junctions can be seen the gallb ladder a nd intestinal tract. T hey are ch aracterized
fluids conta ining gases, metabolites, and waste products and metaboli tes between cells and the bloodstream. The in a t yp ical cross section of a continuous capillary. N u- by fenestrations, 80 to 100 nm in d iameter, w hich provide
to move t h rough their thin wa lls. The human body con- ratios of capillary vo lume to end oth elial surface a rea and merous pinocytotic vesicles underlie both the luminal and channels across the capillary wa ll (Fig. 12.12). Fenestrated
ta ins approximately 50,000 miles of capillaries . Each con- thickness a lso favor movement of substa nces across the basal plasma membrane surfaces. T he vesicles are app rox- capilla ries also have pinocytotic vesicles. Som e research
sists of a single layer o f endoth elia l cells and their basal vessel wall. imately 70 nm in diameter a nd functio n in transport of suggests t hat fenestrations are formed when a form ing
lami na. The endot heli a l cells form a tube just large materials between the lumen and the con nective tissue and pinocytotic vesicle spa n s the narrow cyt oplasmic layer a nd
e no ugh to al low the passage o f red blood cells o ne at a vice versa. simultaneously opens on the opposite sur face. A fen est ra-
Classification of Capillaries
ti me. In many capillaries the lumen is so narrow that t he In some co ntinuou s capilla ries and postcapillary tion may have a t h in, non membranous diapluagm across
red cells literall y fold upon themselves to pass th rough the Capillary structure varies in different tissues and organs. ven ules, pericytes (Rouget cells) may be associated with its open ing. This diaphragm has a central thickening and
vesse l. The passing red blood cells fi ll virtua lly t he entire Based on t heir morph o logy, three types of capillaries are t he endotheli um (Fig. 12.11 ). The pericyte, when present, may be the remna nt of th e glycoca lyx fo rmerly enclosed in
intima te ly surroun ds the ca p illary, with branching cyto- the p inocytotic vesicle from which the fenestration may
p lasmic processes, and is enclosed by a basal lamina that have formed.
is continuous w ith th at of th e endoth e lium. T he pericyte Fenestrated capillaries in the gastrointestinal tract and
disp lays fea tures of a relatively unspecial ized cell with a ga ll bladder have fewer fenestrations and a t h icker wal l
.~..;..;
I .:.
pericyte
i
\ .
when no absorption is occurring. When absorption takes called arteriovenous (AV) anastomoses, or shuttts (see Fig. possess an endotheJjal lining with its basal lamina and peri-
12.1 ). AV shunts are commonly fo und in the skin of the fin-
9VE INS
place, the walls thin, and the number of pinocytotic vesi- cytes. T he endotheliLll11 of postcapillar y venules is the prin-
~les and fenestrations increases rapidly. The ionic changes gertips, nose, and lips and in the erectile tissue of the penis cipal site of action of vasoactive agents such as histamine
The tunics of veins are n ot as distinct or weU defined as the
in the perivascular connective tissue, ca used by the ab- and clitoris. The arteriole of AV sh unts is often coiled, has and serotonin. Response to these agents results in extrava-
tunics of arteries. Traditio nall y, vei ns are divided into three
sorbed solutes, stimulate pinocytosis. These observations a relatively thick sm ooth muscle layer, is enclosed in a con- satio n of fluid and emigration of white blood cells from the
types on the basis of size:
support the suggested mode of formation of the fenestra- nective tissue capsule, and is richl y innervated. Contrary to vessel during .inflammation and allergic reactions. PostcapiJ-
tions described above. the ordinary precapillary sphi ncter, contraction of the arte- Small veins or venules, fur ther subclassified as postcap- Iar y venules of lym ph nodes also participate in the trans-
Discontinuous capillmies (sinusoidal capillaries, or si- riole smooth muscle of the AV shunt sends blood to a cap- illary and muscular venules mural migration of lymphocytes from the vascula r lumen
nusoids) are typicaUy found in the liver, spleen, and bone illary bed; relaxation of the smooth muscle sends blood to Medium veins into the lymphatic tissue. The postcapillary venules in the
marrow. T hey are larger in diameter and more irregularly a venule, bypassing the capillary bed. AV shunts serve in Large.veins lymph nodes are also called high endothelial venules
shaped than other capillaries. Structural features of these thermoregulation at the body surface. Closing an AV shunt (REVs) because of the prominent cuboida l appearance of
Altho ugh large and m edium veins have three layers, a lso
capillar ies vary from organ to o rgan and include specialized in the skin causes blood to fl ow tbJough the capillary bed, their endothelial cells and their ovoid nuclei.
designated tunica intima, tunica media, and tu nica adven-
cells. Stellate sinusoidalmacrophages (Kupffer cells) and vi- en hancing heat loss. Opening an AV shunt in the skin re- Muscular venules are located distal to the postcapillary
ti tia, these layers are not as distinct as they are in arteries.
ta min A-storing hepatic stellate cells (Ito cells) in the liver duces the blood flo w to the skin capillaries, conserving venules in the returning venou s network and ha ve a dia m-
Large- and medium-sized veins usually travel with large-
occur in association with the endothelial cells. In the spleen, body heat. In erectile tissue, such as the penis, closing the eter up to 1 mm. Whereas postcapillary ven ules have no
and m ediu m-sized arteries; arterioles and muscular venules
endothelial cells exhibit a unique spindle shape with gaps AV shunt directs blood flow into the corpora cavernosa, true tun ica media, the m uscular venules have one o r two
a lso sometimes travel together, tbus a llowing comparison
between the neighboring cells; the basal lamina underlying initiating the erectile response (see page 711 ). layers of smooth muscle that constitute a tunica media.
in histologic secti o ns. Typically, veins ba ve thinner wa lls
the endothelium may be partia lly or even completely absent. In add ition, preferential thoroughfares, whose proximal These vessels also have a thin tu nica adventitia .
than their accompanying arteries, and the lumen of the
segm ent is called a metarteriole (Fig. 12.13 ), also allow
vei11 is larger than that of the artery. The arteriole lu men is
Functional Aspects of Capillaries some blood to pass more directly from artery to vein. Cap-
usually patent; that of the vein is often collapsed. Ma ny Medium Veins
illaries aTise from both arterioles and metarterioles. Al-
To understand capillary function, two important points, veins, especially those that convey blood against gravity,
though capillaries themselves have no sm ooth muscle in Medium veins ha ve a d iameter of up to 10 mm . Most
blood flow and extent or richness of the capillary network, such as those of the limbs, contain va lves that allow blood
their walls, a sphincter of smooth muscle, ca lled the pre- named veins are in this category. Va lves are a chara cteris-
sho uld be considered. Blood flow is controlled through lo- to flow in on ly one directio n, back towa rd the heart. The
capillary sphincte1; is located at their origin from either an tic feature of these vessels and are most numero us in the
cal and systemic signals. In response to vasodilating agents va lves are semilunar flaps consisting of a thin com1ective
arteriole or a metarteriole. These sphincters control the inferior portion of the body, particularly the legs, to pre-
(e.g., EDRFs, NO, low 0 2 tension), the smooth muscle in tissue core covered by endothelial cells.
amount of blood passing through the capillary bed. vent retrograde m ovement of blood beca use of gravity. The
the walls of the arterioles relaxes, resulting in vasodilation tluee tunics of the venous wall are most evident in
and increased blood flow through the capillary system. Venules
medium-sized veins (Fig. 12.1 4):
Pressure within the capill aries increases, and much of the
Muscular venules are distinguished from postcapillary venules The tunica intima consists of an endothelium with its
p lasma fl uid is driven in to the tissue. This process occurs
by the presence of a tunica media basa l lamina, a thin subendothelial layer with occas ional
in pet'ipheral edema. Systemic signa ls carried by the auto-
nom ic nervous system and release of norep inephrine by the smooth muscle cells scattered i11 the connecti ve tissue el-
ad renal gland cause the smooth muscle of the arterioles to Postcapillmy venules receive blood from capillaries and em ents, and, in some cases, a thin internal elastic mem-
contract (vasoco nstriction ), resulting in decreased blood have a diameter as small as 0.2 mm or slightly larger. They brane.
flow through the capilla1y bed. Tn this condition, capillary
pressure can decrease and gr eatly increase absorption of
unmyelinated
ti ssue fluid . This situati o n occms dming loss of blood vol- collagen
ume and can add approximately 1 L of fluid into the fibers
. .. .
sel wall. Along with the usual collagen and elastic fibe rs trial septum and an interventricular septum separate the
~rni~'iiia ~t ner than the same layer in medium-sized arteries. It con-
tai ns several layers of circularly arranged smooth muscle
and fibroblasts, the tunica adventitia also contains longitu-
dinally disposed smooth muscle cells .
right and left sides of the heart. The right atrium receives
blood returning from the body via the inferior and supe-
tun i~media . cells with interspersed collagen and elastic fibers. In ad- rior venae cavae, the two largest veins of the body. The
dition, longitudinally arranged smooth muscle cells may 1ight vent1icle receives blood from the right atrium and
be present just beneath the tunica adventitia Atypical Veins
pumps it to the Iungs for oxygenation via the pulmonary
The tunica adventitia is typically thicker than the tunica In several loca tions, veins with a highly atypical structure arteries. The left atrium receives the oxygenated blood re-
media and consists of collagen fibers and networks of are present. For example, venous channels in the cranial turning from the lungs via the four pulmonary veins. The
elastic fibers (Fig. 12.15). cavity, called venous or dural sinuses, are essentially broad left ventricle receives blood from the left atrium and
spaces in the dura mater that are lined with endothelial pumps it into the aorta for distribution into the systemic
large Veins cells. Veins in certain other locations (e.g., retina, placenta, circulation.
trabeculae of the spleen ) also have atypica l walls and are The walls of the heart contain
I discussed in the chapters that describe these organs.
In large veins, the tunica media is relatively thin, and the tunica A musculature of cardiac muscle for contraction to pro-
adventitia relatively thick pel the blood.
A fibrous s!~eleton, which consists of four fibrous rings
Veins with a diameter greater than 10 mm are classified '!HEART surrounding the valve orifices, two fibrous trigones
as large veins. The tunica intima of these veins (Fig. 12.16) connecting the rings, and the membranous part of the
The heart is a muscular pump that maintains unidirectional
consists of an endothelial lining with its basal lamina, a interventricular and interatrial septa . The fibrous rings
flow of blood
small amount of subendothelial connective tissue, and are composed of dense ir regular connective tissue.
some smooth muscle cells. Often, the boundary between T hey encircle the base of the two arteries leaving the
the tunica intima and tunica media is not clear, and it is not The heart contains four chambers, the right and left
heart (aorta and pulmonary trunk) and the openings
always easy to decide if the smooth muscle cells close to atria and right and left ventricles, through which blood is
between the atria and the ventricles (right and left A-V
the in timal endothelium belong to the tunica intima or to pumped (see Figs . 12.2 and 12.17). Valves guard the exits
orifices) (Fig. 12.18 ). These rings provide the attach-
FIGURE 12.15
the tunica media. of the chambers, preventing backflow of blood. An intera-
Photomicrograph of the wall of a medium-sized vein. This photomi- ment site for the leaflets of all fou r va lves of the heart
crogra ph shows the three tunics in a section through the wall of a The tunica media is relatively thin and contains circum- that allow blood flow in only one direction through the
medium-sized vein. The tunica intima consists of endothelium and a ferentia lly arranged smooth muscle cells, collagen fibers, openings. The membranous part of the interventricular
very thin subendothelial layer of connective tissue containing some and some fibrobl asts. In some animals, but not in humans, septum is devoid of cardiac muscle; it consists of dense
smooth muscle cel ls. The tunica media contains circularly and spirally cardiac muscle cells extend into the tunica media of the ve- connective tissue that contains a short length of the un-
arranged smooth muscle cells with collagen and elastic fibers. Note nae cavae and the pulmonary veins, near their junction
the tunica adventitia, which contains an abundance of collagen and with the heart.
some elastic fibers. The few nuclei seen in this layer belong to fibro superior
The tunica adventitia of large veins (e .g. , the subclavian vena cava fibrous ring
blasts. x360. veins and the venae cavae) is the thickest layer of the ves- of pu lmonary
trunk
~~)
cellular and extracellular components
t. trigone
are labeled. The tunica intima con
t. intima sists of an endotllelial lining ahd a
\' small amount of connective tissue. The
-~r"\~
tunica media contains circumferentially opening for atrioventricular
arranged smooth muscle cells. The tu- bundle (of His)
~'
.' This fibrous network (indicated in blue) serves for the attachment of
. tudinally arranged smooth muscle cells heart has been cut open in the coronal plane to expose its interior cardiac muscle; it also serves for the attacl1ment of the cuspid valves
near the tunica media. t., tunica. (Based and the main parts of its impulse-conducting system (indicated in yel between tile atria and ventricles and for tile semilunar valves of the
on Rhodin JAG. Handbook of Physiology. low). Impulses are generated in the sinuatrial (S-A) node; they are aorta and tile pulmonary artery. Tile atrioventricular bundle passes
collagen fibers bundles of smooth New York: Oxford University Press, transmitted through the atrial wall to the atrioventricular (AV) node from the right atrium to tile ventricular septum via the membranous
muscle cells 1980.) and then along the AV bundle to the Purkinje fibers. septum of the fibrous skeleton.
3 44 CHAPTER 12 Cmliotwsculnr System CHAPTER 12 Ccwliovnsculnr Systrrrr 34 5
branc hed atr ioventricula r (A-V) bundle of the cardiac connective tissue. T he blood vesse ls and nerves that is much t hinner than the interventricular septum. Except in
cond uction system. The f ib rous skeleton provides inde- suppl y the heart lie in the epicardium and are sur- certain localized areas t hat contain fibrous tissue, it has a
pendent attachments for t he a tr ial an d ventricu la r ro unded by adipose tissue that cus hi ons the heart in the center layer of cardiac muscle and a lining o f end oca rdium
myocardium. It a lso acts as a n electri cal ins ulator by per icardia! cavity. facing each chamber.
p reve nt in g the free flow of e lectrical impulses between Myocardium, consisting of card iac muscle, the p rincipal
component of t he heart. The myoca rd ium o f the ven tri- Heart valves are vascular structures composed of connective
atri a a nd ventricles.
An impulse-conducting system for ini tiation an d propa- cles is su bsta ntia lly thicker t han t hat of the atr ia because tissue with overlying endocardium
gation of e lectr ica l impulses fo r cardiac muscle contrac- of the la rge amo unt of cardiac muscle in the walls o f t he
tion. It is fo rm ed by highly s pecia lized ca rdi ac mu scle two pumping cha m bers. T he hea rt valves attach to the complex framework o f
cells, wh ich generate and co nduc t electrica l impulses Endocardium, consisting of an inner layer o f e nd othe- den se irregu lar connecti ve tissue that form s the fibrous
rapidly through th e heart. lium and subendothel ia l conn ective tissue, a m idd le rings and surro unds t he o rifices containi ng the valves.
layer of co nn ective t iss ue and smooth muscle cells, and Each va lve is composed of three layers (Fig. 12.20) :
The wall of the heart is composed of three layers: epicardium, a deeper layer of co nnective tissue, also called the suben- Fibmsa fo rms t he core o f the va lve and c ontains fibrous
myocardium, and endocardium docardiallayeJ; which is co nti nu ous with t he con nect ive extensions from t he dense irregu lar connective tissue of
tissue of the myocardium. The impulse-conducting sys- the skeletal rings of the heart.
The structural organiza tion of the wall of the heart is tem of the hea rt (see below) is located in the subendo- Spongiosa represents loose connective tissue located on
continuous w ithin the atria and ventricles (see Fig. 12.19). cardial layer of the endocardium. the atrial and/or blood vesse l side of each valve. It is
The wall of the heart is composed of t h ree layers . From the T he interventricular septum is the wall between t he composed of loosely arranged collagen and elastic fibers
outside to the inside they a re rig ht an d left ventricles. It contai ns ca rd iac muscle except infiltrated with a large amount of p roteoglycans. T he
Epicardium, con sisti ng of a layer of mesothe lia l cells in the mem branous portion. Endocard iu m lines each sur- spongiosa acts as a shock a bsorber as it dampens vibra-
o n the outer s u r fa ce of th e hea rt a nd its underlying face of t he interventricula r se pt u m. T h e interatrial septum tions associated with the closing of the valve. It also
confers flexibili ty and plasticity to the va lve cusps. In
the aortic and pulmona r y va lves, spongiosa loca ted on
t he blood vessel side is cal led arteria/is. It corresponds FIGURE 12.20
C?ronary / , IcE~~~~-=- circumflex branch ro the loose connective t issue located on the atrial side Photomicrograph of a mitral valve. This photomicrograph shows a
s1nus ~ of left coronary artery of the A-V (tricus pid and mitra l) valves, ca lled the section through one of the two cusps of the mitral va lve near its at-
auricularis. tach ment to the fibrous ring. Both sides of the cusp are covered by
the endothelium. Note that the valve exhibits a layered architecture.
Ventricularis is immediately ad jacen t to t he ven tric ul ar
Beginn ing at the atrial side (top oft11e image), the first layer underlying
a nd/or atria l surface of each va lve a nd is covered w ith
tile endothelium Is the spongiosa- not well developed in this part of
endothe lium. It contains dense con nective tissue with the cusp. The second layer is the fibrosa, which forms the majority
many layers of elastic fibe rs. In the A-V valves, the ven- of the dense connective tissue in the core of the valve. The third layer,
tricu laris contin ues into the chordae tendineae, wh ich the ventricularis, is formed by dense connective tissue containing lay
are fibrous, thread- like cords a lso covered with endothe- ers of elastic and collagen fibers. x 125.
lium. T hey extend from the free edge of the A-V va lves
to muscular projectio ns from the wa ll of the ventricles,
ca lled papillary muscles. th icken. T he va lves become rigid and inflexib le, which af-
fec ts the ir abil ity to open a nd close.
Valve c usps are normally avascu lar. Sma ll blood vessels
a nd smooth m uscle c an be found o nly in the base of th~
c usp. The s urfaces o f the valve are exposed to blood, and Intrinsic Regulation of Heart Rate
th e c usps are thin enough to allow nutrients and oxygen to
d iffuse from the blood. Contraction of the heart is synchmnized by specialized cardiac
Severa l d iseases affect the valves of the hea rt, causing muscle fibers
their degeneratio n (e.g., calcificatio n, fibros is) a nd res u lt-
in g in heart ma lfu nction due to insuffici ency or stenosis of Cardiac muscle ca n con tract in a rhyth m ic manner with-
va lvular orifices . These co nd itions, kno w n collectively as out any di rect stim ulus fro m the nervous system. T he pace
FIGURE 12.19 va lvu lar heart disea se, include rheu ma tic heart disease of t he beating action in the hea rt is initiated at the sinu-
Photomicrograph of the left atrial and left ventricular wall. a. This tissue. The layers of the mitral valve are shown at higher magnifica- vegetative endocardi tis, degenerative calcific aortic va lve' . atrial (S-A) node, a g roup of specialized cardiac muscle
photomicrograph shows a sagittal section of the posterior wall of tile tion in Figure 12.20. x 35. b. This high magnification of the area indi- stenosis, a nd mitr a l annular calcification. Rheuma t ic fever cells located near the junction o f the superior vena cava
e.g., causes in flammation of the heart va lves (va lvulitis ).'
left atrium and left ventricle. T11e line of section crosses the coronary cated by the rectangle in a shows the characteristic features of the in-
and the rig ht atrium (see Fig. 12.17) . The S-A node is a lso
(A-V) groove containing the coronary sinus and circumflex brancl1 of ner surface of the heart. Note that the endocardium consists of a
Inflammation induces a ngiogenesis in the va lve and vasc u- referred to as t he pacemal~e1: The pacema ker rate of the S-
the left coronary artery. Note tllat the section has cut through the fi- squamous inner layer of endothelium (End), a middle layer of suben-
dothelial dense connective tissue (DCT) containing smooth muscle la rization in the normally avascu lar layers of the va lve. A node is about 60 to I 00/rnin . T he S-A node initiates an
brous A-V ring of the mitral valve, which provides the attachment site
cells (SMC), and a deeper subendocardia l layer containing Purkinje These c hanges most commonly affect the mitra l va lve (65 impulse that spreads along the ca rdiac muscle fi bers of the
for the muscle of the left atrium and the left ventricle and the cusp of
the mitral va lve. The ventricular wall consists of three layers: (1 ) en- fibers (PF). Tl1e myocardium contains cardiac muscle fibers (CMF) and to 70%) an d aortic va lve (2 0 to 25 %). T h is in fl amm a tion atria and along internoda l tracts composed of mod ified
docardium (arrowheads); (2) myocardium; and (3) epicardium. The vis- is seen on the left. x 120. ca n lead to progressive replacement of e lastic tissue by ir- cardiac m uscle fibers. T he impulse .is th en picked u p at the
ible blood vessels lie in the epicardium and are surrounded by adipose regu lar masses of co llagen fibers, causing the valve to atrioventricular (A-V) node and conducted a cross the fi-
346 C HA PTER 12 Cnrdiovnsculnr Sys tew CHAPTER 12 Cnrdiovnsculnr Systrw 34 7
brous skeleton to the ven tricles by the atriove1ttri.cular (A- cardiac muscle fi bers t hat are la rger than normal. The Specialized receptors monitor heart function empty into the blood vascula r systen'l by draining into the
V) bundle (of His). The bundle d ivides into smaller right components of t he conducting system convey the impu lse la rge veins in the base of the neck. They enter the vascular
and Left bundle branches and then into subendothelial at a rate approx imately 4 times faster than the cardi ac Specialized sensory nerve receptOrs for physiologic re- system at the junctions of the internal jugular and subcla-
branches commonly called Purkinje fibers. muscle fibers a nd are the only elements that ca n co n vey im- flexes are located in the wa lls of large blood vessels near vian veins. T he largest lymphatic vessel, dra ining most of
T he A-V bu nd le, the bu nd le branches, an d the Purkinje pulses across the fi brous skeleto n. T he conducting system th e heart. They fu nction as the bc:>dy and emptying into the veins o n the left side, is the
fibers are modified cardiac muscle cells t hat are specialized also coordinates th e co ntractions o f the atria and ventr i- thoracic duct. T he other main cha nn el is the right Lym-
Baroreceptoi'S, which sense genera l blood pressure.
to conduct impulses (Fig. 12.21 ). The nodes and A-V bun- cles. T he contraction is initiated in the atria, forcing blood phatic trunl~.
T hese receptors are located in t he carotid sinus and aor-
dle and its branches are modified ca rd iac muscle fibers that into the ventricles. A wave of contr action in the ven tricles
tic arch.
are sma ller than norma l. T he Purkinje fibers are modi fi ed then begins at t he apex o f t he heart, forcing blood from t he lymphatic capillaries are more permeable than blood
hea rt t hrou gh the aorta and p ulmo na ry trunk.
Chemoreceptors, w hich detect alterations in oxygen and
capillaries and collect excess protein-rich tissue fluid
car bon dioxide tension and in pH . These receptors a re
the carotid and a01'1ic bodies located at the bifurcation
Lymphatic capillaries are a unique part of the circ ula-
Systemic Regulation of Heart Function of the carotid arteries and in the aortic arch, respectively.
tory system that form a network of small vessels w ithin the
T he heart is innervated by bo th di visions of the autonomic T he carotid body consists of cords and irregular gro ups tissues. Because of their greater permeability, lymphatic
nervous system. The a uto nomic nerves do not initiate con- o f epit helioid cells. A rich supply of nerve fi ber s is as.wci- capillar ies a re more effec ti ve tha n blood capillaries in re-
traction of the cardiac muscle but rather regulate the heart ated w ith these cells. The neural elements are both afferen t moving protein-rich flu id from the intercell ular spaces.
rate accord ing to the bod y's immediate needs. Parasympa - a nd efferent. The st ruct ure of the aortic bodies is essen- Once the collected fluid enters t he lymphatic vessel it is
thetic fibers term inate chiefly at t he S-A an d A-V no des but tially similar to t hat of the carotid bodies. Both receptors called lymp h. Lymphatic vessels a lso serve to convey pro-
also extend into the myoca rdium. Sympa thetic fibe rs sup- fu nction in neural reflexes that adjust cardiac output and teins a nd lipi ds that a re too large to cross the fenestrations
ply the S-A and A-V nod es, extend into the myocardium, respira tory ra te. of the absorptive capillaries in the small intestine.
and a lso pass through th e epica rdium to reach t he coro - Before lymph is retu rned to t he blood, it passes through
na ry arteries t hat suppl y the hea rt. T he a utonomic fiber s lymph nodes, where it is exposed to t he cells of the im-
regul ate only the rate of impulses ema na ti ng from t he S-A '9 lYMPHATIC VESSElS mune system . T h us, the ly mp ha tic vessels serve not only as
node. T he sym pat hetic component ca uses the rate of con- an adj unct to the blood vascular system but also as an in-
traction to increase; the pa ra sym pat hetic compo nen t lymphatic vessels convey fluids from the tissues tegral compo nent of the immune system.
ca uses the ra te of co ntra ction to dec rease. to the bloodstream Lymphatic capillaries are essen tia lly tubes of endothe-
limn that, unl ike t he typical blood capillary, lack a contin-
Tn addition to blood vessels, anot her set of vessels circu- uous basa l lamina. T his incomplete basa l lam ina can be
lates fluid, called lymph, through most parts of the body. correlated with their high permeabili ty. Anchoring fila-
T hese lymphatic vessels serve as adjuncts to the blood ves- ments extend between the incomplete basal lamina and the
sels . U nli ke the blood vessels, wh ich con vey blood to an d perivascu lar coll agen. T hese filam ents may help maintain
fro m tissues, the lymphatic vessels are un idirectional, con- t he patency of t he vessels during times of increased tissue
Ischemic heart disease Is defined as the imbalance between the
veying fl uid only fro m tissues. The smallest lymphatic ves- pressure, as in inflammation .
supply and demand of the heart for oxygenated blood. The
most common cause of ischemic heart disease is atherosclero-
sels are called lymphatic capillaries. T hey are especially As lymphatic vessels become large1; the wall becomes
sis. In atherosclerosis, the lumina of t11e coronary arteries pro- nu merous in the loose con nective tissues under the epithe- thicker. T he increasing thickness is due to connective tissue
gressively narrow because of accumulation of fibrojatty intimal lium o f the skin an d mucous membranes. The lymphatic and bu ndles of smooth muscle. Lymphatic vessels possess
plaques (see Fig. 12.10). Plaques are formed by lipid deposition, capillar ies begin as "bli nd -ending" tubes in the microcap- valves that prevent backlow of the lymph, thus aiding unidi-
smooth muscle proliferation, and increased synthesis of pro- illary beds (see Fig. 12.13). Lymphatic cap.illaries con verge rectional flow. There is no centra l pump in the lymphatic sys-
teoglycans and collagen within tile Intima. Blood flow becomes into increasi ngly larger vessels, called Lymphatic vessels, tem. Lymph moves sl uggishly, d riven primarily by compres-
critical when it is reduced by 90%. A sudden occlusion of the wh ich ultima tely unite to form two main chan nels that sion of the lymphatic vessels by adjacent skeletal muscles.
FIGURE 12.21
narrowed lumen by a thrombus, or clot, released from the sur-
Photomicrograph of the ventricular wall containing the conducting
face of an atheromatous plaque precipitates an acute ischem ic
system. This photomicrograph shows a Mallory-Azan-stained section
event. Ischemic events are c11aracterized by anginal pain asso-
of the ventricular wall of a human heart. Tile upper two thirds of the
ciated with tile loss of oxygenated blood to the region of the
micrograph is occupied by the endocardium (E) containing a thick
heart supplied by the affected coronary vessel. Coronary artery
layer of Purki nj e fibers. The free luminal su rface of tile ventricle (top)
thrombosis usually precedes and precipitates a myocardia l in-
is covered by endothelium and an underlying layer of subendothelial
farct, i.e., a sudden insufficiency of blood supply that results in
connective tissue (stained blue). TI1e deep layer of endocardium con-
an area of muscle cell death. With time, a sca r forms and re-
tains the Purkinje fibers. Note the intercalated disks in tile fibers (ar-
places the damaged tissue, but the area of infarction loses con-
rows). The Purkinje fibers contain large amounts of glycogen, which
tractile function. Multiple infarctions over time can produce suf-
appear as homogeneous, pale-staining regions tllat occupy the cen-
ficient loss of cardiac function to cause death. Infarction also
ter portion of the cell surrounded by the myofibrils. The nuclei (N) are
commonly occurs in the brain, spleen, kidney, lung, intestine,
round and are larger than the nuclei of the cardiac muscle cells in the
testes, and tumors (especially of tile ovaries and uterus). The
myocardium (M). They are frequently surrounded by the ligh ter-
risk of developing atherosclerosis Increases with age, family
stained cytoplasm that represen ts the j uxtanuclear region of the cell.
history, hypertension, cigarette smoking, hypercholesterolemia,
Because of the considerable size of the Purklnje cells, the nuclei are
and diabetes.
often not included in the section. Among the Purklnje fibers course
nerves (NF) that belong to the autonomic nervous system. x 320.
C HAPTER 12 Cnrdio11o1sculnl' Sysle111 34 9
B
Figure 1, heart, atrioventricular septum, human, be seen extending from the wall of the atrium into the upper
H&E x 45; inset x 125. portion of the valve. Inset. This higher-magnification view
This micrograph of the field shows portions of the atrial of the field outlined by the rectangle (turned -90) shows
(A) and ventricular (V) walls at the level of the atrioventric- more clearly the endothelial layer of the endocardium (En)
ular septum and the root of the mitral valve (MV). Both and the dense fibrous connective tissue of the endocardium
chambers and the valve are lined with the squamous en- (DCT) and subendocardial layer. A thin layer of smooth
dothelium of the endocardium (En). Purkinje fibers (PF) of muscle (SM) appears between the more densely packed fi -
the cardiac conduction system are seen in the atrial wa ll be- brous tissue immediately subjacent to the endothelium and
tween the relatively thin subendocardial connective tissue the more loosely packed dense fibrous tissue of the suben-
(CT) and the underlying modified cardiac muscle cell s (CM) docardium. Particularl y evident are the longitudinally sec-
of the atri oventricul ar node (A VN). Some of the adipose tis- tioned Purki nje fibers (PF) of the cardiac conduction sys-
sue (AT) that forms a major component of the septum and tem . These modified cardiac muscle cells contain the same
serves to cushion the heart is seen near the lower left corner fibrillar contractile system as their sma ller counterparts in
of the i111age. Dense fibrous connecti ve tissue (DCT) that is the myocard ium, bu t the fibri ls are fewer, are more loosely
conti nuous with that of the septum and the subendocardial packed, and often surround what appear to be vacuolated ar-
layers of the atrium and ventricle extends from the root of eas. Intercalated disks (ID), typical of cardiac muscle cell
the valve into the leaflet. Thin cardiac muscle fibers can also organization, are evident in some areas.
Figure 2, Heart, atrioventricular septum, coronary (TM) is also easily disti nguished from the thinner, fibrous
KEY
A, atrium CT, connective tissue MV, mitral valve
A' , artery CV, cardiac vei n J>F, Purkinje fi bers
AT, adipose tissue DCT, dense connective tissue SM, smooth muscle
AVN, atrioventricular node En, endothelium TA, tu nica adventitia
B, blood ID, intercalated disk TM, tunica media
CA, coronary anery IEM, internal clastic membrane TI, tunica intima
CB, conduction bundle LN, lymph node V, ventricle
CM, cardiac muscle MF, muscle fibers
C H AP TE R 12 Cnrdiovascodnr Systrm 35 I
rn ....
Figure 1, aorta, human, H&E x 65.
The layers that make up the wall of the ao rta are shown
and tun ica adventitia (TA). T he tuni ca adventiti a is the out-
ermost part. It consists mainly of co nnective tissue and con-
..' \
in thi s figure. This is a longitudinal secti on throug h the e n- tains the blood vessels (vasa vaso rum) and nerves (nervi
tire thi ckness of the ar terial wall. Tluee laye rs can us ually vascularis) that s upply the arteri al wa ll.
be recognized : the tu nica intima (Tl), tunica media (TM),
Figure 2, aorta, human, H&E x 160. (Fig. l ). T he tunica inti ma consists of a li ning of endothe- 2
T he tunica intima (TI) is shown here at higher magnifi- lial ce lls that rest on a layer o f c on nective tissue. Howe ver,
cation. T he boundary between it and the tissue be low, the
tuni ca media, is not sharply defi ned. Largely because of
the endothelium is difficult to preserve in these vessels and
is freq uently lost. Both coll agenous fibe rs and elastic la mel-
lae are in the connective tissue. Smooth muscle cells are
- - -- -
-
sta ining characte ristics a nd degree of cellu lari ty, the two
tun ics are more easi ly distingui shed at low magnification also prese nt in the intima of the aorta (arro ws).
--
cle; the more distinctive feature, however, is its large amou nt
of e lastic mate rial. The elastic materi al is present not in the the deep porti on of the tunica intima (Tl). T he tunica adven- l ___.
form of fibers but as fenestrated membranes. This fi gure and titia (TA), however, essent ially lac ks these elastic lam inae.
- - -----
-
rn Figure 4, aorta, human, H&E x 160.
T his fi gure shows a hig her mag ni ficati on of the tunica
media of Figure l. Here, the elastic lame llae are unstained,
as is usually the case Ln H &E sectio ns. (In some instances,
presence is recognized by the appare nt absence of structure,
which, in turn, is d ue to the absence of sta ini ng of the elas-
tic material. T he smooth muscle cells of the med ia are
arranged in a closely wound s piral between the e lastic
--
the e lastic materi al will stain l ightly with eosin.) T he ar-
row/Jeads reveal the sites of some of the la me llae. T heir
membranes. Th is arra ngement, however, is d ifficult to rec-
og nize in sectioned material.
3
- 4
Figure 5, aorta, human, resorcin-fuchsin x 300. of the elastic lamellae. These are actuall y the fenestrations
Careful examination of the tunica media at higher mag- or openings in the elasti c me mbranes.
ni fi cation reveals what appear to be interrupti ons of some
Figure 6, aorta, human, H&E x 160. though relatively few in number. T he ce lls of the ad venti tia,
T he outermost layer of the aorta, the tunica adventitia , is re presented by the nuclei seen in the ad ve ntitia, are fi bro-
show n he re. T he tuni ca ad ventitia (TA) consists mostly of blasts. Occasionall y, gang lio n cells are present, as well as
collagenous fi bers that course in longitudina l spirals. (Their
course, like that of the smooth muscle fibers, however, is
unrecogni zable in tissue secti o ns.) T here are no e lastic
so me scattered smooth musc le cells. T he gmrglio n cells,
when present, are quite co nspic uo us, whereas the smooth
muscle cells may be overlooked.
- TA
lame llae in the ad ventitia, but e lastic fibers are present,
- - 6
KEY
TA, tunica ad ventitia TM, tunica media arrowheads (Fig. 4), un stained elastic
Tl, tunica intima arrows (Fig. 2), smooth muscle cell lamellae
350
CHAPTER 12 Cardiovascular Sy sltm 3 53
the tunica adven titi a. M uscular arteries, or arteries of medium caliber, constitute the majority of the named arteries in the body.
Veins usuall y accompany arteries as they travel in the loose connective tissue. The veins have the same three layers in their
N"y , ' .
walls, but the tu nica med ia is thinner than in the accompanyi ng artery, a nd the tuni ca adventitia is the predominant layer in the
~ I
wall. The veins usuall y have the same name as the artery they accompany. I "" '
~
@
border of the latter is obscured by its ble nding almost im-
x365. perce ptibly wi th loose connecti ve tissue separating it from
In th is photomicrograph, the lumen of the artery is at the the tu nica ad ventitia of the accompanying vei n (TA). T he
right; the lumen of the vein is at the left. T he arterial e n- arterial tunica adventitia is identified by the elastic fibers
dothe lium (AEn) is clearly seen on the corrugated surface (EF) in it. In this specimen, onl y a few small smooth mus-
of the tunica intima, whe reas the venous e ndothelium cle cells ( SSm) are visible in the tunica media of the vein.
(VEn) is somewhat harder to disting ui sh. The internal e las- T he tunica adventitia (TA) is much thicker than the tuni ca
tic lam in a (IEL) is seen as a thin clear zone immed iately be - media and is c haracteri zed by a pale ex tracellular compart-
neath the endothelial layer, separating the tunica inti ma ment contai ning a small number of cell nuclei (N), most of
from the underlying smooth m uscle (SM) of the tun ica me- which appear to be those of fibroblasts, and a sparsity of
d ia (TM ). It is ev ident here that the tunica media is almost elastic fibers.
twice as thkk as the tunica ad ventitia (TA ')even if the outer
@
Figure 2, muscular artery, monkey, H&E x 545. mos t luminal layer of smooth muscle cells ( SM) of the thick
T his is a higher-magnification mi crograph of the porti o n tunica medi a (TM). T he thinner tun ica adventitia (TA ') is
of the fig ure above o utlined by the rectangle turned 90. At recognized by the presence of numerous elastic fibers (EF)
thi s magnification, it is evident that the flatte ned e ndotheli al separati ng collagen bundles (C). Nuclei (N) in thi s layer are
cells (EN) fo llow the contours of the refracti le, corrugated those of fibroblasts.
internal e lastic lami na (I EL), which rests d irectl y o n the
KEY
AEn, arterial endothelium N, nuclei TA, tun ica adventitia of accompanying vein
C, collagen bundles SM, s mooth muscle T I , tunica intima TA'I
-._ N~
EF, e lastic fibers SSm, small smooth muscle TM, tunica media
EN, endothelial cells TA ', tunica adventi tia of artery VEn , venous endothe lium 2
IEL, interna l elastic lamina
352
C H APTER 1 2 Cardiovascular Syslt w 3 55
Figure 1, arteriole, venule, and small nerve, hu- tion of fl ow. Thus, the ir nucle i are seen here as c ross-sec-
man, H&E x600. tioned profiles. The arteriole on the right is a very small ar-
Thi s mk rog raph shows two cross-sectioned arterio les teriole, having o nly a single layer of smooth muscle. Again,
(A ) and a ven ule (V). The arteriole on the left is identified the muscle cell nuclei are seen in longitudinal profile. The
as a large arte riole, based o n the presence of two di screte endotheli al cell nucle i appear as the small round profiles at
layers of smooth muscle cells that form the tunica medi a of the lumi nal surface. A venule is seen in proximity to the
the vessel. The nuclei of the muscle cells appear in longitu- larger arteriole, and a cross secti on of peripheral nerve (N)
dinal profi le as a result of the c ircumferential arrangement is seen in prox imity to the smaller arteriole. Compare the
of the cells. The endothelial cell nuclei of the ve ssel appear wall of the venule, consisting o nly of endothelium and a
as small round profiles s urro unding the lumen. These ce lls thin layer of connective tissue, with the arterioles. Also,
are elongate and oriented w ith their long axis in the direc- note the relati vely large lumen of the venule.
W
Figure 2, arteriole, human, H&E x 350. After the arteriole makes an acute turn (segment numbered
This mi crograph shows a lo1.1gitudinal section of an arte- 2), the vessel wall is cut to re veal the lumen. Here, the
ri ole. Because of its twisting path throug h the secti o n, its smooth muscle nuclei appear as ro und profiles and the nu-
wall has been cut such that the single layer of muscle ce lls clei of the endothelia l cells lining the lumen appear in lon-
of the tunica media is seen in d ifferent planes along its gitudinal profile. In the segment numbered 3, the vessel
length. In the segment numbered 1, at the left, the vessel wall is again only g razed. In the segment numbered 4, the
wall has been cut tangentially. Thus, the vessel lume n is not cut is deeper, again showing the lume n and some of the en-
inc luded in the plane of section, but the smooth muscle cell dothelial ce lls in face view ( an vwheads). The structure be-
nuclei of the tunica medi a are seen in longitudinal profile. low the vessel is a Pacinian corpuscle (P). ,
Figure 3, lymphatic vessel, human, H&E x 175. within the vessel. It is formed of a miniscule layer of con-
The lymphatic vessel shown in this figure shows a re- nective ti ssue that is covered on both sides by endothelium.
gion whe re the vessel is making a U-shaped turn in the The arrows indicate nuclei that are just barely visible at this
plane of the section, thus di sappearing at the to p and bot- magnificatio n; most of them belong to endothelial cells.
tom of the mi crog raph. The call of the vessel consists of an Typically, the lumen contains prec ipitate d lymph materi al
endotheli al lining and a small amount of connective ti ssue, ( L); sometimes, lymphocytes may be present. Adj acent to
with one being indistingui shable from the other. A val ve the vessel, on the right, is adipose ti ssue (A T) and on the up-
( Val), whi ch is characteri sti c of lymphatic vessels, is seen per left is dense connective tiss ue (D CT).
Figure 4, lymphatic vessel, human, Mallory x375. connective tissue that is present outside of the endothelium
The lymphatic vessel shown here is contained w ithin blends w ith the de nse connective tissue beyond the wall of
dense con nective tissue ( DCT). The lume n is irregula r, ap- the vessel. A venule (V) is a lso present; it can readi ly be dis-
pearing relati vely narrow below the valve (Val). A few en- tingui shed from the lymphatic vessel by the presence of red
dothelia l cell nucle i are ev ident (arrows). A thin layer of blood cells in the lumen.
KEY
A, arteriole L, lymph materi al Val, valve
Ad, adipocyte N, nerve
P, Pacinian corpuscle
arrowheads, endothelial cell s
arrows, endothe lial cell nuclei
..
AT, ad ipose tissue 3 ~
DCT, dense connective tissue V, venu le I '-,.
354
within an organism) and "nonself' (foreign molecu les, i.e.,
those not normally present).
\1 LYMPHATIC CELLS
An antigen is any substance that can induce a specific immune
Overview
response Cells of the immune system include lymphocytes and various
supporting cells
356 357
358 CHAPTER 1 3 C H A PTER 13 Ly111(>hnlic Sy ste111 359
p orting cells include 1'eticulm cells, macrophages, follicular directl y to the tissues, especia ll y into the connective tissue
TAB LE 13.1. Most Common CD Markers Used in Clinical Practice
dendritic cells, Langerhans' cells, and epithelio1eticular cells. that underli es the linu1g epith elium of t he respiratory, gas-
trointestina l, and urogenital tracts as well as into the in- Marker Main Cellular Expression Function/ Identity Molecular Weight (kDa)
Supporting cells in the lymphatic organs are organized into tercellular spaces of these epithelia. T cells in the midstage of development Developmental marker forT cells and 49
COl
loose meshworks Langerhans' cells cit the skin
Functionally, three types of lymphocytes are present in the
C02 T cells Clinical marker forT cells 50
body: T lymphocytes, B lymphocytes, and NK cells
In lymph nodules, lymph nodes, an d the spleen, reticu- CD3 T cells Forms complex with T cell receptor (TCR) 100
lar cells and the reticulm- fibers produced by these cells The fun ction a l classification of lymphocytes is inde- CD4 Helper T cells Interacts with MH C II m olecules 56
form ela borate meshworks. Lymphocytes, macropbages, pendent of t heir morphologic (size) ch aracteristics. Func- CDS T cells, some 8 cells High levels in chronic lymphocytic leukemia 67
follic ular dendritic ceJis a nd other cells o f th e immune sys- ti onall y, three t ypes of lymphocy tes are recognized: CD7 T cells Useful clinical marker forT cell leukemia 40
tem reside in these mesh works a nd in the loose connective
T lymphocytes (T cells) are n am ed for the th ymus, CD8 Cytotoxic T cells Interacts with MHC I molecules 34
tissue of the body; Langerha n s' cells are fo und only in the
wh er e th ey differentiate. They h ave a long li fes pan and CD9 8 cells Facilitates aggregation of platelets 24
middle layers of epidermis. At these sites, they carry out
are involved in cell-mediated immunity. They acco unt CO l O PreB cells Common marker for acute lymphoblastic 100
their mission of surveilla nce a nd defense. In the thymus,
for 60 to 80 % of circ ulating lymphocytes. T cells ex- leukemia
e pithelioreticular cells fo rm t he structural meshwork
press C D2, CD3, and CD7 markers; howeve1~ they a re CD16 Granulocytes, monocytes, NK cells Fe receptor for aggregated lgG, mediates phago- 27
w ithi n the tissue. Despite their name, these cells neither
cytosls, clinical marker for NK cells
produce nor are rela ted to reticular fibers. subclassified accordin g to the presen ce or a bsence of two
o ther important surface ma rkers, CD4 a nd CD 8. T cells CD19 B cells Clinical marker for all stages of 8 cell develop 90
ment
Different types of cells in lymphatic tissue are identified by that also express CD4 markers are called helper CD4+ T
CD20 B cells Marker for late stage of B cell development 37
specific cluster of differentiation (CD) markers on their surface lymphocytes. T cells that also express C D 8 markers are
CD21 B cells Receptor for C3d complement protein and for 145
called cytotoxic CDS+ T lymphocytes.
Epstein-Barr virus
Different lymp hatic and hematopoietic tissue cells pos- B lymphocytes (B cells) are so named because they were
CD22 B cells Participates in B cell adhesion 140
sess unique cell surface molecules. These specific markers, first recognized as a separate population in the bursa of
CD24 8 cells Expressed in late stage of B cell differentiation 41
called cluster of differentiation (CD) molecules, are d esig- Fab ricius in birds (page 361) or bursa-equivalent orga ns
such as bone marrow an d GALT in mammals. They have CD34 Pluripotential stem cells (PPSCs) in bone Clinical marker for PPSCs and ligand for CD62L 120
nated by numbers accordin g to an internationa l system that marrow
relates them to a ntigens expressed at different stages of variable lifespa ns a nd are involved in the production and
CD35 8 cells, monocytes Promotes phagocytosis of complement-coated 250
their differentiation. CD mo lecules can be visualized by un- secretion of the va rious circulating antibodies, also called
particles, binds C36 and C46 complement
muno histoche mical metho ds using mo nocl ona l a ntibod ies immunoglobulins, the immune proteins associa ted with protein
and are useful in identifying sp ecific subtypes of lymphatic humoral immunity (Fig. 13 .2 a nd Table 13.2). B cells ac- 45
CD38 Activated T cells Marker forT cell activation
or hematopoietic cells. Some CD markers are expressed by count for 20 to 30% of the circulating lym phocytes. In
CD40 B cells Active in proliferating 8 cells, receptor for 48
a cell line throughout its entire life; others are expressed addition to secretu1g circula ting immunoglobulu1s, B cells CD40L
o nly during one ph ase of differenti atio n or during cell acti- express immunoglo bulin M (IgM) and immunoglo bulin
CD40L Activated CD4 + T cells Facilitates interaction between T and B cells, 39
vation . Table 13.1 lists the most clinically useful ma rkers . D (IgD ) as well as the m ajor histocompatibility complex ligand for CD40
IT (MH C II) molecules on t he cell surface. Their CD CD45 All l1uman leukocytes Leukocyte common antigen 220
markers are C D9, CD19, CD20, and C D24.
CD4 5RA Suppressor/cytotoxic CD8 ~ T cells Facilitates TCR signaling 205
Lymphocytes NK cells~ which devel op from the same precursor cell as B
CD 56 Nl< cel ls Clinical marker for NK cells, isoform of neural 135
and T cells, are named for their abi lity to kill certain types ad l1esion molecules (NCAM)
Circulating lymphocytes are the chief cellular constituent of of transforrned cells. They constitute abou t 5 to 1.0% of
CD62L Leukocytes Represent selectins, leukocyte adhesion m ole- 150
lymphatic tissue circulatin g lym phocytes. Dming their development, they cules
are genetically programmed to recognize transformed cells CD94 NK cells Clinical marker for NK cells 43
To understa nd the function of lymphocytes, o ne must re- (i .e., cells infected with a virus or tumor cells). Fo llowing
a li z.e that m ost lymphocytes (approximately 70%) in blood recognition of a transformed cell, th ey release pe1forins
or lymph represent a circulating pool of immunocornpetent a nd fragmentins, substances that create channels in the
cells. These cells pa rti cipate in a cycle during which they cell's p lasma membrane and cytoplasm, which u1duces phatic organs. Lymphocytes differentiate into immuno- organize a round retic ular cells and their reticular fibe rs to
exit the syste mic circulatio n to enter the lympha tic tiss ue. them to self-destruct (a process known as apoptosis) a nd co mpetent cells in these organs. Initially, lymphocytes are fo rm the adult effector lymphatic tissues a nd organs, i.e.,
Wh ile there, they a re res ponsible for immunologic su rveil- lyse. Their specific markers include C D1 6, CD 56, a nd gen e tical ly prog ramm ed to recogn ize a single a ntigen out lymphatic n odules, lymph nodes, tonsi ls, a nd spleen.
la nce of surro unding tiss ues. T he cells then return to the CD94. of virtuall y an infi ni te number of possible antigens, a Within these secondary or jJeripherallymphatic organs, T
system.ic circulation. This population o f cells is represented process called antigen-independent proliferation and dif- an d B lymph ocytes undergo antigen-dependent activation
mainly by long-li ved, mature lymphocytes (mainly T cells). LYMPHOCYTE DEVELOPMENT ferentiation. These im m unocom petent cells the n enter the into effector lymphocytes and memory cells.
Mature lymphocytes have develo ped the capacity to recog- AND DIFFERENTIATION blood or lymp h a nd a re transported throughout the body,
nize a nd respond to fo reign antigens and are in transit from w he re they are dispersed in the connec tive tissu e.
one site of lymphatic tissue to a nothe~:. Lymphocytes undergo antigen-independent differentiation in IMMUNE RESPONSES TO ANTIGENS
The remaining 30 % of lymphocytes in the blood vessels the primary lymphatic organs Lymphocytes undergo antigen-dependent activation in the
do not circ ul a te between the lymph a tic tissu es a nd the sys- secondary lymphatic organs Inflammation is the initial response to an antigen
tem ic circulation. This population comp ri ses mainly sho rt- ln humans a nd othe r m amma ls, the bo n e marrow a nd
li ved , imma ture cells or activated cell s destined for a spe- GALT (together called the bursa-equivalent 01'gan) a nd Immunocompetent lymphocytes (together w it h plasm a The initial r eaction of the body to in vasion by a n a nti gen,
cific tiss ue. These cells leave the capillaries a nd migra te th e thymus have been identified as primary or centrallym- cells derived rom B lym phocytes and with macrophages) ei the r a foreign molec ule or a pathogenic orga nism, is the
3 6Q CHAPTER 1 3 Lym ]J !J~ ti c Sys lt'lll CHA PTER 1 3 Lym]>lmtic Sys tem 36 I
lgD 185 0.03 <1 B cells Acts as an antigen receptor (together with antige n (e.g., a ntigen a ssociated with path ogenic m i-
lgM) on the surface of mature B lympho cr oorgan isms, tissue tra nsp lants, or toxins), a specific To understa nd how the specific imm une responses (hu-
cytes (on ly traces in serum) immune response to the an tigen is generated. mo ral and cell-medi ated responses) are initi ated, one must
lgE 190 0.0003 <1 Mast cells, Stimulates mast cells to release l1istamine, A primary immune response refers to the body's first grasp the centra l role played by the helper and cytotoxic T
basopll ils 11eparin, leukotrienes, SRSAc, and enco unter with an antige n. This r esponse is character- lymphocytes. H elper T a nd cytotoxic lymphocytes act as
eosinopllil chemotactic factor of anaphy
laxis; is responsible for anaphylactic hyper- ized by a lag peri od o f severa l days before antibodies the immune system "patrols." Both kinds of lymphocytes
sensitivity reactions; increased levels in (mostly JgM) or speci fic lymphocytes directed aga in st have a T cell receptor (TCR), a transmemb rane protein
parasitic infections the inva ding antigen can be detected in the blood. Th e whose ex posed portion is on the T cell membrane in close
initi a l response to an antigen is initia ted by only one or proximity to the CD3 marker (Fig. 13.3). T he TCR r ecog-
tgM found in serum as a pentameric molecule. nizes antigen o nl y w hen it is attached to "identification
a few B lymphocytes tbat have been genetically pro-
"lgA found in serum as dimeric molecule.
'Slow-reacting substance of anapllylaxis. gra mmed to respond to that specific antigen . Following molecules, " the MHC molecules. Tn addition, helper T
361 CHAPTER 1 3 C HAPTER 1 3 Lylllf>lmlic System 363
~2 microglobulin
FIGURE 13.3
Schematic diagram of t he molecular struc-
ture of the CD3-TCR complex. Tile CD3 mol- c
ecule consists of five different polypeptide
chains with molecular weights ranging from
16 to 28 kDa. This molecule is closely associ-
ated with the T cell receptor (TCR), which has
two polypeptide chains (ex and [3). The T cell
may be activated followin g the interaction of
the TCR witl1 antigen displayed on the surface c
c c of a MHC molecule. This interaction transmits
c
I the signals to tile interior of the cell through
CD3 TCR the CD3 molecule. This signal stimulates tile T MHCII
cell to secrete interleukins, which in turn stim-
CYTOPLASM OF T CELL ulate T cells to divide and differentiate. FIGURE 13.4
Schematic diagram of the molecular structure of MHC I and MHC II valently attached {32 microglobulin polypeptide (12 kDa). The {32 mi-
m olecules. The MHC I molecule is a glycoprotein that is expressed on croglobulin promotes maturation ofT cells and acts as a c11emotactic
the surface of all nucleated cells of the body and on platelets. MHC I factor. The MHC II molecule is also a glycoprotein but is expressed
lymphocytes can only recognize an antigen when it is "pre- are products of a "supergene" located on chromosome 6
molecules present endogenously synthesized peptides for recognition only on a restricted population of cells known as antigen-presenting
sented" to them by cells called antigen-presenting cells in hum ans, known as the major histocompatability gene
by cytotoxic CDS+ T lymphocytes. Therefore, tile MHC I molecule acts cells (APCs). MHC II molecules present exogenous (foreign) peptides
(APCs). Cytotoxic T lym phocytes can only recognize an ti- complex. The expression of this ge ne complex p roduces as the target for the elimination of abnormal host cells producing ab- to helper CD4 + T lymphocytes. They consist of two chains: an a chain
gen o n other body cells, such as cells transformed by can- molec ules that a re specific not only to the indi vidual cell normal proteins (e.g., cells infected by an intracellular agent, sucl1 as (33 kDa} and a {3 chain (29 kDa), each of which possesses oligosac-
cer or infected with a virus. that pr od uces them , but also to the tissue type and degree a virus, or cells that have been transformed, such as cancer cells). d1aride groups.
W hen a helper T lymphocyte recogn izes an antigen bound of cellul ar differentia tion . M HC I consists of an a heavy chain (45 kDa) and a smaller, nonco-
to a ~ u-IC molecule, the TCR attaches to the antigen- MHC MHC I is expressed on the surface of all nucleated cells
complex. The binding of the TCR to the antigen-1\llHC com- and platelets . MHC I molecules act as a target to allow the
plex then triggers the helper T lymphocyte to release inun une elimination of abno rm a l host cells (e.g., virus-infected or
chemicals, or cytokines, immune substances (proteins) that transformed cancer cells). MHC I molecules perform this the class of the MHC molecule engaged . This restricted The humoral immune response: Activated B lymphocytes
are biologic modulators of immune responses. The specific functio n by displaying on their surface all of the jJeptides presentation of foreign antigens by MHC molecules to ei- differentiate into plasma cells that produce antibodies or into B
cytokines produced by helper CD4 T l ymphocytes are that are actively synthesized by the cell. Therefore, all en- ther cyto toxic or helper T .lymphocytes .is a key component memory cells
called inted eukins. Jnterleuki.ns stimu late other T cells, B dogenous "self" peptides are displayed on the surface of of im1uune sur veillance.
cells, and NK cells to differentiate and proliferate. every cell in the body, but viral or cancer-specific peptides T he MHC 1 molecule wit h the peptide a nt igen dis- Each B lymphocyte reacts only with a single antigen o r
W hen a cytotoxic T lymphocyte recognizes a n anti- are displayed only on the surface of infec ted o r trans- played o n its surface interacts o nl y with the T CR and type of an tigenic site that it has been genetically pro-
gen-MH C complex and the T CR attaches to it, the cyto- formed cells (fig. 13.4). CDS+ mo lecule expressed on cytotoxic CDS + T lym pho- grammed to recognize. The reacti o n o f a B lymphocyte
toxic T lymphocyte also releases cytokines that stimulate MHC II is limited in its distributi on (see Fig. 13.4). It is cytes; these cells are therefor e described as MHC I re- with a T CR-MH C II-antigen comp lex activates the cell .
the cell to proliferate. These new cytotoxic T cells then expressed on the surface of a ll APCs and is critical in im - stricted. This interacti on allows cyto toxic T lymp hocytes Details of B cell acti va tio n ar e illustrated in Fig. 13.6. Ac-
seek out and destroy the abnorma l host cells. mune interactions. The MHC ll molecules f7resent par- to recognize infected o r transform ed ta rget cells (Fig. tivated B lymphocytes ar e transformed into immunoblasts
tially digested, endocytosed foreign peptides to helper l3 .5a) . (plasmablasts) that proliferate and then dillerentiate into
The two classes of MHC molecules display peptides on the CD4 + T lymphocytes . In ~ Jntrast, the M H C II molecule with the peptide anti -
Plasma cells, w hich synthesize a nd secrete a specific an-
surface of cells gen d1splayed on its surface interacts onl y with the T CR
tibod y
CDS+ T lymphocytes are MHC I restricted, and CD4 + T and CD4 molecule expressed on helper CD4+ T lympho-
Memory B cells, whjch respond more quickly to the next
M H C molecules displa y small fragments of digested lymphocytes are MHC II restricted cytes (Fig. 13 .5b); these .cells a re therefo re described as
encou nter with the same antigen
fore ign proteins on the surface of cells. These proteins MHC II rest1icted. M I-TC II molecules are fo und o n APCs,
bind to MHC molecules inside the cell and are then trans- MHC molecules are recognized by helper CD4+ T lym- such as macr ophages, whose main function is to present The specific antibody produced by the plasma cell binds
ported to the cell surface. MHC I a nd MHC II m olecules phocytes or cyto toxic CDS+ lymphocytes, dependi ng on antigen toT lymphocytes. to the stimulating antigen, forming an antigen-antibody
364 CHAPTER 1 3 Lywplwtic Syslew C HAPTER 13 Lyw pbntic Syslrw 36 5
f ragmentins
Fe receptors
0
oo 0
Q ())
\); Ql "'
o~o
0
0 00'{/n
ot
Q
O <( ' o 1 0
IFN-y receptor
0 Human immunodeficiency virus (HIV) is a RNA retrovirus; it con- ducing their number. The helper CD4 + T cell count is used as a
tains an enzyme called reverse transcriptase. HIV is the virus that clinical indicator of the progress of HIV infection. Infected individ-
causes acquired immunodeficiency syndrome (AIDS). HIV has an uals eventually become incapable of generating an immune re-
incubation period that may be as long as 11 years before symp- sponse against bacterial or viral infections. They usually die of sec-
toms of clinical AIDS occur. The great majority of HIV-infected in- ondary infections caused by opportu nistic microorganisms or of
dividuals eventually develop AIDS. HIV gai ns entry to helper T ma lignancies.
cells by binding to CD4 molecules. The virus then injects its own Anti-HIV treatment Is the major strategy against HIV infection
genetic information into the cell cytoplasm (Fig. 13.9 ). This in- and AIDS. Currently, the most effective is multiple drug therapy
jected genetic information consists of single-stranded RNA. The vi- known as highly active antlretroviral therapy (HAART), which uses
ral RNA is incorporated into the infected T cell genome through re- a combination of several chemotherapeutic agents. These include
0 verse transcription of the RNA into DNA. The transcribed DNA is nucleoside and nonnucleoside reverse transcriptase inhibitors and
then incorporated into the host DNA. The T cell then makes copies HIV protease inhibitors. HAART offers several advantages over
CD8 of the virus, which are extruded from the T cell through exocyto- monotherapy such as synergistic dosage effects and reduced side
sis. These HIV particles then infect other helper T cells, greatly re- effects as well as reduced drug resistance.
reverse
transciptase
macrophage
FIGURE 13.8
Schematic diagram of T cell activation leading to elimination of a also possesses IL-2 receptors. IL-2 binding to these receptors stimu-
virus-infected host cell. The TCR-CD3 complex on a helper CD4+ T lates the cell to divide and differentiate. The newly formed cytotoxic
lymphocyte recognizes foreign antigen displayed on a MHC II mole- COB+ T lymphocytes migrate to the site of viral infection. There the
cule on the surface of a macrophage. This recognition triggers a rapid TCRs recognize the viral antigens displayed on the surface of MHC I
response from B lymphocytes and release of interleukin-2 (I L-2). The molecules of infected cells. After successfully recognizing these non-
same macrophage also expresses MHC I molecules (like every other self" proteins, the cytotoxic COB+T lymphocytes secrete perforins and
cell in the body) that interact with the appropriate TCR on the surface fragmentins, ki lling the infected cells.
of a cytotoxic COB+ T lymphocyte. The cytotoxic COB+ T lymphocyte
Cytokin es ar e soluble p o lypeptide substances, synthe- APCs interact with helper CD41 T lymphocytes to facilitate
sized ma inl y by activated T lymphocytes, wh ich a ffect immune responses
the functi o n of o ther im mune system cells. These sub- FIGURE 13.9
stances a lso stim ula te the ac tivity of mon ocytes a nd Schematic diagram of the interaction between HIV and the viral entry into the cell. These proteins interact with CD4 mole-
The interacti on between most antigens and the antibodies
helper CD4+ T cell. Human immunodefi ciency virus (HIV) is the cules. The injected genetic Information is incorporated into the
macrophages in cell-medi ated immun ity. Included on the sur face of B cells is insufficient to stimulate B cell pro-
RNA virus that causes AIDS. It contains reverse transcriptase. HIV host cell genome through reverse transcription of RNA into DNA.
a mo ng these substa nces are chemo tacti c and mitoge nic liferati on, differentiation, and secretion of antibodies. Fo r B gains entry into the helper CD4+ T lymphocyte by binding to the This DNA containing viral information is then incorporated into
agents, m ig ratio n inhibito ry fac tors, interfer o n, a nd cell stimulatio n to occur, the antigen must be broken into CD4 molecule and injecting its genetic information into the cell cy- host DNA.
interleuki ns. small peptides and presented in co njuncti on with M H C II toplasm. Accessory cell surface molecules such as gp 120 assist in
Interleukins are synthesized m ainly by helper CD4 + T molecules by APCs to the appropriate hel per CD4+ T lym-
lymp hocytes and to a lesser extent by mo nocytes, macro- phocytes. Most APCs belong to the mononuclear phagocy-
phages, and end othelia l cells. ln terl eukins prom ote growth totic system (MPS) (described in Chapter 5, page 144 ). APCs
an d differentiation of T cells, B cells, and hemato poietic include macrophages, perisinusoidal macrophages (Kupffer To present an antigen to a helper T cell, the APC first partment of the APC, th e peptides bind to M H C II mole-
cells. Presentl y, mo re than 17 interle ukins have been iden- cells) of the liver, Langerhans' cells in the epidermis, and processes the antigen intracellula rl y and then d isplays anti- cules. The M H C II-antigen co mplex is then transloca ted
tified . Interleukin-2 was the first cytokine to be disco vered reticular dendritic cells of spleen and lymph nodes. Two gen peptides on its surface. Antigen processing begins to the plasma membra ne of the APC and displayed o n the
and characterized. The major functions of kn own inter- APCs that do not belo ng to the MPS are B lymphocytes and w hen the APC end ocytoses the antigen and brea ks it down cell surface (Fig. 13.J 0 ).
leukins are summar ized in Ta ble 13.3. type II and type III epithefioreticular cells of the thymus. into 8 to 10 am ino ac id pepticles. In the endosom al com-
368 C HAP TE R 13 Lymf>lurlic Syslrm CHA PTER 13 Lymplwlic Syslrm 369
MHC II
TABLE 13.3. Characteristics of lnterleukins with invariant chain
exogenous Ag
Name Symbol Source Major Functions MHCI
with endogenous peptide MHC II
lnterleukin-1 IL-l Neutrophils, monocytes, Stimulates various cells in inflammatory response; induces fever; facilitates with processed Ag
macrophages, endothelial cells proliferation of CD4+ T cells and proliferation and differentiation of B cells
lnterleukin-2 IL-2 CD4+ T cells Induces proliferation and differentiation of CD4+ T cells and to a lesser de-
gree cos+ T cells, B cells, and NK cells
lnterleukin-3 IL-3 CD4 ' T cells Induces proliferation of hematopoietic stem cells
lnterleukin-4 IL-4 CD4 + T cells, mast cells Induces proliferation and differentiation of B cells, CD4 + T cells; activates
macro phages
lnterleukin-5 IL-5 CD4 ' T cells Induces proliferation and differentiation of eosinophils; stimulates B cells
to secrete lgA
lnterleukln-6 IL-6 Endothelial cells, neutrophils, Stimulates differentiation of hematopoietic cells; induces growth of acti-
macrophages, T cells vated B cells
lnterleukln-7 IL-7 Adventitial cells of bone mar- Stimulates growth and differentiation of progenitor B and T cells
row
lnterleukin-8 IL-8 Macrophages, endothelial cells Acts as a chemotactic factor on T lymphocytes and neutrophils
lnterleukin-9 IL-9 CD4 4 T cells Facilitates growth of CD4 + T cell (but not COB ' T cells); stimulates growtll
of hematopoietic cells
lnterleukin-10 IL-10 Macrophages, T cells Acts on T cells as a cytokine synthesis inhibitory factor
lnterleukin-1 1 IL-11 Macrophages Facilitates growth of hematopoietic cells, mainly megakaryocytes
lnterleukin-12 IL-12 T cells Stimulates growth of NK cells, CD4 T cells, and CD8 4 T cells
lnterleukin-13 IL-13 T cells Modulates B cell responses and promotes lgE synthesis
lnterleukin-14 IL-14 T cells, follicular dendritic cells Induces production of B memory cells
In terleu kin-15 IL-15 T cells Induces proliferation and differentiation of cos+ T cells
lnterleukin-16 IL-16 T cells Activates migration of COB ' T cells, monocytes, and eosinophils
lnterleukin-17 IL-17 Memory CD4 + T cells Stimulates endothelial cells and fibroblasts to secrete cytokines
In addition to acting as APCs, macrophages perform other Activated macrophages destroy phagocytosed bacteria and
crucial functions in the immune response foreign antigens FIGURE 13.10
Schematic diagram of processing pathways for MHC I and MHC 11 binding side. At this point the MHC II molecule and the invariant
synthesis and antigen presentation. During the processing and pres- chain are secreted to the cell surface {blue pathway). After a brief stay
In add ition to presenting antigens to both T and B lym- Macrophages also play a vita l ro le in sequestering and re-
entation of cytoplasmic antigen (Ag) for MHC I molecules (red path- on the cell surface, the MHC II molecule and invariant chain are en-
phocytes, macro phages have other importa nt, a lthough moving foreign materia ls and organisms that either do not
way), cytoplasmic protein antigens are degraded by protease into 8 docytosed, and in an early endosome, t he invariant chain Is de-
nonspeci fic, functio ns in the immune response: provoke an inu11 une response or are ingested but not di- to 10 amino acid fragments, w hich then enter the rER. In the rER, graded. The foreign (exogenous) antigen is endocytosed and partially
gested. T hese incl ude both organic and inorgan ic pa rticulate newly synthesized a chains of MHC I molecules interact with bot11 the digested by proteolytic degradation in endosomes (w/1/te pathway).
They endocytose a nd pa rtially degrade both protein a nd
materials (e.g., ca rbon particles), pigment (e.g., from tat- processed antigen and {32 microglobulin ({3;vt) and form a stable com- The MHC II molecule can now bind the processed foreign antigen
polysaccharide antigens befo re they present th em in con-
toos), cellulose, an d asbestos, as well as tuberculosis and lep- plex. This complex leaves the rER via the typical secretory pathway and return with it to the cell surface. On the cell surface, the anti-
junction with MHC II molecules to helper CD4 ' T lym-
rosy bacilli and the organism s that ca use ma laria and other through the Golgi apparatus. The antigen- MHC I complex is dis gen- MHC II complex Is recognized by helper CD4+ T lymphocytes,
ph ocytes.
diseases. In these instances, macrophages o ften fuse to form played on the cell surface, where it is available for recognition by cy- which initiates the immune response. If the MHC 11 molecule fails to
They diges t pathogenic microorganisms thro ugh lysoso- totoxic cos+T lymphocytes. MHC II molecules are assembled in the capture the antigen, It will be degraded in the lysosomal compart-
multin ucleate, foreign bod y gian t cells called Langhans' gi-
mal actio n in combination w ith the helper CD4+ T lym- rER and then bind to an invariant chain, which blocks the antigen ment (green pathway).
ant cells, w hich isolate these pathogens from the body.
phocytes.
T hey secrete multiple cytokines incl uding lym phokines,
complemen t compo nents, a nd interleukins, as wel l as
acid hydrolases, p ro teases, a nd lipases.
'I LYMPHATIC TISSUES AND ORGANS
Followi ng contact wi th an an ti gen, macrop hages un - Lymphatic Vessels the epithelium of skin and mucous membra nes. These ves- As lymph circulates through the lymphatic vessels, it
dergo an activa tio n process characteri zed by multi ple func- sels remove substances and fluid from the extracell ular passes throug h lymph nodes. Wi th in the lymph nodes, for-
tional and morpho logic changes. T he macrophage in- Lymphatic vessels are the route by which cells and large spaces of the cmm ective tissues, thus producing lymph. Be- eign su bstances (antigens) con veyed in the lymph are
creases in size, as do the num ber of lysosomes and molecules pass from the tissue spaces back to the blood cause the wa lls of the lymphatic capillari es are mo re per- trap ped b y the fo llicular dendritic cells and concentrated.
cytoplasmic vacuoles. The activated macrop hage beco mes meab le than the walls of blood capillaries, large mo lecules, These APCs process the a ntigens and present them to lym-
avidl y phagocytotic w ith a grea ter a bil ity to lyse ingested Lymphatic vessels begin as networks of blind capillaries includ ing antigens and cells, ga in entry more readjly into phocytes, which leads to an immune response that elimi-
pathogenic microorganisms (Fig. 13.11). in loose connective tiss ue. They are most numero us beneath the lymphatic capillaries than into blood ca pillaries. nates the antigens from the body.
3 70 CHAPTER 13 CHA PTER 13 / Lympl)(JticSysttm 371
through the walls of postcapillary (high endothelial) A germinal center located in the central region of the
venules (Fig. 13.12.). BandT cells migrate to and popu- nodule (Fig. 13.15), which in histologic sections appears
late different regions within the lymph node. Some lym- lightly stained. The ger mina l center develops w hen a
phocytes pass through th e substance of the node and leave lymphocyte th at has recognized an antigen returns to a
via the efferent lymphatic vessels, which lead to the right primary nod ule and undergoes proliferation. The lighter
lymphatic trunk or to the thoracic duct. In turn, both of staining is due to the large lymphocytes (lymphoblasts
cg
\,. these channels empty into the blood circulatio n at the junc- and plasmablasts) that it contains. These lym phocytes
tions of the internal jugular and subclavian veins at the have large amou nts of dispersed euchromatin in their
(? D ~
otfc o base of the neck. The lymphocytes are conveyed to and nuclei rather than the dense heterochromatin of small
QP~ col?0 from the vario us lymphatic tissues via th e blood vessels.
IL-2
8 ~~a Nodules
A ma11tle zone or corona, which represents an o uter ri ng tions of nodules are found m specific locations. These ules, tonsi ls do not possess afferent ly mphatic vessels;
of small lymphocytes that encircles the germinal center. include however lymph drains fro m the lymphatic tissue of the
tonsil via efferent lymphatic vessels.
Lymphatic nodules are usually found in structures associated Tonsils, which form a ring of lymphatic tissue at the en- Peyer's patches, which are located in the ileum (dista l
with the alimentary canal such as the tonsils, ileum, and tra nce of the oropharynx . The pharyngeal tonsils, or portion of the small intestine). They consist of numerous
vermiform appendix adenoids, located in the roof of the pharynx; the pala- aggregations of lymphatic nodules containing T and B
tine tonsils, or simply the tonsils, o n either side of the lymphocytes (Fig. 13.17). In add ition, numerous, iso-
Generally, nodules are dispersed singly in a r andom pharynx, between the palatopharyngeal and palatoglos- lated single (solitary) lymph nodules are located along
manner. In the alimentary canal, however, some aggrega- sal arches; and the Lingual tonsils, at the base of the both large and small intestines.
tongue, all contain aggrega tes of lymphatic nodules. The Ve11nif01-m appendix, which arises fro m the cecum. The
palati ne tonsils consist of dense accumulations of lym- lamina propria is heavily infiltrated with lymphocytes and
phatic tissue located in the mucous membrane. The contains numerous lymphatic nodules. Although the ap-
squamous epithelium that forms the surface of the ton- pendix is often described as a vestigial organ, the abun-
sil dips into the underlying connective tissue in nu mer- dant lymphatic tissue tha t it contains during early life sug-
o us places, forming tonsil/at crypts (Fig. 13.1 6). The gests that it is functionally associa ted with bursa-
wa lls of these crypts usually possess numerous lym- equivalent organs. With age, the amount of lymphatic tis-
phatic nodules. Like other aggregations of lymph nod- sue within the organ regresses and is difficult to recognize.
FIGURE 13.14
Photomicrograph of a lymphatic nodule. This photomicrograph
shows a section of the wall of the small intestine (duodenum). Short
villi and intestinal glands are present in the upper part of the micro-
graph. A lymphatic nodule (LN) occupies most of the remainder of the
micrograph. The lighter central region of the nodule is the germinal
center. The lymphocytes in the germinal center are larger than those
in the more dense region of the nodule. They have more cytoplasm; crypt
consequently, their nuclei are more dispersed, giving the appearance
of a less compact cellular mass. x 120.
FIGURE 13.15
Photomicrograph of a lymph node. This photomicrograph shows the
superficial cortex (SC}, deep cortex (DC}, and medulla (M) of the lymph
node in a routine H&E preparation. The capsule (Cap) is composed of
dense connective tissue from which trabeculae (T) penetrate into the
organ. Below the capsule is the subcapsular sinus (SCS}. It receives
lymph from afferent lymphatic vessels that penetrate the capsule. The
FIGURE 13.16
subcapsular sinus is continuous with the trabecular sinuses that course
along t11e trabeculae. Tl1e superficial cortex contains the lymphatic Photomicrograph of a palatine tonsil. a. This low-magnification pl1o nective tissue layer (CT) from the lymphatic nodule (LN). In the upper
tomicrograph shows a H&E- stained palatine tonsil. The stratified portion of the photomicrograph, the SSE is just barely recognized be-
nodules (LN). The deep cortex is nodule free. It consists of densely
squamous epithelium that forms the surface of the tonsil dips into the cause of the heavy infiltration of lymphocytes; the epithelial cells are
packed lymphocytes and contains the unique high endothelial
underlying connective tissue in numerous places, forming tonsillar present, however, although they are difficult to identify. In effect, the
venules (not visible at this magnification). The medulla consists of nar-
row strands of anastomosing lymphatic tissue ca lled medullary cords crypts. X25 . b. This higher-magnification photomicrograph of the rec- lymphatic nodule has literally grown into the epithelium, distorting it
tangular area in a shows the stratified squamous epithelium (SSE) lin- and resulting In the disappearance of the more typical, well-defined
(MC), separated by ligl1tappearing spaces, the medullary sinuses (MS).
ing the to nsillar crypt. In the portion of the photomicrograph below epithelial-connective tissue boundary. x 450.
The medullary sinuses receive lymph from the trabecular sinuses as
the lumen of the crypt, SSE is well defined and separated by a con-
well as lymph that has filtered through the cortical tissue. x 140.
3 74 CHAPTER13 Lymplwtic System CHAPTER 1 3 LymplJtJtic System 37 5
trabecu la r sinus
Lymph Nodes
Lymph nodes are small encapsulated organs located along the
pathway of lymphatic vessels
Filtration of lymph in the lymph node occurs within a network Specialized high endothelial venules (HEVs) are the site of entry
of interconnected lymphatic channels called sinuses for circulating lymphocytes into the lymph node
There are three types of lymphatic channels called si- In addition to lymph, lymphocytes also circulate through
nuses in the lymph node. Just beneath the capsule of the the lymph nodes. Although some lymphocytes enter nodes
lymph node is a sinus interposed between the capsule and through afferent lymphatic vessels as components of
the cortical lymphocytes called the subcapsular sinus or lymph, most enter the node through the wall of postcapil-
cortical sinus. Afferent lymphatic vessels drain lymph into lary venules located in the deep cortex (see Fig. 13.22). Be-
this sinus. Trabecular sinuses that originate from the sub- cause the postcapillary venules are lined by cuboidal or
capsular sinuses extend through the cortex along the tra- columnar endothelial cells, they are referred to as high en-
beculae and drain into medullary sinuses. Lymphocytes dothelial venules (HEVs) (Fig. 13.23). These specialized
and macrophages or their processes readily pass back and endothelial cells possess receptors for antigen-primed lym-
forth between the lymphatic sinuses and the parenchyma phocytes. They signal lymphocytes to leave the circulation
and migrate into the lymph node. Both Band T cells leave
the bloodstream through HEVs, crossing the endothelium
@
subcapsular @
afferent sinus ' ~,
lymphatic
trabecular
vessel ,
FIGURE 13.21
FIGURE 13.19 Diagram of a follicular dendritic cell. This cell, usually found in ger- germinal
Photomicrograph of a lymph node. This silver preparation shows the minal centers, has multiple, thin, hair-like cytoplasmic processes that center
connective tissue capsule (at the top), subcapsular sinus, and the su- interdigitate between B lymphocytes. Antigen-antibody complexes
perficial cortex of tile lymph node (at the bottom). The reticular fibers adhere to the dendritic cytoplasmic processes by means of Fe recep-
(arrows) form an Irregular anastomosing network throughout the tors. Follicular dendritic cells are not antigen-presenting cells because
stroma of the lymph node. Note elongated oval nuclei of reticular
cells (arrowheads), wh ich are in intimate contact with reticular fibers in
they lack MHC II molecules.
- ....... ....... .......
'
the sinus. X640.
tiating an immune response . The physical accumulation connective tissue surrounds the thym us and subdivides it into sue of the organ. The occluding junctions between these
of microorganism s and particulate substances conveyed thymic lobules cells reflect their function as a barrier that isolates d evel-
in t he lymph and phagocytosis of the pa rticu late materia l oping T cells from the co nnective tissue of the organ, i.e.,
help to concentrate antigen, thus enhancing its presenta- The thymus possesses a thin connective tissue capsule capsule, t rabeculae, and perivascular connective tissue.
tion to lymp hocytes. Antigens conveyed in the lymph from which trabeculae exten d into the parenchyma of the Type II epithelioreticular cells are located w ithin the
percolate through th e sinu ses and penetrate the lymph organ. The capsule and trabeculae contain blood vessels, cortex. The transmission electron microscope (TEM) re-
nodu les to initiate a n immune response. Some antigens efferent (but not affer ent) lymphatic vessels, and nerves. In veals maculae adherentes (desmosomes) that join lo ng
become trapped on the surface of the fo llicul ar dendritic addition to collagen fibers and fibroblasts, t he connective cytoplasmic processes of adjacent cells. The cell body
cells, w hile others are processed by macrophages and tissue of the thymus contains variable n umbers of plasma and cytoplasmic processes contain abundan t intermedi-
B cells, leading to activation and differentiation of B cells cells, granulocytes, lymphocytes, mast cells, ad ipose cells, ate filaments . Because of their processes, these cells are
into antibody-producing plasma cells and memory B and macrophages. stellate. They have a large nucleus that stains lightly w ith
cells. The trabeculae establish domains in the thymus called H &E because of its abundant euchromatin. This nuclear
The plasma cells then migrate to the medullary co rds thymic lobules. They are not true lo bules, but cortica l feature allows the cell to be easily identified in the light
where they synthesize and release specific antibod ies into ca ps over portions of the highly convoluted but continu- microscope. Type II cells compartmentalize the cortex
the lymph flowing through the sinuses. Plasma cells ac- o us inner medullary tissue (Fig. 13.2 4 ). In some planes of
count for 1 to 3 % of the cells in resting lymph nodules. section, the " lobular" arrangement o f the cortical cap
Their number increases dramatically during an immune re- and medullary tissue superficially resem bles a lymp hatic
sponse, thereby increasing the amount of circulating im - nodule w ith a germinal center, which often co nfuses stu- -~22,9 :.v~essels ~
dents. O ther m o rpho logic characteristics (described be- . ~,~}
munoglobulins. Memory B cells may leave the lymph
nodes and circulate to various regions through the body, l ow) allow positive identification of the thymus in histo-
w her e they can proliferate in response to subseq uent ex- logic sections.
posure to their specific antigen . The presence o f memory
cells in vario us sites thro ughout the body ensures a more The thym ic parenchyma contains developing T cells in an
rapid response to an antigen, the secondary r esponse. extensive meshwork formed by epithelioreticular cells
Lymph nodes in which lymphocytes are responding to
antigens often enlarge, reflecting formation of germinal cen- The o uter portion of the parenchyma, the thymic cortex,
ters and proliferation of lymphocytes . This phenomenon is is markedly basophilic in H&E preparations because of
most often seen in th e lymph nodes of the neck in response the closely packed d eveloping T lymphocytes w ith their in-
to nasa l or oropharyngeal infection. These enlarged lymph tensely staining n uclei. These T lymphocytes, a lso called
nodes are commonly referred to as "swollen glands." thymocytes, occupy spaces within an extensive meshwork
of epithelioreticular cells (Fig. 13.25 ). Macrophages are
also dispersed among the cortical cells. T he developing T
Thymus cells arise from CFU-Ls, w hich originate in bone marrow.
As d evelopmen t proceeds in the thymus, the cells deri ved
FIGURE 13.23 The thymus is a lymphoepithelial organ located in the superior from CFU-Ls pass t hro ugh a series of developmental stages
Photomicrograph of the deep cortex of a lymph node. This pho- m ediastinum that are reflected by t heir expression of d ifferent CD
tomicrograph shows several longitudinally sectioned high endothe- molecules.
lial venules (HEVs) as well as several that are seen in cross section (ar- The thymus is a bilobed orga n located in the superi or As t heir name implies, epithelioreticular cells have fea-
rows). These vessels are lined by cuboidal endothelial cells. In some tures of both epithelial and reticular cells . They provide 'a
mediastinum, anterior to the heart and great vessels. It de-
preparations, the walls of a HEV may be infiltrated with migrating framework fo r the developing T cells; thus, they corre-
velops bilaterally from the third (and sometimes a lso t he
lymphocytes, making it difficult to recognize. X400. Inset. The cross
fo urth) bra nchia l (oropharyngeal) pouch. During develop- spond to the reticular cells and their associated reticular
section of a HEV shown here at higher magnification reveals several
lymphocytes (arrowheads) in the process of migrating from the HEV m ent, the epit heLi um invagina tes, and th e thymic rudiment fibers in other lymphatic tissues and o rgans. Reticul ar
into the parenchyma of t11e lympll node. X 640 grows ca udally as a tubular pr ojection of the endodermal cmm ective tissue cells and t heir fibers, however, are not
epithelium into the mediastinum of the chest. The advanc- pr esent in the thymic parenchyma . Epithelioreticular cells
ing tip proliferates and ultimately becomes disconnected ex hibit certain features characteristic of epitheli um, such
by dia pedesis, i.e., by migratin g between the endothelial frorn the bra nchial epithelium. Multipotential lymphoid as intercellular junctions and inter mediate filaments. FIGURE 13.24
cells, in a manner similar to that described for neutrophils stem cells (CFU-Ls) from the bone marrow that are des- Six types of epit helioreticular cell s are recogni zed o n the Photomicrograph of an infant human thymus. This H&E preparation
(see page 222). The T cells rema in in th e thymus-dependent tin ed to develop into immun ocompetent T cells invade the basis of function: three types in the cortex and three types reveals multiple lobules separated by conn ective tissue trabeculae
epit helial rudin1ent and occ upy spaces between the epithe- in the m ed ulla. Each type is designated by roma n numer- that extend into the organ from the surrounding capsule. Each lobule
d eep cortex; the B cells migrate to the nodular cortex. Most
als. In the cortex the fo.llowing cell types are recognized: is composed of a dark-staining basophilic cortex and a lighter-
lym phocytes leave the lymph node by entering lymp hatic si- lial cells so that the th ymus develops into a lymphoepithe-
staining and relatively eosinophilic medulla. The medulla is actually a
n uses fro m w hich th ey flow to an efferent lymphatic vessel. lial organ. continuous branching mass surrounded by the co rtex. The cortex
The thymus is fully formed a nd functional at bircl1. It Type I epithelioreticular cells are located at the bound- contains numerous densely packed lymphocytes, whereas the
The lymph node is an important site for phagocytosis and persists as a large orga n until about the time of puberty, ary of t he cortex and the connective tissue capsule as well medulla contains fewer lymphocytes. Note that in some instances the
initiation of im mune responses when T cell differentiation and proliferation are reduced as between the cortical parenchyma and the tra beculae. medulla may bear a resemblance to germinal centers of lymphatic
and most of the lymphatic tissue is replaced by adipose tis- They a lso surro und the adventitia of the cortical blood nodules (upper right and center left). Such isolated medullary profiles
Phagocytosis of particu late ma terial by phagocytotic sue (invo lution). The organ ca n be restimulated under con- vessels. In essence, type I epithelioreticular cells serve to are continuous with the overall medullary tissue, but this continuity
cells w ithin the lym ph nodes is an important step in ini- ditions that demand r apid T cell proliferation. separate the thymic parenc hyma from the connective tis- may not be seen within the plane of section. X 25.
380 CHAPTER 13 Lywp/Jt~tic Systr111 CHAPTER 1 3 Ly mphatic Sys tem 38 I
stains less intensely than the cortex because, like the ger-
minal centers of lymph nodules, it contains mostly large
lymphocytes. These lymphocytes have pale-staining nuclei
and quantita tively more cytoplasm than small lympho-
cytes. Like the cortex, the medulla also contains three
types of epithelioreticular cells:
lymphocytes, plasma cells, and gra nul ocytes. Splenic type of circulation is referred to as open circulation, and it
macrophages phagocytose damaged red blood cells. The is the only route by which blood returns to the venous cir-
iron from destroyed red blood cells is used in the forma- culation in humans. In other species such as the rat and
tion of new red blood cells; splenic macrophages begin dog, some of the blood from the sheathed capillaries passes
spleniclgerminal
nodule center the process of hemoglobin breakdown and iron reclama- directly to the splenic sinuses of the red pulp. This type of
(white marginal tion. Megakaryocytes are also present in certain species, circulation is referred to as closed circulation.
pulp) area such as r odents and the cat, but not in humans except Open circulation exposes the blood more efficiently to
during fetal life. the macrophages of the red pulp. Both transmission and
scanning electron micrographs often show blood cells in
The splenic or venous sinuses are special sinusoidal vessels transit across the endothelitll11 of the sinus, presumably
lined by rod-shaped endothelial cells r eentering the vascular system from the red pulp cords.
The blood collected in the sinuses drains to tributaries of
The endothelial cells that line the splenic sinuses are ex- the trabecular veins that converge into larger veins and
tremely long. Their longitudinal axis runs parallel to the eventually leaves the spleen by the splenic vein. The splenic
direction of the vessel (Fig. 13.30). There are few contact vein in turn joins the drainage from the intestine in the he-
points between adjacent cells, thus producing prominent patic portal ve in (see page 535).
intercellular spaces. These spaces allow blood cells to pass
readily into and out of the sinuses. Processes of The spleen performs both immune and hemopoietic functions
trabecular macrophages extend between the endothelial cells and into
artery the lumen of the sinuses to monitor the passing blood for Because the spleen filters blood as the lymph nodes filter
and vein lymph, it functions in both the immune and the hemopoi-
foreign antigens.
The sinuses do not possess a continuous basal lamina. etic systems.
Strands of basal lamina loop around the outside of the si- Immtme system functions of the spleen include
nus much like the hoops that loop around the staves of a Antigen presentation by APCs and initiation of immune
barrel. These strands are at right angles to the long axes of response
the endothelial cells. This material stains with silver- Activation and proliferation of B and T lymphocytes
containing reagents or with the PAS reaction. Neither Production of antibodies against antigen present in cir-
smooth muscle nor pericytes are present in the wall of culating blood
splenic sinuses. Reticular cell processes may extend to the Removal of macromolecular antigens from the blood
a basal side of the endothelial cells and are probably associ- Proliferation of lymphocytes and differentiation of B
ated with the reticular fibers that appear to merge with the cells and plasma cells, as well as secretion of antibodies,
FIGURE 13.29 perisinusoidalloops of basal lamina. Blood fills both the si- occm in the white pulp of the spleen; in this r egard, the
Schematic diagram and photomicrograph of splenic structure. a. The infiltrated by numerous myofibroblasts. Blood vessels traverse the nuses and cords of the red pulp, often obscuring the un-
substance of the spleen is divided into wl1ite pulp and red pulp. White white pulp is the equivalent of othe1 lymphatic organs
capsule and trabeculae before and after passage within the substance derlying structures and making it difficult to distinguish
pulp consists of a cylindrica l mass of lymphocytes arranged around a of the spleen. Lymphatic vessels originate in the white pulp near the Hemopoietic functions of the spleen include
between the cords and the sinuses in histologic sections.
central artery that constitutes the periarterial lymphatic sheath (PALS). trabeculae. b. This low-magnification photomicrograph of the spleen
Splenic nodules occur along the length of the PALS. When observed reveals the same components shown in the previous drawing. Note Removal and destruction of senescent, damaged, and
Circulation within red pulp allows macrophages to screen
in cross section through part of the sheath that contains a nodule, the the capsule with several trabeculae projecting into the substance of abnormal erythrocytes and platelets
central artery appears eccentrically located with respect to the lym- antigens in the blood
the spleen. In the center, there is a trabecula containing a trabecular Retrieval of iron from erythrocyte hemoglobin
phatic mass. The red pulp consists of splenic sinuses surrounded by vein througl1 which blood leaves the organ. The red pulp constitutes Formation of erytluocytes during early fetal life
splenic cords (cords of Billroth). A capsule surrounds the spleen and the greater bulk of the splenic tissue. The white pulp contains lym-
Branches of the splenic artery enter the white pulp from
Storage of blood, especially red blood cells, in some
from it trabeculae project into the substance of the spleen. Both cap- phatic tissue that follows and ensheathes the central artery. Expan- the trabeculae. The central artery sends bran~hes to the
species
sule and trabeculae give the appearance of dense connective tissue sion of tile white pulp creates the splenic nodules. X45. white pulp itself and to the sinuses at the perimeter of
the white pulp, called marginal sinuses (see Fig. 13.29). The role of the red pulp is primarily blood filtration, i.e.,
The central artery continues into the red pulp, where it removal of particulate material; macromolecular antigens;
branches into several relatively straight arterioles called and aged, abnormal, or damage d blood cells and platelets
surround the nodules. Thus, the PALS may be considered Red pulp contains large numbers of red blood cells that it from the circulating blood. These functions ar e accom-
penicillar arterioles. The penicillar arterioles then con-
a thymus-dependent zone similar to the deep cortex of a filters and degrades
tinue as arterial capillaries. Some arterial capillaries are plished by the macrophages embedded in the reticular
lymph node. The nodules usually conta in germinal centers, surrounded by aggregations of macrophages and are thus meshwork of the red pulp. Senescent, damaged, or abnor-
which, as in other lymp hatic tissues, develop as B cells pro- Red pulp has a red appearance in the fresh sta te as called sheathed capillmies. Sheathed capillaries then empty mal r ed cells are broken down by the lysosomes of the
liferate following their activation. In humans, germinal well as in histologic sections because it contains large d irectly into the reticular meshwork of the splenic cords macrophages; the iron of the hemoglobin is retrieved and
centers develop within 24 hours after antigen exposure numbers of red blood cells. Essentially, red pulp consists rather than connecting to the endothelium-lined splenic si- stored as ferritin or hemosiderin for future recycling. The
and may become extremely large and visible with the of splenic sinuses separated by splenic cords (cords of nuses. Blood entering the red pulp in this manner percolates heme porti on of the molecule is broken down to bilirubin,
naked eye. These enlarged nodules are called splenic nod- BilJroth). Splenic cords consist of the now-familiar loose through the cords and is exposed to the macrophages of the which is transported to the liver via the portal system and
ules or Malpighian corpuscles (not to be confused with the meshwork of reticular cells a nd reticular fibers that cords before returning to the circulation by sq ueezing there conjugated to glucuronic acid. Conjugated bilirubin
renal corpuscles that have th e same name). contain large numbers of erythrocytes, macrophages, through the walls of the splenic sinuses (Fig. 13.31). This is secreted into the bile, giving it a characteristic color.
38 6 CHAPTER 13 LymfJIJatic System C HAPTER 13 Lymphatic System 387
trabecular artery
trabecular vein
central artery
splenic
nodule
FIGURE 13.31
Schematic diagram of open and closed
splenic circulation. In the open clrcula
\ tion, which occurs in humans, penlcillar
1 arterioles empty directly into the retlcu
lar meshwork of the cords rather than
I connecting to the endothelium-lined
/ splenic sinuses. Blood entering the red
pulp then percolates through the cords
and is exposed to the macrophages re
siding there. In the closed circulation,
which occurs in other species, the penl
clllar arterioles empty directly into the
sheathed capillaries splenic sinuses of the red pulp.
Macrophages recognize senescent or abnormal blood In addition, specific changes in glycosylation of gly-
cells by several different mechanisms: cophorins (see page 217) in aging erythrocytes act as a
recognition signal that triggers the elimination of senes-
Nonspecific mechanisms involve morphologic and bio- cent erythrocytes by macrophages.
chemical changes that occur in aged erythrocytes; they
become more r igid and are thus more easily trapped in Despite these important functions, the spleen is not es-
the mesh of the red pulp. sential for human life. It can be removed surgically, which is
Specific mechanisms include opsonization of the cell often done following trauma that causes intractable bleed-
FIGURE 13.30 membrane with anti-band 3 IgG anti bodies, which trig- ing from the spleen. The removal and destruction of aging
Splenic sinus and splenic cord structure. a. This scanning electron mi ger Fe receptor- dependent phagocytosis of erythrocytes. red blood cells then occurs in the bone marrow and liver.
crograph shows a cross section of a splenic sinus (SS), revealing the
lattice structure of its wall. Through the multiple openings in the wall,
processes of macrophages (arrows) are inserted Into the sinus lumen.
The remainder of the micrograph shows characteristically smooth
surfaced processes of reticular cells (RC). The spaces of the reticular
cell framework contain neutrophils (N), macrophages (M), and blood
platelets (P). x 4,400. b. Schematic diagram of the reconstructed struc
ture of splenic sinus. Note the direction of blood flow In open and
closed circulation. c. Scanning electron micrograph of the splenic si
nus, showing the architecture of the sinus wall as seen from Its lumi
nal side. Rod-like endothelial cells run in parallel and are intermit
tently connected to each other by side processes. A nuclear swelling
is shown at lower right. The tapered ends of a few of the rod cells are
seen. The macrophage (M), neutrophil (N), and lymphocyte (L) are out
side the sinus. x 5,300. (From Fujita T, Tanaka K, Tokunga J. SEM Atlas
of Cells and Tissues. Tokyo: lgakuShoin, 1981.)
CHAPTER 13 yrmpiHitic Systrm 389
B
lighter central region of the nodule. The darker-staining pe-
This shows, at a higher magnification, part of the same ripheral portion of the nodule contains numerous, closely
crypt as in the survey micrograph, as well as the adjacent packed small lymphocytes intimately related to the epithe-
epithelium (Ep) and one of the lymphatic nodules (LN). limn ; they have actually become incorporated in the epithe-
The crypt contains some cellular debris, a frequent occur- lium. Portions of the germinal center have also become in-
rence. The lymphatic nodule exhibits a germinal center, the corporated into the epithelium.
Figure 2, tonsil, human, H&E x400; inset x 800. ent, though difficult to identify, in the gernlinal center as
KEY
Ep, epithelium arrow (survey micrograph), tonsillar crypt small a rrows (Fig. 2), strands of epithelial
LN, lymphatic nodule la rge arrow (Fig. 1), crypt cells in nodule
L P, lamina propria rectangula r area (Fig. 1), shown at higher
magnification in Fig. 2
388
CHAPTER 13 Lymphatic System 39 I
B
cortex. Whereas lymph nod ul es and their lighter-staining
An area from the cortex is shown here at higher magnifi - germinal cente rs c haracteri ze the outer cortex, a more
cation. The capsule (Cap) is composed of dense con nective dense mass of lymphocytes, which im part a distinct ba-
ti ss ue fro m which trabeculae (T) penetrate into the organ. sophilia, characterize the deep cortex. In contrast to these
Immediately below the capsule is the cortical or subcapsu- areas, the medulla is characterized by narrow strands of
lar sinus (CS), which receives lymph from the afferent lym- anastomosi ng lymphatic tissue containi ng numerous lym-
phatic vessels after they penetrate the capsule. T he cortical phocytes, the medullary cords (M C), separated by light-ap-
sinus is conti nuous with the trabecular sinuses (TS) that pearing areas known as the medullary sinuses (MS). T he
course along the trabeculae. medull ary sinuses receive lymph from the trabecular si-
The cortex contains the lymphatic nodul es (LN) and a nuses and lymph fi ltered through the cortical tissue.
deeper component that lacks nodules, known as the deep
B
Figure 2, lymph node, human, H&E x400; inset deus, and its cytoplasm forms long processes that surrou nd
X640. the reticular fibers. In H&E preparations, the reti cular fibers
This higher-magnification micrograph of a lymphati c and the surrounding cytopl asm are difficult to identify.
nodul e fro m Figure 1 illustrates the germin al center (GC) Reticu lar cells are best seen in the sinuses, where they ex-
containing medium and large lymphocytes. Germin al cen- tend across the lymphatic space and are relatively unob-
te rs also contain plasma cells. Divid ing lymphocytes are scuted by other cells.
shown at slightly higher magni fication in the inset (ar- A unique vessel, the postcapi llary venule (P CV), is
rows), which corresponds to the area in the circle in Figure fou nd in relation to the lymphatic nodules, particularly in
2. The inset a lso reveals nuclei of the retic ular cells (RC) the deep cortex. T hese vessels have an e ndothelium com-
that form the connective ti ssue stroma throughout the or- posed of tall cells between which lymphocytes mi grate
gan. The ovoid reticular cell has a large pale-stain ing nu- from the vessel lumen into the parenc hyma.
KEY
C, cortex LN, lymphatic nodule RC, reticular cells
Cap, caps ule M, medulla T, trabecula
CS, cortical or subcapsular sinus MC, medul lary cords TS, trabecular sinus
GC, germinal center MS, medullary sinus arrows, d ividing lymphocytes
H,hilum PCV, postcapillary venule
f
C H APTE R 13 Ly mpiMtic System 39 3
Figure 1, lymph node, human, H&E x365. dothelium, which is composed of cells that are cuboidal. A
Ea
becular framework of the node. The inset reveals the boxed
The area shown here, near the hilar reg ion of the node, area at higher magnification (X530). The nuclei of the
shows part of a lymph nodule (LN) , the cortical sinus (CS) reticular cells (RC) are larger and less densely staining than
just below the capsule (Cap) , and some of the medullary si- the lymphocyte nuclei, which are round and densely
nus (MS). Both the cortical sinus and the medullary sinus stained. In H&E preparations, these characteristics allow
are spanned by reticular cells (RC). These cells wrap for the distinction between the reticular cell and the lym-
around the collagen bundles that form the supporting tra- phocyte.
Figure 3, lymph node, monkey, H&E x 530. hibits what appears to be an incomplete wall. The openings in
KEY
A, artery PCV, postcapillary venule arrowheads, endothelial cells of postcapil-
Cap, capillary RC, reticular cells lary venu le
CS, cortical sinus V, vein arJ'ows, Fig. I, endothelial cells; Fi g. 3,
LN, lymph nodule Val, valve opening of medull ary sinus to lymph ves-
MS, medullary sinus Ven, venule sel
C H APTER 1 3 Lymphatic Syste111 39 5
@
Figure 1, spleen, human, H&E x 65.
This low-magnification micrograph of the spleen reveals lymphatic tissue that constitutes the white pulp differs from
its two major components, the red pulp (RP) and white pulp nodules seen elsewhere in that it follows and ensheathes a
(WP). In the center of the figure, there is a trabecula con- blood vessel, the central artery. The lymphatic tissue sur-
taining a blood vessel, a trabecular vein (TV) through rounding the artery exhibits periodic expansion, thus form-
which blood leaves the organ. The red pulp consti tutes the ing the nodules. When this occurs, the central artery (CA)
greater bulk of the splenic tissue. In life, the red pulp has is displaced peripherally within the nodule.
pulp-like texture; it is red as a result of the natural col- In those regions where the lymphatic tissue is not in
oration of the numerous red blood cells present, hence its nodular form, it is present as a thin cuff around the central
name. artery and is referred to as the periarterial lymphatic sheath.
The white pulp, on the other hand, is so narned because If the plane of section does not include the artery, the
its content of lymphocytes appears in life as whitish areas . sheath may appear only as a localized and irregular aggre-
ln tissue sections, however, the nucle i of the closely packed gation of lymphocytes.
Figure 2, spleen, human, H&E x 160. Near the top of the micrograph, two venous sinuses (ar-
This figure reveals, at a higher magnification, the red pulp rows) empty into the trabecular vein (TV), thus showing the
and a portion of the trabecular vein from the area enclosed in continuity between venous sinuses and the trabecul ar veins.
the uppermost rectangle in Figure 1. The red pulp is com- The wall of the vein is thin, but the trabecula (T) contain-
posed of two elements: venous sinuses ( VS) and the splenic ing the vessel gives the appearance of being part of the ves-
cords (of Billroth), the ti ssue that lies between the sinuses. In sel wall. In humans as well as in other mammals, the cap-
this specimen, the venous sinuses can be seen to advantage sule and the trabeculae that extend fro m the capsule contain
because the red blood cells in the sinuses have lysed and ap- myofibroblasts. Under conditions of increasing physical
pear as unstained "ghosts"; only the nuclei of the white cells stress, contraction of these cells will occur and cause rapid
are readily seen. (This is better shown in Plate 36.) The paler, expulsion of blood from the venous sinuses into the trabec-
unstained areas thus represent the sinus lumina. ular veins and, thus, into the general circul ation.
some pass into the retic ular network of the marginal zone,
KEY
CA, central artery T, trabecula aiTows (Fig. 2), venous sinuses emptyi ng
GC, germinal center TV, trabecu lar vein into the trabecular vein
MZ, marginal zone VS, venous sinus
RP, reel pulp WP, white pulp
394
CHAPTER 1 3 LytupiMiic Syslrm 39 7
Figure 2, spleen, human, H&E x 1200. narrow intercellula r spaces then appear as slits between the
This fi gure reveals, at hig her mag nifi cati on, one o f the cross-sectioned cells. Occasio nall y, the wall of a sinus is
venous s inuses and the surrounding spleni c (Billroth 's) tangentially sectioned, and the cyto plasm of the endothelial
cord (BC) fro m the preceding fig ure. The wa ll of the s inus cells appears as a series of narrow stripes, as can be seen in
cons is ts of elongate d rod-like endothelial cell s that are ori- the lower left of F igure 1 (aste risks). Each linear compo-
ented paralle l to each o ther in the long ax is of the sinus. A nent here is a s ingle endothel ia l cell.
narrow, but clearly v is ibl e, intercellular space is usually The e ndotheli al cell nuclei (En) project into the sinus lu-
present between adjacent cells. (The s pace seen in light mi- men. In e ffect, the nuclei fo rm a bleb-like struc ture that
croscopic prepar ations is an exaggeration clue to shrinkage then appears to sit within the lumen of the vessel. Unless
during routine pre paration.) Whe n a veno us si nus is cut in examined carefull y, they m ay give the impression that th ey
cross section, as in th is figure, the rod-shaped endothelial are nuclei of whi te blood cells. T his is especia lly true if the
lining cells are also cut in cross sectio n, and the cut edges white blood cells ( WBC) within the lume n of the sinus are
of the adjo ining cells are seen in the form of a ring. The numerous.
Figure 3, spleen, human, silver preparation x 120; inset has been sectioned ta ngentially along its wall, and its
inset x 300. c ircumscribing fib ers can be seen lying p arallel to o ne an-
The fra mework of the spleen consists of a capsul e, tra- other like the rungs of a ladder (arrows). The vessel above
beculae that extend fro m the capsul e into the s ubstance of and in very close proximi ty (w ith the label VS in its lumen)
the spleen, and a re ticular stro ma. T he s il ver-stained reticu- has also been sectioned lo ng itud ina lly, but the sectio n
lar stroma is illus trated in this figu re. Tn the white p ulp, the passes deeper into the vessel; thus, the c ut e nds of the fi bers
germinal centers (GC) can be recognized by the c ircular are seen in cross-sectio nal pro file (arrowheads) and give
arra ngement a nd, to some degree, the pauci ty of the reticu- the appearance o f a series of dots outlin ing the wall of the
lar fibers. The central ar teries (CA) are surrounded by a rel- vessel. These fi bers are actuall y com posed of basal lamina
ative abundance o f reticular fi bers, hence the dense outline material. The basal lami na is not a thin sheath in thi s in-
of these vessels. T he arrangement of the fibers in the red stance but, rather, forms a cord-like s tructure that fac ilitates
pul p is more variable in appearance. A special arrangem ent the passage o f cells across the endothel ium. T he true retic-
of blackened fibers is seen in re latio n to the veno us sinus ular fi bers (composed of coll agen fi brils) are darke r stain-
(VS) of the red pulp. These fibers often ap pear as a n organ- ing and thi cker. They can be seen between the closely ap-
ized lattice that circumscribes the vessel. posed vessels.
T he inset in Fig ure 3 is a hig her magnification of the
area immediately above it. One of the vesse ls seen in the
KEY
BC, Bill roth's cord (splenic cord) a rrowhead s (Fig. 3, inset ), silver-positive positive fibers (basal lamina materi al) cir-
CA, central artery fibe rs (basal lamina material) circum- cumscribing the venous sinus endothe-
En, endothe lial cell nucleus scribing the venous sinus endothelium lium
GC, germi nal center seen in cross-sectional profi le asterisks (Fig. 1), wall of venous si nus seen
VS, venous sinus arrows : Fig. I, pig ment (contained in in tangential section
WBC, white blood cells macrophages); Fig. 3 (inset), silver-
396
CHAPTER 1 3 Lympl,atic System 39 9
6_j
Figure 1, thymus, human, H&E x40.
Examination of the thymus at low mag nification reveals lymphocytes, whereas the medulla contains fewer lympho-
the lobules ( L) composed of a dark-staining basophilic cor- cytes and is consequently less densely packed.
tex (C) and a lighter-staining and relatively eosinophilic
6_j
Figure 2, thymus, human, H&E x 140.
It is the rel ative difference in the lymphocyte population medulla appears to extend across several lobules.
(per unit area) and, in particular, the staining of theiJ nuclei The main cellular constituents of the thymus are lym-
with hematoxylin that creates the difference in appearance phocytes (thymocytes), with characteristic small, round,
between cortex (C) and medulla (M ). Note that some of the dark-staining nuclei, and epithe lioreticular supporting cells,
medullary areas bear a resemblance to germinal centers of with large pale-staining nuclei. Both of the cell types can be
other lymphatic organs because of the medulla appearing as di stinguished in Figure 3, which provides a high-magnifi-
isolated c ircular areas (upper left of Fig. 1). The medullary cation view of the medulla. Because there are fewer lym-
component, however, is actually a continuous branching phocytes in the medulla, it is the area of choice to examine
mass surrounded by cortical tissue. Thus, the " isolated" the epithe lioreticular cells. The thymu s also contains
medullary profiles are actually united with one another, al- macrophages; however, they are difficult to distinguish
though not within the pla ne of section. A suggestion of s uch from the epithelioreticular cells.
Figure 3, thymus, human, H&E x600. The thymus gland remains as a large structure until the
The medulla usually possesses varying numbers of ciJ- time of puberty. At that time, regressive changes occur that
cular bodies called HassaU's, or thymic, corpuscles (HC). result in a significant reduction in the amount of thymic tis-
The corpuscles are large concentric layers of flattened ep- sue. The young thymus is hi ghly cellul ar and contains a
ithelio retic ular cells ( Ep ). They stain readily with eosin and minimum of adipose ti ssue. On the other h<Uld, in the older
can be distinguished eas il y with low magnification, as in thymus, much adipose tiss ue is present between the lob-
Figures 1 and 2 (arrows). The center of a corpuscle, partic- ules . With continued involution, adipose cells are found
ul arly a large one, may show evidence of keratinization and even within the thymic ti ss ue itself. Occasional plasma
appear somewhat amorphous. cells may be present in the periphery of the thymic cortex
of the involuting thymus gland.
KEY
BV, blood vessels HC, Hassall 's corpuscles arrowheads, nuclei of epithelioreticular
C, cortex L, lobule cells of Hassall 's corpuscles
Cap, capsule M, medulla arrows (Figs. 1 and 2), Hassall 's corpus-
Ep, epithelioreticular cells T, trabeculae cles
398
nourished individuals and in individuals living in cold cli- as thick skin. Elsewhere, the skin possesses a much thinner
mates, the adipose tissue can be quite thick. epidermis and is called thin skin. It contains hair follicles
The epidermal derivatives of the skin (epithelial skin in all but a few locations.
appendages) include the following structures and integu- The terms thick skin and thin skin, as used in histologic
mentary products : description, are m.isnomers and refer only to the thickness
of the epidermal layer. Anatomically, the thickest skin is
Hair follicles and hair
Integumentary System
Sweat (sudoriferous) glands
Sebaceous glands
Nails
found on the upper portion of the back where the dermis
is exceedingly thick. The epidermis of the upper back,
howevet; is comparable to that of thin skin found else-
where on the body. ln contrast, in certain other sites such
Mammary glands as the eyelid, the skin is extremely thin.
OVERVIEW OF THE INTEGUMENTARY SYSTEM 400 The integumentary system performs essential functions
The cells of the stratum spinosum characteristically exhibit varies from one to three cells thick. The cells contain nu-
spinous processes merous keratohyalin gra1tules, hence the name of th e
la yer. These g ra nules con tai n cystine-rich and histidine-
The stratum spinosum is a t least severa l cells thick. T he rich proteins, w hich are the precursors of the protein filag-
cells are larger tha n those of th e stratum basale. They ex- grin th at aggrega tes the kera tin filaments present with in
hibit numerous cytoplasmic processes or s pines, w hich the cornified cells of the stratum corneum. Keratohya lin
gives this layer its na m e (Fig. 14.3). The processes are a t- granules are irregular in shape and va riable in size. Beca use
tached to similar processes of adjacent cells by desmo- of their intense basophi lic staining, they are readily seen in
somes . In the light microscope, the site of the desmosome routine histo logic sectio ns.
appears as a slig ht thickenin g called the node of Bizzozero.
The processes ar e usuall y ver y conspicuous, in part because The stratum corneum consists of a nucleate squamous cells
the cells shrink during prep aration and a res ultant ex- largely filled with keratin fila ments
panded intercellular s pace d evelops between the spines. Be-
Usuall y, an a brupt transition occurs between the nu cle-
ated cells of the stratum gran u los um and the flatten ed, des-
iccated, anucleate cells of the stratum comeum. The cells
in the stratu m co rne um a re t he most differentiated cells in
the sk in . They lose t heir nucle us and cytoplasmic or-
gane ll es a nd becom e fil led a lmost entirely with kera tin fil-
aments. The thick plasma m em bra ne of these corn ified,
keratinized cells is coated fro m the outside, in t he deep er
portion of this layer, w ith a n ex tracellular la yer of lipids
that for m the major constituent of the water ban-ier in the
epidermis (see page 406).
The stra tum corne um is t he layer that varies most in
thickness, being thickest in thick skin. The thickness of thi s
layer con stitu tes the princ ipa l d ifference between the ep i-
FIGURE 14.1
dermis of thic k a nd t hi n skin. This cornified layer wi ll be-
Photomicrograph showing the layers of thin skin. Tl1is H&E- stained
co m e even thicker at sites subjected to un us ua l amount s of
specimen from human skin shows the two ch ief layers of the skin, the
epidermis (Epi) and dermis (Derm). The epidermis forms the surface; it friction, as in t he fo rma ti on of ca ll uses on the palms of the
consists of stratified squamous epithe lium that is keratinized. The der hand and o n the finge rtips.
mis consists of two layers: the papillary layer, which is the most su- T he stratum lucidum, considered a subdivision of th e
periicial layer and is adjacent to the epidermis, and the more deeply FIG URE 14.3 stra tum corneum by some h istologists, is found only in
positioned reticular layer. The boundary between these two layers is Photomicrograph of the stratum spinosum and stratum basale. The thick skin. In the lig ht mic roscope, it often has a refractile
not conspicuous; the papillary layer is, however, more cellular than epidermis of thin skin is shown here at higher magnification. The one- appea rance and may stai n poorly. This highly refracti le
the reticular layer. In addition, the collagen fibers of the reticular layer cell-deep layer at the base of the epidermis just above the connective
layer contains eosinoph ilic cells in w hich t he p rocess of
are thick (clearly visible in the lower part of the figure); those of the tissue (CT) of the dermis is the stratum basale (58). The cells of this
keratinization is we ll a d va nced. T h e nucl eus a nd cytoplas-
papillary layer are thin. x 45. layer rest on the basement membrane. A layer referred to as the stra-
tum spinosum (55) is located just above the stratum basale. It consists mic o rga nelles becom e disrupted a nd disappear as the cell
of cells with spinous processes on their surfaces. These processes are gradua ll y fil ls wi th kerati n.
)~
cell also involves breakdown of th e nucleus and o ther or-
filaggrin
ganelles and thickening of the plasma mem brane. Finally,
cells are regu lar ly exfoliated (desquamated) from the su r- ~
()
face of the stratum corneum. The cells that will desqu a-
)
mate accumul ate acid phosphatase, which is tho ught to _j~
_l _j
1
9~
Lamellar bodies contribute to the for mation of the intercellular
epidermal water barrier
9::UJ
_j>
zUJ
An epidermal water ba rrier is essential for m amma lian
" dry" epithelia and is responsible for ma intaining body
homeostasis. The barrier is established primari ly by two
factors in terminally differentiating keratinocytes: (a) dep-
osition of insoluble proteins on the inner surface of the
plasma membrane and (b) a li p id layer that is attached to
th e outer surface of the plasma membrane.
As the keratinocytes in the stratum spinosum beg in to
produce keratohyalin granules, they a lso produce mem-
brane- bounded lamellar bodies (membrane-coating gran- FIG URE 14.6
ules). Spi nou s and granular cells synthesize a heterogenous Electron micrographs of keratinocytes.
mixture of glycosphingolipids, phospholipids, and ce- lamellar -iffi~~<% a. Mucll of the keratinocyte cytoplasm is
ramides (Fig. 14.5 ); this mix ture is assembled into lamel- body filled witll tonofilaments. One keratinocyte
lar bodies in the Golgi appar atus. The contents of th e gran- exhibits a kerato11yalin granule (KG). Near
ules is then secr eted by exocytosis into the intercellular the plasma membrane closest to tile sur-
spaces between the stratum granul osum and stratum FIGURE 14.5 face (upper left), two keratinocytes display
corneum. The organization of these intercellular lipid Schematic diagram of the epidermal water barrier. The heteroge- lamellar bodies (arrow/leads). xa,soo. b. A
lamellae is responsible for the fo rmation of the epidermal neous mixture of glycosphingolipids, phospholipids, and ceramides lamellar body at higller magnification.
makes up the lamellae of the lamellar bodies. The lamellar bodies, X l 35,000. c. Part of a keratinized cell and
water barrier (Fig. 14.6).
produced within the Golgi apparatus, are secreted by exocytosis into tile underlying keratinocyte. Located be-
The epidermal water barri er thus consists of two struc- tween the cells are t11e contents of the
the intercellular spaces between the stratum granulosum and stratum
tural elements: lamellar bodies, which have been dis-
corneum, where they form the lipid envelope. The lamellar arrange-
The cell envelope (CE), a 15-nm-thick layer of insolu ble ment of lipid molecules is depicted in the intercellular space just be- charged into the intercellular space (arrow)
low the thickened plasma membrane and forms the cell envelope of to form the lipid envelope. X 90,000. (Cour-
proteins deposited o n the inner surface of the plasma
the keratinized keratinocyte. The innermost part of the cell envelope tesy of Dr. Albert I. Farbman.)
mem brane that contrib utes to the strong mechanical
properties of the barrier. The th ickness of the CE in- consists primarily of loricrin molecules (pink spheres) that are cross-
linked by small proline-rich (SPR) proteins and elafin. The layer adja-
creases in epithelia that are subject to considerable me-
cent to the cytoplasmic surface of the plasma membrane consists of
chanica l stress (e .g., lip, palm of the hand, sole of the tio n of the epidermal barrier over large areas, as in severe 14 .7). T hey ar e called dendritic cells because the round ed
the two tightly packed proteins involucrin and cystatin a . Kerati n fila-
foot) . T he CE is formed by cross-link ing small proline- ments (tonofilaments) bound by filaggrin are anchored into the cell burns, can lead to life-threaten ing loss of fluid from the cell body res ides in the basal la yer and extends long
1'ich (SPR) proteins and larger structura l proteins. The envelope. body. processes between the keratinocytes of the stratum spin-
stru ctural proteins include cystatin, desmosomal pro- osum. Neither the processes nor the cell body forms
teins (desmoplakin), elafin, envoplaldn, filaggrin, in- Melanocytes desmosomal attachments with neigh boring kera tinocytes.
volucrin, five different keratin cha ins, and loricrin. Lori- H owever, melanocytes that reside close to the basal lanuna
in cell signa ling and are pa rti a ll y respons ible fo r induc-
erin is the major structural protein and accounts for Neural crest-derived melanocytes are scattered among the have structures that r esemble hemidesmosomes. The ratio
ing cell differentiation, triggering apoptosis, and reduc-
almost 80% of the total CE pro tein mass. Tllis 26-kDa basal cells of the stratum basale of melanocytes to keratinocytes or their precursors in the
ing cell proliferation. As the cells continue to move
insolu ble protein has the highest glycine con tent of any basa l layer ranges from 1:4 to 1:10 in different parts of the
toward the free surface, the barr ier is constantly main-
known protein in the bod y. Du ring embryon ic li fe, m elanocyte precursor cells body and is constant in a ll races. ln routine hematoxylin
tained by keratinocytes entering the process of terminal
The lipid envelo[Je, a 5-nm-thick layer of lipids at- migrate from th e neur al crest and enter the deve loping and eosin (H&E) prepa rations melan ocytes are seen in the
differentiation. Lamellae may remain as recognizable
tached to the cell surface by ester bo nds. T he maj o r epiderm is. A specific functiona l association is th en esta b- str atum basa le with elongated nuclei surro unded by a clear
disks in the intercel lula r space or may fuse into broad
lipid components of the lipid envelope are ceramides, lished, the epidermal-melanin unit, in w hich one me- cytoplasm. With the TEM, howevet; they are readily iden-
sheets or layers.
wh ich belong to the class of sphingolipids; cholesterol; la nocyte mainta ins an associa tion w ith a given number of tified by the developing and mature melanin gran ules in
and free fatty acids. However, the most important Experiments have shown that the epidermis of animals keratinocytes. T his ratio va ries in different parts of the the cytoplasm (Fig. 14.8). Mela nocytes maintain the ca-
component is the monomolecu lar layer of acylglucosyl- w ith induced essential fatty acid deficiency (EFAD) is more body. pacity to repl icate th roughout their life, altho ugh at a
ceramide, wh ich provides a "Teflon-like" coating on permeable than normal to water. The membrane-coating The epiderma l melanocyte is a dendritic cell that is scat- much slower ra te tha n keratinocytes, thus ma intaining the
the cell surface. Ceram ides also play an important role granul es a lso have fewer lamellae tha n normal. Destruc- tered amo ng the basal cells of the stratum basale (Fig. epidermal-melanin unit.
408 C HAP TE R 14 l~ttegumelll<lry System C HAPTER 14 l~ttegum r 11tary Systrm 409
arrector pili muscle the shape of its proximal end. Eccrine sweat glands, which a re distributed over the en-
Hairs vary in size from long, coarse terminal hairs that may
sebaceous g land tire body s urface except for the lips and part of t he ex-
reach a meter or more in length (sca lp hair and beard hair in
internal root sheath ternal ge nita lia.
males) to short, fine vellus hairs that may be visible only with
the aid of a magnifying lens (vellus hairs of the forehead and Apocrine sweat glands, which are limi ted to the ax illa,
anterior surface of the forearm). Terminal hairs are produced areola and nipp le o f the m amm ary g land, skin around
by large-diameter, long follicles; vellus hairs are produced by the a nus, and the external genitalia. The ceruminous
relatively small follicles. Terminal hair follicles may spend up to glands of the external acoustic m eatus ca na l and the
several years in anagen and only a few months in telogen. In apocrine glands of eyelashes (glands of Moll ) are a lso
the balding individual, large terminal follicles are gradually apocrine-type g lands.
blood vessel connective tissue papilla converted into small veil us fo llicles after several growth cycles.
a The ratio of vellus follicles to terminal foll icles increases as
Eccrine Sweat G lands
baldness progresses. The completely bald' scalp is not hair-
FIGURE 14.14
less but is populated by vellus follicles that produce fine hairs
Hair follicle and other skin appendages. a. Diagram showing a hair The growing end of a hair follicle consists of an expanded hair bulb and remain in telogen for relatively long periods. Eccrine sweat glands are simple coiled glands that regulate
follicle. Note the cell layers that form the hair shaft and the surround (HB) of epithelial cells that is invaginated by a papilla of connective tis- body temperature
lng external and internal root sheaths. The sebaceous gland consists sue. The epithelial cells form the unspecialized matrix surrounding the
of the secretory portion and a short duct that empties into the in- papilla; as the cells leave the matrix, t11ey form cell layers that differ- Eccrine sweat glands a re independent s tructures, not as-
fundibulum. The arrector pili muscle accompani es the sebaceous entiate into tile shaft of the hair and the inner and outer root sheaths sociated with the hair fo llicle that arises as a downgrow th
gland; its contraction assists in gland secretion and discharge into the of tile hair fo llicle (HF). Note that several oblique and longitudinal sec- SEBACEO US GLANDS from the feta l epidermis. Each eccrine gland is arranged as
infundibulum. The apocrine gland also empties into the infundibulum tions of the hair follicles are embedded in the adipose tissue (AT) of the
a blind -ended, s imple, coiled tubular structure. It consists
of the hair follicle. Note that eccrine sweat glands are independent hypodermis. Some of them reveal a section of the hair. Sebaceous
structures and are not associated directly with t11e hair follicle. b. Pho- glands (SG) are visible in conjunction with the upper part of tile hair
Sebaceous glands secrete sebum that coats the hair and skin of two segments: a secretory segment lo cated deep in the
tomicrograph of H&E-stained section of thin skin from human scalp. follicle. x 60. surface dermis or in the upper part of the hypodermis and a di-
rectly continu o us, less coiled duct segment that leads to th e extends to the face a nd to th e rest o f th e bo dy, and occurs , gentle sp ira l course until it reaches the epidermis, w here it
then continu es in a tighter spiral to the surface. When the
epiderma l surface (Fig. 14. 16). last on the pa lms and soles. Under conditions of emo- secretory d uct enters the epidermis, however, the duct cells end and
Eccrine sweat glands play a major role in temperature ti o na l stress, howeve1~ th e pa lms, soles, and axillae are component the epiderma l cells fo rm the wall of the duct. T he duct is
~
regulation th ro ug h the cooling that results fro m evapora- the first surfa ces to sweat. Control of th ermoregul a tory composed of stratified cuboidal epithelium, consisting of a
tion of water from sweat on the bod y surface. The secre- swea ting is cholinergic, wh ile emotional sweating may be FIGURE 14.16 basa l cell layer a nd a lu mina l cell layer. T he duct cells are
tory portio n of the glands prod uces a secretion similar in stim ulated by ad renergic po rtions of the sympathetic di- Photomicrograph of an eccrine sweat gland. This photomicrograph smaller a nd appear darker than the cells of the secretory
co mpositio n to an ultrafiltrate of blood. Reso rpti on of vision of the a uto nomic nervous system. of a HaE-stained section of human skin shows profiles of both the portio n of the gla nd . Also, the duct has a smaller di a meter
some of th e sodium a nd wa ter in the duct r es ults in the r e- secretmy component and the duct of an eccrine sweat gland. The se- than the secretory portion. In co ntrast to the secretory por-
lease of a hypoto ni c sweat a t the skin surface. T his hypo- The secretory segment of the eccrine sw eat gland contains cretory component appears as a double layer of cuboidal epithelial tion of the eccrine gland, th e d uct portion d oes not possess
to ni c watery solution is low in protein and conta ins va ry- three cell types cells and peripherally, within the basal lamina, a layer of myoepithe- myoepithelia l cells. These fea tures are useful in distin-
lial cells. The duct portion of the gland has a narrower outside diam-
ing amounts of sod ium chloride, urea, uric ac id, and g uishing the d uct from the secretory portion in a histol ogic
eter and lumen than the secretory portion of the gland. It consists of
am monia. T hus, th e eccrin e sweat gland a lso serves, in Three cell types are present in the secr etory segment of section (see Fig. 14. 16) .
a double layer of small cuboidal cells without the myoepithelial cells.
pa rt, as an excretory organ. the gland : clem cells and dark cells, both of which a re se- T he basa l or periphera l cells of the d uct ha ve a r o unded
X 320.
Excessive sweating ca n lead to loss o.f other elec- cretory ep ithelial cells, a nd myoepithelial cells, which are o r ovoid nucleus and contain a prom inent n ucleolus. T he
tro lytes, such as potassiu m and magnesium, a nd to contractile epithelial cells (Fig. 14.1 7 ). All of the cells rest cytoplasm is fi lled with m itochondria and ribosomes. T he
s ignificant water loss. Norma lly, the bod y loses a bo ut on the basa l lamina; thei r arrangement is that of a pseu- acid-Schiff (PAS) metho d. l n routine H &E prepara- apica l or lumi nal cells are smaller than the basal cells, but
600 mL of water a da y through evaporation from the dostratified epithelium. tio ns, the cytoplasm of clear cells sta ins poorly. Mem- their nuclei are similar in appearance. The most consp icu-
lungs and skin . Under condi tions of high a m bient tem- bra nous orga nelles include n umerous mi tochondria, o us feat ure of the lumi na l cells is the deeply sta ined, glassy
pera tu re, wate r loss can be incr eased in a regulated ma n- Clem cells are characterized by ab undant glycogen. The profiles of sER , and a relative ly sma ll Golgi apparatus. (hya linized ) ap pearance of the apical cytoplasm . The
ner by an increased rate of sweating. T his themto1'egula- g lycogen is conspicuous in Fig. 14.1 7a beca use of its T he plasma mem bra ne is rema rkab ly a mpl ified a t the g lassy appearance is due to the presence of large num bers
t01y sweating first occurs on the fore head and sca lp, amount it wou ld stain intensely w ith the perio dic lateral and apical surfaces by extensive cytoplasm ic of aggrega ted to nofilaments in the apical cytoplasm.
C HAPTER 14 lutegumwtnry System 4 19
Figure 1, skin, human, H&E x 45. shaped surface contours represent a cross section through
In thi s sample of thick skin, the epidermis (Ep) is at the the minute ridges on the surface of thic k ski n that produce
top; the re mainder of the field consists of dermis, in which a the characteristic fingerprints of a n individual.
large nu mber of sweat glands (SW) can be observe d. Al- In addition to sweat glands, the dermis displays blood
though the layers of the epidermis are examined more ad- vesse ls (BV) and adi pose tissue (AT). The ducts of the sweat
vantageously at higher magnification (e.g., Fig. 3), it is easy glands (D ) extend from the glands to the epidermis. One of
to see, even at this relatively low magnification, that about the ducts is show n as it enters the epidermis at the bottom
ha lf of the thickness of the epidermi s consists of a distinc- of an epithelial ridge. It wi ll pass through the epiderm is in
tive surface layer that stains more lightly than the remainder a spiral course to open onto the skin surface.
of the epidermis. This is the keratini zed layer. The dome-
Figure 2, skin, human, H&E x 60. follicle. Often, as in th is tissue sample, the hair fo llic les
A sample of thin skjn is show n here to compare with the and the glands, both sebaceous and sweat, extend beyond
thick skin in Figure I . In addi tion to sweat glands, th in the dermis (D e) and in to the hypodermis. Note the blood
skin contains hair foll ic les (HF) and their associated seba- vessels (BV) a nd ad ipose ti ssue (AT) in the hypoderm is.
ceous glands (SCI). Each sebaceous gland opens into a hai r
Figure 3, skin, human, H&E X320; inset X640. hyalin granules (anvwhead, inset). O n the surface is the
The layers of the epidermis of thin ski n are shown here stratum corneum (SC). This consists of keratini zed cells,
at hi ghe r magni fication. T he cell layer that occupies the i.e., cells that no longer possess nuclei. The keratin ized
deepest locati on is the stratum basale (SB). T his is one cell cells are flat and generally adhere to other cells above and
deep. Just above this is a layer several cells in th ickness, the below without evidence of cell boundaries. In thick skin , a
st ratu m spinosum (SS). It consists of cells that have spinous fifth layer, the stratum luc idum, is seen between the stratum
processes on their surface. T hese processes meet with spi- granul osum and the stratum corneum. The pigment in the
nous processes of ne ighboring cells and , togethe r, appear as cells of the stratum basale is me lanin; some of this pigment
intercellular bridges (arrows, inset). The next layer is the ( P) is also present in connective ti ssue cells of the dermis.
stratu m granulos um (SGr), whose cells contain kerato-
KEY
AT, ad ipose tissue J>, pig ment SS, stratum spinosum
BV, blood vesse ls S B, stratum basale SW, sweat gland
D, duct of sweat g lands SC, stratum corneum a nowhead (inset), granules in cell o f stra-
De, dennis SGI, sebaceous gland tum granulosum
Ep, epidermis SG r, stratum granulos um a rrows (inset), "i ntercellu lar bridges"
H F, hair fo llicle
C H A PTER 14 luteg ~<mwtnry System 425
Figure 1, light skin, human, H&E X300. cells of the e pidermis are melanocytes. For example,
In routine H&E-staine d paraffin sections of lig ht skin, Langerhans' cells may also appear as clear cells, but they
such as thi s sample, the m elanocytes are among the cells are located more superficially in the stratum spinosum.
that appear as small, rounded, clear cells (CC) mi xed with Merkel's cells may also appear as clear cells, thus making
the other cells of the stratum basale. However, not all clear it difficult to identify these three cell types with certainty.
Figure 2, dark skin, human, H&E x300. in keratinocytes of the stratum spinos um and in the stratum
In clark skin, most of the pigme nt is in the basal portion corneum. In lig ht skin, the melanin is broken down before
of the epidermi s, but it is also present in cells progress ing it leaves the upper part of the s tratum spinosum . Thus, pig-
toward the surface and within the no nnucleated cell s of the ment is not seen in the upper layers of the epiderm is.
ke ratini zed layer. The anvws indicate the melanin pigment
Figure 3, skin, human, H&E and elastin stain thick and conspicuous in the reticular layer (see a lso inset),
X200; inset x 450. whe re they appear as the dark-blue profiles, some of which
This fi gure is included because it s hows certain features are e longate, whereas others are short. In the papillary
of the dermis, the connective tissue layer of the skin. The layer, the elastic fib ers me thinner and relative ly sparse (ar-
dermis is di v ided into two layers: the papillary layer ( PL) of mws). The inset shows the typical eosinophilic staining of
loose connective ti ssue and the reticular layer (RL) o f more the thick coll agenous fib ers in the reti cular layer. Although
dense connective tiss ue. The papillary layer is immediate ly the collagenous fibers at the lower mag nification of thi s fi g-
under the epidermis. It includes the connective ti ss ue papil- ure are not as pro mine nt, it is neverthe less poss ible to note
lae that project into the undersurface of the epidermis. The that they are thicker in the reticular layer than in the papil-
reti cul ar layer is deep to the papillary layer. The boundary lary layer. The papillary layer is evide ntly more ceJJul ar
between these two layers is not demarcated by any specific than the retic ular layer. Many of the s mall dark-blue pro-
s tructural feature except for the change in the histo logic files in the reticul ar layer re present oblique and cross sec-
compos ition of the two layers. tio ns through elastic fibers (see inset) and not nuclei of
This spec imen was s tained with H&E and also w ith a ce ll s.
procedure to display elast ic fibers ( EF). They are relatively
KEY
CC, clear cells PL, papi ll ary layer arrows, Figure 2, pigment in different lay-
EF, e lastic fibers RL, reticul ar layer ers of e pidermis; Figure 3, delicate el astic
fi bers
424
C HAPTER 1 4 /ntrgnmmtary System 4 '2 7
Figure 1, skin, human, H&E x120; insets x1 200. These can be seen in the uppet rectangulm inset. The ep-
Figure 2, skin, human, H&E X400; inset X800. ductal unit (D). T he duct has been cut as it tu rns, so that in
KEY
aSG, apocrine sweat gland G, granules in apocrine secretory cells arrowheads, myoepithelial cell cytoplasm
BV, blood vessel HF, hair foll ic le arrows, myoepithelial cell , nuclei
C, capill ary SG, eccri ne sweat g land, secretory portion astel"isk, lumen of eccrine duct
D, duct of eccrine sweat g land
CHAPTER 14 IHie!JIIIIi rllifl ry Sysir111 4 29
Figure 1, skin, human, H&E x 1000. are of two types, designated dark cells and clear cells. Un-
Figure 2, skin, human, H&E x 160. rounding the hair shaft. The sebaceous gland (Seb) appears
Figure 3, skin, human, H&E X320. hair follicle . The sebaceous secretion inc ludes the entire
The same sebaceous gla nd as in Figure 2 is shown here cell, and therefore, cells need to be replaced constantly in
at higher magnification. Numbers 1 to 4 show a series of the functional gland. Cells at the periphery of the gland are
cells fi lled with an inc reasing ly greater amount of lipid and basal cells (BC). Dividing cells in the basal layer replace
progress ively closer to the opening of the gland into the those that are lost with the secretion.
KEY
BC, basal cells RS, external root sheath of hair folli cle asterisks, lumina of glands
CT, connecti ve tissue Seb, sebaceous gland large arrows, myoepithelial cell cytoplasm
D, duct of eccrine sweat gland SG, secretory component of eccrine sweat (longitudinal section)
eRS, junction between sebaceous gl and and gland numbers 1 to 4 (Fig. 3), see text
external root sheath arrowheads, myoepi theli al cell cytoplasm small aiTOWS, intercell ular canaliculi
M, myoepithel ial cell (cross section)
428
C HAPTER 14 hrtegumrulnry System 43 )
tE
Figure 4, skin, human, H&E x550. area of the dermal papill a. The flat spi1aJ path of the neuron
At the even hi ghe r magnificati on of this figure, the close (not seen) and its supporting cells is evident here, as is the
appositi on of Meissner's corpuscle to the undersurface of fibrous capsule (FC) that surrounds the ending.
the epidermis is well demonstrated tluoughout the e ntire
KEY
0, ducts of sweat glands Hy, hypodermi s SG, sweat glands I
De, dermis MC, Mei ssner's corpuscles arrowhead, nerve fiber in center of Pacin- I
E p, epidermis N, nerve bund les ian corpusc le I
FC, fibrous capsule PC, Pac inian corpuscles J) h
430
lutegumwlary Systron 433
CHA PTER 14
.....
... ,.., . -. . .
PLATE 43. HAIR FOLLICLE AND NAIL
Hairs are composed of keratinized cells that develop from hair follicles. H airs are present over almost the entire body, be-
ing conspicuously absent only from the sides and palmar surfaces of the hands, from the sides and plantar surfaces of the feet,
from the lips, and from the skin around the urogeni ta l orifices. Coloration of the ha ir is due to the content and type of melanin
that it contains. The follicle varies in appearance, depending on whether it is in a growing or a resting phase; the growing fol-
licle is the more e laborate.
The skin appendages (adnexa), especially hai r follicles and sweat glands, are particularly important in healing of skin
wou nds. They serve as the source of new epithelial cells when there is extensive loss of epidermis, as in deep abras ions and
second-degree burns.
B
Figure 1, skin, human, H&E x 300; inset X440. The root sheath (RS) has two parts: the outer root sheath,
The growing end of a hair follicle consists of an ex- whic h is continuous with the epidermis of the skin, a nd the
panded bulb of epithelial cells that is invaginated by a inner root sheath, which extends only as far as the level at
papilla (HP) of connective tissue. The epithelia l cells sur- which sebaceous g lands enter the hair follicle. The inner
rounding the papilla at the very tip of the follicle are not yet root sheath is furthe r di vided into three layers: Henle's
specialized; they constitute the matrix, the region of the hair layer, Huxley's layer, and the cuticle of the inner root
follicle where cell division occ urs. As the cells leave the ma- sheath. These layers are seen in the growing hair follicle '
tlix, they form cell layers that will become the shaft of the
hair and the inner and oute r root sheaths of the ha ir follicle.
and are show n at higher magnification in the inset with
numbers I to 5: 1, cells of the outer root sheath; 2, He nle's '
....
'
The cells that will develop into the shaft of the hair are layer; 3, Huxley's layer; 4, cuticle of the inner root sheath;
seen just to the right of the expanded bulb. They constitute and 5, future c uticle of the hair.
tl1e cortex (C), medulla (M ), and c uticle (asterisks) of the Many of the cells of the growi ng hai r follicle contain
hair. The cells of the cortex become keratinized. T his layer pigment that contributes to the color of the hair. Most of
will come to constitute most of the hair shaft as a thick this pigment is inside the cell (inset); however, in very dark
cylinder. The medulla forms the centrally located axis of hair some pigment is a lso extracell ular.
the hair shaft; it does not always extend through the entire The connective tissue surrounding the hai r follicle forms
le ngth of the hair and is absent from some hairs. The cuti- a distinct layer referred to as the sheath, or dermal sheath
cle consists of overlapping cells that ultimately lose their (DS), of the hair follicle.
nuclei and become filled with keratin. The c uticle covers
the hair shaft like a layer of overlapping shingles.
Figure 2, skin, human, H&E x 12. itheli um under the nail and the unde rlying dennis (D) con-
KEY
8, bone Hypon, hyponychium SL, stratum lucidum
C, cortex M, medulla asterisks, cuticle of hair
D, dermis N, nail or nail plate numbers : /, external root sheath; 2, Henle's
DS, dermal sheath NM, nail matrix layer; 3, Huxley's layer; 4, cuticle of in-
EP, epiphyseal plate NR, nail root ner root sheath; 5. futu re cuticle of the
Epon, eponychium PC, Paci nian corpuscles hair
HP, dermal papilla of hair follicle RS, root sheath
o f the al imentary can al are m orp ho logica lly specia lized for ch eeks, and teeth. T he oral cavity proper lies behind the
specific aspects of d igestion and absorption. teeth and is bounded by the ha rd and soft palates s uperi -
After preliminary maceration, moisten ing, and forma- orl y, the tong ue and th e Aoor of th e mouth inferiorly, a nd
tion into a bolus by the actions of rhe structures of the oral the entrance tO th e o ropha rynx posteriorly.
cavity a nd sa livary glands, food passes rap idly th ro ug h the Each of the th ree majo1' salivmy glands are paired struc-
pharynx to the esoph agus. The ra pid passage of food t ures; t hey include the
Digestive System 1: thro ugh the ph arynx keeps it clea r for the passage of air.
The food passes more slowly through the gastrointesti na l
traer, and during its transit th rough the stomach and small
Parotid gland, th e largest of the three glands, located in
the temporal region of the head. Its excretory duct, th e
Oral Cavity and intestin e, the major alterations associated with digestion,
solu bilization, and absorption occu r. Absorption occurs
chiefly through t he wall of the sma ll intestine. Und igested
parotid (Stensen's) duct, opens at t he parotid papilla, a
small elevation o n the mucosal surface of the cheek op-
posite the second upper mola r tooth.
Associated Structures food and other substa nces w ithin the a lime nta ry ca na l,
such as mucus, bacteria, desqu a ma ted cells, a nd bile p ig-
ments, a re excreted as feces.
Submandibular gland, located in the submandibu lar tri-
angle of the neck. Its excretory duct, the submandibular
(Whm1:on's) duct open s a t a small flesh y prominence
(the sublingual caruncle) on each side of the ling ual
The alimentary mucosa is the surface across which most frenulum on the fl oor of the oral cavity.
OVERVIEW OF THE DIGESTIVE SYSTEM 434
substances enter the body Sublingual gland, lying inferior to the tongue withi n the
ORAL CAVITY 435 sub lingual folds a t the flo or of the oral cavity. It has a
TONGUE 437 The a limenta ry mucosa performs numerous functions in nu mber of sma ll excretory ducts; some enter the sub-
TEETH AND SUPPORTING TISSUES 440 its role as an interface between the body a nd the environ- ma ndibu lar duct, a nd others enter individually into the
Enamel 441 ment. T hese include oral cavity.
Cementum 448 Secretion. The lining of the alimentary ca nal secretes, at
Dentin 448 The parotid and subma ndibu lar gla nds have r elatively
specific sites, digestive enzymes, hydrochl oric acid,
Dental Pulp and Central Pulp Cavity (Pulp Chamber) 451 long ducts tha t extend from the secretory portion of the
mucin, a nd antibodies.
Supporting Tissues of the Teeth 452 gla nd to th e o ral ca vity. The sub lingual ducts are relati vely
Absorption. The epithelium of the mucosa absorbs
short.
SALIVARY GLANDS 454 metabol ic substra tes, e.g., the brea kd own p roducts of
The minor salivmy glands ar e located in the submucosa
Secretory Gland Acini 454 di gestion, as well as vitamins, w a ter, elect ro lytes, recy-
o f the o ra l ca vity. They e mpty directl y into the cavity via
Salivary Ducts 456 clable ma terials suc h as bile compone nts a nd choles-
short d ucts and are na med fo r their location i.e., buccal,
Major Salivary Glands 459 tero l, and other substa nces essential to the functions of
la bial, lingual, a nd pa la tine.
Parotid Gland 459 the bod y.
Submandibular Gland 459 Ban'ier. The mucosa serves as a ba rrie r to prevent the
The tonsils consist of aggregations of lymphatic nodules that
Sublingual Gland 459 entry of noxious substa nces, a ntigens, a nd pa thogenic
are clustered around the posterior opening of the oral and
Saliva 459 o rga n isms.
nasal cavities
Immunologic protection. Lym phatic tissue within the
BOXES mucosa serves as the body's first line of immune defense.
Lymphatic tiss ue is o rga ni zed into a tonsillar 1ing
BOX 15. 1. Clinical Correlations: Inherited Absence of Taste 440
The functions listed a bove are disc ussed at the beginning (Waldeyer's l'ing) of immunologic protection lo cated at the
BOX 15.2. Clinical Correlations: Classification of Permanent (Secondary) and
of th e n ext chapter. Th e digestive system is co nsidered in shared en trance to the digestive and respiratory tracts.
Deciduous (Primary) Dentition 441
three chapters t hat dea l, resp ectively, w ith the oral cavity This lym phatic tissue surrounds th e posterior orifice of the
BOX 15.3. Functional Considerations: Histologic Preparation
and phar ynx (th is c hapte r ), the esophagus a nd gastroi n- oral a nd nasal cavities and contai ns aggregates of lym-
of Tooth Tissues 449
testi na l trac t (Chapter 16 ), a nd the liver, gallbladder, and p ha tic nodules tha t include
BOX 15.4. Clinical Correlations: Dental Caries 453
pa nc reas (C hapte r J 7).
Palatine tonsils, o r simpl y the tonsils, which are located
at either side of the ent ra nce to the oro pharynx between
9 ORAL CAVITY th e pa latopha ryngea l a nd pa latog lossa l arc hes
Tubal tonsils, w h ich a re located in the lateral wa lls of
9 OVERVIEW OF THE DIGESTIVE The lumen of the alimentary canal is physically and
The oral cavity consists of the mouth and its structures, which the nasopha ryn x p osterior to the opening of the audi-
SYSTEM functionally external to the body
include the tongue, teeth and their supporting structures tory tube
(peridontium), major and minor salivary glands, and tonsils Pharymgeal tonsil, o r adenoid, which is loca ted in th e
The digestive system co nsists of th e alimentary canal a nd As it passes thro ugh the alimenta ry canal, food is broken roof o f the n asopharynx
its principa l associa ted organs, name ly, th e tongue, teeth, down ph ysically and chemi cally so that the degraded prod- T he oral cavity is di vided into a vestibule and th e oral Lingual tonsil, wh ich is loca ted a t the base of the ton gue
salivary glands, pancreas, live1; and gallbladde1: ucts can be absor bed into t he body. The various segments cavity pmper. The vestibule is the space betwee n th e lips, on its superior surface
434 435
436 C HAPTER 15 Digrstim Systr111 [, Om/ Ctwity '""/ Associntrd Structures C HAPTER 1 5 /Jiyestioe Systr111 /: Om/ Cnoity nut! Associntrd Stmcl~~res 437
The oral cavity is lined by a masticatory mucosa, a lining true of the gingiva. \Xlhere there is a subm ucosa underlying T he cells of the mucosa l epithelium are sim ilar to those of their associa ted taste buds constitut~ the specialized mu-
mucosa, and a specialized mucosa the lamina propria on the ha rd palate (see Fig . 15.1), it con- the e pidermi s of the skin an d include ker atinocytes, cosa of the oral cavity. Four types of papillae are described:
tains adipose t issue anteriorly (fa tty zone) and mucous La ngerha ns' cells, melanocytes, an d Mer kel's cells. filiform, fungifomt, circumvallate, a nd foliate.
The masticatory mucosa is found on the gingiva (gums) glands posteriorly (gla ndu lar zone) that are continuo us with The la mina propria contains b lood vessels, nerves that
and the hard palate (Fig. 15 .1 ). It has a keratinized and, in Filiform papillae ar e t he sm allest a nd most numerous in
those of t he soft p alate. In the su bmucosal regions, thick col- send bare axon endings in to the basa l layers of the epithe-
some areas, a pamkeratinized stratified squ amous epithe- humans. They are con ica l, elonga ted pro jections of con-
lagenous bands extend from the mucosa to the bone. liu m, a nd encap sulated sensory e ndings in some papillae.
lium (see Fig. 15 .2). Parakerat inized epitheli um is similar to nective tiss ue tha t are covered w ith highly keratinized
Lining mucosa is fo und on th e lips, ch eeks, alveolar mu- T he sharp contrast between the numero us d eep papillae of
keratinized epithelium except that the superficia l cells do not stratified squa mous e pithelium (Fig. 15.4a). This epithe-
cosa l surface, floor of t he mouth, inferior surfaces of t he t he a lveola r mucosa and the shallow papillae in the rest of
lose their nuclei a nd their cytoplasm does not stain intensely limn does not contain taste buds. The papillae serve only
tongue, and soft palate. At these sites it covers striated mus- the lining mucosa allows easy iden tificati on of the two dif-
with eosin . The nuclei of the p arakeratinized cells are py- a mechanical r o le. Filiform papillae are distributed over
cle (lips, cheeks, a nd tongue), bone (alveolar muco sa), and fe rent regio ns in a histo logic section .
knotic (hi ghly condensed ) a nd remain until the cell is exfoli- the entire ante rior d orsa l surface of the tongue, with
glands (soft palate, c heeks, inferi or surface of the tongue). A distinct submucosa underli es the lining mucosa except
ated (see Fig. 15.2). The keratinized e pithelium of th e masti- their tips pointing backward. They appear to form rows
The lining mucosa has fewer an d shorter papillae so that it o n th e inferior surface of the tongue. This la yer contains
catory mucosa resembles that of the sk in but lacks a stratum that d iver ge to the left an d right from the midline a nd
can adjust to the movement of its underlying muscles. large bands of collagen a nd elastic fibers that bind the mu-
lucidum. The underlying lamina propria consists of a thick tha t p a rallel the arms of the sulcus terminalis.
Gene rally, the epitheli um of t he lining mucosa is non ker- cosa to the underlying muscle; it a lso contai ns the many
papi lla ry layer of loose cotmective tissue tha t contains blood min o r salivary gla nds of the lips, tongue, and c heeks. Oc-
Fungiform papillae, as the name implies, are mush-
a tinized, a lthough in some places it may be parakera-
vessels and nerves, some of which send ba re axon endings room -s haped p rojections loca ted on the dorsal sur face
tiuized. The epi th elium of t he verm ilion border of th e lip casionall y, sebaceous gla nds not associated w ith a hair fol-
into the epithelium as sensory receptors, a nd some of wh ich (t he reddish portion between the mo ist in ner surface and licle a re foun d in the submucosa just la teral to the corner
end in Meissner's corp uscles. Deep to the lamina propria is the facial skin ) is kerati n ized. The nonkeratin ized li ni ng of the mouth and in t he cheeks opposi te t he mo lar teeth.
a r eticu lar layer of mo re d ense connect ive tissue. epithelium is t h icker t han keratinized e pithelium. It con- T hey a re visible to th e eye and a re called Fordyce spots.
As in the sk in, the depth a nd number of con nect ive tissue sists of only three layers: The submucosa contains th e larger blood vessels, ner ves,
papillae contribute to the rela t ive immobility of t he m asti- a nd lym p hatic vessels th a t supply th e subepithelial neu-
catory mucosa, thus protecting it from frictiona l a nd shea r- Stratum basale, a si ngle layer of cells resting on the rovascular networks in the lamina propria thro ug hout t he
ing stress. At the mid line of the hard p ala te, in the palatine basal lamina ora l ca vity.
raphe, the mucosa ad heres firml y to the underl ying bone. Stratum spinosum, w hi ch is severa l cells thick Specialized mucosa is restri cted to t he dorsa 1 surface of
The reticular layer of the lamina propria blends with the Stratum supe1jiciale, the most supe rficial layer of cells, the tongue, w h ere it contains papillae a nd t aste buds.
pe riosteum, an d thus there is no submucosa . The same is also referred as th e su1face layer o f t he muco sa
9 TONGUE
parakeratinized
incisive papilla
epithelium The tongue is a muscular organ p rojecting into the oral cav-
-- -- \ ity from its inferior surface. Lingual (i.e., pertaining to the
tongue) muscles a re both extrin sic (havi ng one a ttachment
o utside of the tongue) a nd intrinsic (confined ent irely to the
tongue, w ithout external attachment). The striated muscle
of th e tongue is arranged in bundles that generally run in
th ree planes, with each arranged at right a ngles to the other
two. This arra ngement of muscle fibers allows enormous
flex ibility a nd precision in the movemen ts o f the tongue1
~
which a re essen tial to huma n speec h as well as to its role in
raphe digestion a nd swallowing. This form of m uscle organizat ion
is fo und only in th e tongue, which a llows easy identi fication fl!Jiilgiferrm
of this tiss ue as lingua l muscle. Variabl e amou nts of adipose papillae
tissue are fou nd among the muscle fiber groups.
Grossly, the dorsal surface of the tongue is d ivided into
an anterior two thirds and a posteri or o ne third by a V-
sha peel depression, t he sulcus tenninalis (Fig. 15.3) . T he
FIGURE 15.1 FIGURE 15.2 a pex o f the V points posteriorly a nd is the locatio n of the
Roof of oral cavity. The hard palate, which contains bone, is bisected Stratified squamous epithelium of the hard palate. This photomicro- foramen cecum, t he r em nant of the site fro m w h ich an
into right a nd left halves by a raphe. Anteriorly, in the fa tty zone, the graph sllows a transition in the oral mucosa from a stratified squa-
evagina tion of th e floor of the embryon ic pha ryn x oc-
submucosa of the hard palate contains adipose tissue; posteriorly, in mous epithelium (on the right) to a stratified squamous parakera FIGURE 15.3
c u rred to form t he thyroid gland.
the glandular zone, there are mucous glands within the subm ucosa. tinized epithelium (on the left). Tile flattened surface cells of the Human tongue. Circumvallate papillae are positioned in a v configu-
Neither the raphe nor the gingiva conta ins a submucosa; instead, the keratinized epithelium are devoid of nuclei. The layer of keratohyalin ration, separating the anterior two thirds of the tongue from the pos-
granule-containing cells is clearly visible in this type of epithelium. Papillae cover the dorsal surface of the tongue terior tl1ird. Fungiform and filiform papillae are on the anterior portion
mucosa is attached directly to the bone. The soft palate has muscle
instead of bone, and its glands are continuous with those of the hard The flattened surface cells of the parakeratinized epitheli um display of the dorsal tongue surface. The uneven contou r of the posterior
palate in the submucosa. (Based on Bhaskar SN, ed. Orbans Oral His the same characteristics as the keratinized cells, except they retain Nu mero us m ucosal irreg ularities an d elevatio ns ca lled tongue surface Is due to the lingual tonsils. The palatine tonsil is at
tology and EmbJyology. St. Louis: CV Mosby, 1991 .) tlleir nuclei; i.e., they are parakeratinized. In add ition, note the paucity li1tgual papillae cover the dorsal sur face of the tong ue a n - the junction between the oral cavity and the pharynx. (Specimen
of keratohyali n granu les present in t11e subsurface cells. X 380. terior to the sulcus termina lis. The lingua l papillae a nd Courtesy of Dr. Gunther von Hagen.)
f
43 8 CHAPTER 15 Digestive Sy stem L O wl Cavity mrrl Associntrd Strrrctrms CHAPTER 15 Digestive Systerrr I: Orn/ Cavity mrd Associated Structu res 439
foliate papilla their serous secretion into the base of the moats. T his se- Taste buds are present on f ungiform, foliate, and circumvallate
cretion presumably flushes material from the moat to en- papillae
able the taste buds to respond rapidly to changing stimuli.
Foliate papillae consist of parallel low ridges separated In histologic sectio ns, taste buds appear as oval, pale-
by deep mucosal clefts (see Fig. 15.4c), w hich are aligned staining bodies that extend through the thickness of the ep-
at r ight angles to the long axis of the tongue. They occur ithelium (Fig. 15.5). A small opening onto the epithelial
on the lateral edge of the tongue. In aged individuals, the surface at the apex of the taste bud is called the taste pore.
foliate papillae may not be recognized; in younger indi- Three p rincipal cell types are fo und in taste buds:
viduals, they are easily fo und o n the posterior lateral sur-
face of the tongue and contain many taste buds in the ep- Neuroepithelial (sensory) cells are the most numerous
ithelium of the facing walls of neighboring papillae (Fig. celts in the taste bud. These elongated cells extend fro m
15.3e). Sma ll serous glands empty into the clefts . In some the basal lamina of the epithelium to the taste pore,
animals, such as the rabbit, foliate papillae constitute the through wh ich the tapered apical surface of each cell ex-
principal site of aggregation of taste buds. tends microvilli (see Fig. 15.5 ). Near their apical surface
they are connected to neighboring neuroepithelial o r
The dorsal surface of the base of the tongue exhibits supporting cells by tight junctions. At their base they
smooth bulges that reflect the presence of the lingual ton- form a synapse with the processes of afferent sensory
sil in the lamina propria (see Fig. 15. 3). neurons of the facial (cranial nerve VII), glossopharyn-
fungiform papilla
taste pore
U--l.P~4--::::::=~ sensory
FIGURE 15.4 cells
a. Structurally, the filiform papillae are posteriorly bent conical pro- buds on their lateral surfaces. The free surface epith elium of each
j ections of the epithelium. These papillae do not possess taste buds papilla is thick and has a number of secondary connective tissue papil-
and are composed of stratified squamous keratinized epithelium. lae projecting into its undersurface. The connective tissue within and
X45. b. Fungiform papillae are slightly rounded, elevated structu res under th e foliate papillae contains serous glands (von Ebner's glands)
situated among the filiform papillae. A highly vascularized connective that open via ducts into the cleft between neighboring papillae. X45.
tissue core forms the center of the fungiform papilla and projects into d. Circumvallate papillae are covered by stratified squamous epithe-
the base of the surface epithelium. Because of the deep penetration lium that may be slightly keratinized. Each circumvallate papilla is sur-
of connective tissue into the epithelium (arrows), combined witl1 a rounded by a trench or cleft. Numerous taste buds are on the lateral
very thin keratinized surface, the fungiform papillae appear as small walls of the papillae. The dorsal surface of the papilla is smooth. The
red dots w hen the dorsal surface of the tongue is examined by gross deep trench surrounding the circumvallate papillae and the presence
inspection. X45. c. In a section, foliate papillae can be distinguished of taste buds on the sides rather than on the free surface are features
from fungiform papillae because they appear in rows separated by that distinguish circumvallate from fungiform papillae. The connective
deep clefts (arrows). The foliate papillae are covered by stratified tissue near the circumvallate papillae also contains many serous-type
squamous nonkeratinized epithelium containing numerous taste glands that open via ducts into the bottom of the trench. X2 5.
a
of the tongue (Fig. 15.4b). T hey project above the fili - Circumvallate papillae are the large, dome-shaped struc-
FIGURE 15.5
for m papillae, among which they are scattered, and are tures that reside in the mucosa just anterior to the sulcus
Diagram and photomicrograph of a taste bud. a. This diagram of a the organization of the cells within the taste bud. The sensory and
just visible to th e unaided eye as small spots (see Fig. terminalis (see Fig. 15.3 ). The human tongue has 8 to 12
taste bud shows the neuroepithelial (sensoty), supporting, and basal supporting cells extend through the full length of the taste bud. The
15.3) . They tend to be more numerous near the tip of of these papillae. Each papi lla is surrounded by a moat- cells. One of the basal cells is shown in the process of dividing. Nerve apical su rface of these cells conta ins microvilli. The basal cells are lo-
the tongue. Taste buds are present in the stratified like invagination lined with stratified squamous epithe- fibers have synapses with the neuroepithelial cells. (Based on Warwick cated at the bottom of the taste bud. Note that the taste bud opens
squamo us epitheli um on the dorsa l surface of these lium that contains numerous taste buds (Fig. 15 .4d) . Ducts R, Williams PL, eds. Gray's Anatomy. 35th ed. Edinburgh: Churchill Liv- at the surface by means of a taste pore. X640.
papillae. of lingual salivmy glands (von Ebner's glands) empty ingstone, 1973.) b. This high-magnification photomicrograph shows
4 40 CH APTER 15 DitJestivt Sys trw L O rnl Cavity nun Associntr.1 Structures C H A PTER 15 DitJtstillt Sy stew f. Oral Cm>ity nun Associated Structum 44 I
the ling ua l ep ithel ium ha s the cha racter ist ics of lin ing e p-
ithe lium. M uc o us lingua l saliva ry glan ds may be seen
w ithin th e ling ua l ton sil and m ay extend in to the m uscle of
the base o f the tongue .
The general ability to taste as well as the ability to sense spe- Three systems are currently used to classify permanent and decid- Ame~ican (Universal) system, which is the most commonly used
cific tastes is genetically determined. At one extreme are those uous teeth (Fig. 15.6): notation In North America. In this system, the permanent den
rare individuals, such as wine tasters and tea tasters, who have The complex nerve supply of the tongue is provided by cranial titian is designated by arabic numerals, and the deciduous
nerves and the autonomic nervous system Palmer system, wllicll was the most commonly used nota-
prodigious taste discrimination and taste memory. At the othe r dentition is designated with uppercase letters. For permanent
tion worldwide. In this system, uppercase letters a re used
extreme are individuals who are totally unable to taste. In one dentition, numbering begins in the UR quadrant, with the UR
fo r the deciduous teeth, and ara bic numerals are used fo r
rare inherited condition, f amilia l dysautonomia, taste buds and Genera l se nsatio n for the anterio r two th ird s of th e third molar designated number 1. Numbering continues across
the permanent teeth. Each quadrant in this system is desig-
fungiform pa pillae a re a bsent. The disease may be diagnosed tong ue (a nte rior t o th e s ulcus termin a lis) is carr ied in the the maxillary arch to the UL third molar, designated tooth num-
nated by angled lines: J for upper right (UR). L fo r upper
easily in the newborn, where the absence of these papillae is mandibular division trigemittal nerve (cranial n er ve V). ber 16. Tooth number 17 is the third molar located In the LL
left (UL), 1 fo r lower right (LR), and r for lower left (LL). For
particularly clear. Ge nera l sensatio n fo r t he p oste rio r o ne th ird o f th e quadrant inferior and opposite to tooth number 16. Then, the
example, permanent canines are ca lled number 3 in
A common test used to identify tasters and nontasters is tong ue is car ried in the glossop ha ryn gea l (c ra nia l ne rve numbering progresses across tile mandibular arch and ter'llli-
each quadrant, and the quadrant is designated by its angled
to place a drop of a solution containing phenylthioca rbamide nates with tooth number 32, the LR third molar. In this sy stem,
IX ) and the vagus nerve (cra n ial nerve X ). line.
(PTC) on the tip of the tongue. Tasters report a bitter taste; non- the sum of th e numbers ofopposing teeth adds up to 33. For the
Ta ste sensation is ca rried by t he chorda tympani, a Internation al sy stem, which uses two arabic numerals to des-
tasters are unaware of any taste. deciduous dentition, the same pattern is followed, but the letters
bra nch of the facia l nerve (cra n ial nerve VII ) a nterior to ignate the individual tooth. In this system, the first numeral in-
A to T are used to designate the individual teeth. Thus, In this
the s ulc us term inalis a n d by the g lossop ha ryngea l (cra- dicates the location of the tooth in a specific quadrant. The
system, the permanent canines are designated 6, 11 , 22, and
nia l nerve IX ) a nd vagus ne rves (cr an ial nerve X ) poste- permanent quadrants are designated UR = 1, UL = 2, LL =3,
27, and the deciduous canines, C, H, M, and R.
rio r to the s ulcus. and LR = 4; tile deciduous quadrants a re designated UR = 5,
UL = 6, LL = 7, and LR = 8. The second numeral designates Also note that in Figure 15.6 the colo r outline demonstrates the
geal (cra nia l nerve IX ), or vagus (cra ni al ner ve X) Moto r inne rva t ion fo r the mu sc ulature of the tong ue is
the individua l tooth, which Is numbered beginning from the relationship of the deciduous and permanent dentitions. Examina
ner ves. T he tu rnover tim e of neuroepith elial cells is supplied by the hypoglossal nerve (cranial nerve X II ).
dental midline. For example, in this system, the permanent ca- tion of the table reveals that deciduous molars are replaced with
a bout 10 days. Vascul ar a nd g la nd u la r in nervation is p rovided b y the nines are named 13, 23, 33, and 43, and the deciduous ca- permanent premolars after exfoliation and that the permanent mo-
Supporting cells are less n ume rous. T h ey a re a lso e lo n- sympathetic a nd parasympathetic tterves. They su ppl y nines would be 53, 63, 7 3, and 83 . lars have no decid uous precursors.
gated cells th a t exten d from t he basa l lamin a to the tas te blo od vessels a nd sma ll sali va ry g lan ds o f t he ton gue .
po re. Like neuroepithelia l cells, t hey con ta in micr ovilli Ganglio n cells are ofte n seen w ith in the tong ue. Th ese
o n the ir apica l surface a nd possess tig ht junctio ns, bu t cells be lo ng to postga ngli o nic pa ra sym pa thetic neu ro ns
they do no t synap se w ith t he nerve cells. The tu rn ove r a nd a re des tined for th e minor sa liva r y g la nds w it h in the A canine, which erupts at age 10 to 12 layer ends a t t he neck or cervix o f the too th at the cemen-
time of s uppo rti ng ce lls is a lso a bout 10 d a ys. tong ue. T he cell bodies o f sym pa th etic postga nglion ic Two fJremolar teeth, wh ich erupt between a ges 10 and 1 2 toenamel junction (Fig. 15 .7); the root of the tooth is then
Basal cells a re small cells located in the basa l portio n of neurons are loca ted in th e superi or cervical ga ng lion. Three molm- teeth, which er upt a t different t imes; the co vered by cementum, a bone-like material. Dentin lies
the taste b ud , near th e basa l la min a. They a re t he stem fir st mola r us ua lly er upts a t age 6, the second m o lar in deep to the enamel an d cementum.
ce lls fo r t he tw o other cell types. t he early teens, and the t hird m o lar (w isdom teeth) dur-
\1 TEETH AND SUPPORTING TISSUES ing the la te teens o r ea rl y twenties
In add iti o n to those a sso cia ted w ith the p apillae, taste Enamel
buds are a lso present o n the glossopa la tine a rch, the soft Teeth a re a major com pon en t o f the o ra l ca vity a n d a re es- Incisors, ca nines, a nd pre mo lars ha ve o ne ro ot ea ch, ex-
pala te, the p osterio r s u rfa ce o f the epiglo ttis, a nd the pos- sentia l for t he beginning of th e d igestive p rocess. Teeth a re cept fo r the firs t premolar o f th e m ax illa, which has two Enamel is the hardest substance in the body; it consists of 96%
terior wa ll of t he ph arynx down to the level of t he cricoid em bedded in an d a ttach ed to the alveo la r processes of t he roots. Mo la rs ha ve three a nd, o n ra re occasions, fo ur to 98% hydroxyapatite
ca rtilage. m axilla a nd ma ndible . Children have 10 deciduous (pri- roo ts. AU teeth ha ve the sa me basic structu re, however.
Taste buds react to o n ly fo ur stimu li: sweet, salt y, bi tter, mary, mill~) teeth in each jaw, on eac h side, consisting of The no nstoichiomenic carbo nated calcium hydroxyap-
and acid . I n genera l, taste buds a t the t ip o f the tong ue de- Teeth consist of several layers of specialized tissues atite ena mel c r ysta ls t hat fo rm t he enamel a re arranged as
tect sweet st im uli, t ho se immediately po sterola ter al t o the A medial (central) incisor, t he fi rst too t h to erupt (usu- rods tha t measure 4 JLm w ide a nd 8 J.l.m h igh . Each enam el
t ip detect sa lty stimuli, a nd t hose mo re poste ro la tera l de- a Ll y in t he ma nd ib le) a t appr oxima tely 6 mo nths o f a ge Teeth ar e mad e up of t h ree specia lized tissues: rod spa ns the fu ll t hick ness of t he ena m el layer fro m the
tect a cid o r sour testing stimuli. Taste b uds o n th e circ u m- (in some infan ts, the fi rst teeth may n o t erupt unt il 12 to de ntinoena me l junct ion to the ename l surface. When ex-
ena mel dentin
valla te pa pillae detect bitte r st im uli. 13 mo n th s of age) amined in cross sec tion a t h igher mag nification, the rods
cem entu m
A lateral incis01; w h ich e rupts at approxima tely 8 revea l a keyhole shap e (Fig. 15 .8; the ba llooned p a rt or
lingual tonsil consists of accumulations of lymphatic tissue at months Enamel is an acellular mineralized t issue t hat covers the head is orien ted superiorly and the tai l is di1ected inferiorly
the base of the tongue A cattine tooth, which erupts at a pproxima tely 15 mo nths c rown o f the too th. O nce formed it ca nnot be repla ced . towa rd the root of the tooth. T he enamel crysta ls are pri-
Tw o molar teeth, the fi rst o f whic h er upts a t 10 t o 1 9 E na mel is a uniq ue ti ss ue beca use unlike bone, w hic h is mari ly o riented para llel to the long axis of t he rod w ith in
T he lingual tousil is located in the la m ina p ropria of the mo nt hs and th e second o f w hic h er u pts a t 2 0 to 3 1 for med fr om co nnecti ve t issue, it is a mineralized material t he head, and in the t a il the y are oriented mo re obl iquely
ro ot or base of the to ngue. It is fo und posterio r to the s ulcu s mo n ths d erived from epitheliu m . Ena mel is more hig hly m inera l- (Figs. 15 .8 a nd 15.9). T he limi ted sp aces betwee n the rods
term ina lis (see Fig. 15 .3). T he ling ua l tonsil conta ins d iffuse ized a nd ha rder t ha n a ny other mi nera lized ti ss ue in the are a lso fi ll ed with en a mel c ryst a ls. Striations o bserved o n
O ver a period o f yea rs, usua ll y beginning at a bo ut age 6
lymph atic tissue with lymphatic nodu les containing germin a l bod y. T he en amel that is exposed a nd vis ible above t he gum enam el rods (contou r lines o f R etzi us) may represent evi-
center s. T hese structures ar e discussed in C hapter 13 . a nd fin ishi ng at a bo ut age 12 to 13, deciduo us teeth a re grad - line is called t he clinical crown; the anatomic crown de- dence of r hyt hmic growth of the enamel in the developing
ually rep laced by 1 6 permattent (secondaty ) teeth in each
Epith elia l crypts usua lly inva gina te into t he ling ua l to n- scri bes a ll of the tooth tha t is covered by en ame l, some o f tooth . A wider li ne of hypo mineraliza tion is observed in
sil. H o weve r, th e str ucture of the e pithel ium may be d iffi- jaw. Each side o f bo th upper a nd lowe r jaws consists o f w h ich is below the gum line. Ena mel va ries in thickness the ena mel of the decidu o us teeth. T h is line, called the
cult to di sting uish beca use o f t he extrem ely la rge n um ber A medial (cetttral) incis01; whic h er up ts a t a ge 7 to 8 o ve r the crown a nd m ay be as thick as 2 .5 mm on the cusps neona ta l line, m a rks the nu t ri t io na l cha nges that take
of lym phocytes that norm a lly inva de it. Between nod ules, A lateral incisor, w hic h eru pts at age 8 to 9 (bit ing a nd g ri nding surfaces) o f some teeth. T he ename l place between prenata l a n d po stna tal life .
44:2 CHAP TE R 1 5 D ig r slillr System /, Ornl Cn11ily mrd A ssociated Strrrclrr res CH APTE R 15 Digesti11e Sy sterrr 1: Orn/ Ctwify <11rd Associated Strllclll l'fS 443
~
I second
molar
first
molar
canine
lateral
incisor
medial
incisor
medial
incisor
lateral
incisor
canine
first
molar
second
molar
c:
c:
~
e
~
~
.5"'
~~
c
Q..Q
~ ~ ~ ~ fl ~ j ~ ~ c:
~
0....
(.)
(ij
(.)
(ij
(.)
:~
dentin showing dentinal tubules
interglobular spaces
"
.g -o
'(3
Q)
A B c D E F G H I J
e
(.)
(.)
.E 0
Q)
u 0 odontoblasts
55 54 53 52 51 61 62 63 64 65 1ii
third second
l
first
_E.]
second first
.Q] .]
canine
.!!]
lateral
~
medial
~
medial
l!!.
lateral
l
canine
l
first
[_
second first second third
c:
Cll
gingival sulcus
epithelium of gingiva
molar molar molar premolar premolar incisor incisor Incisor incisor premolar premolar molar molar molar
..!.;:1,..,.>:,-- cementoenamel junction
r lf\ ~ ~ ~ ~ u ~ D tJ ~ u
1 2 3 4 5 6 7 8 9 10 11
D
12
d (3 (J) ~
13 14 15 16
epithelial attachment
18 17 16 15 14 13 12 11 21 22 23 24 25 26 27 28
pulp canal
third second first second first lateral medial medial lateral first second first second third
molar molar molar premolar premolar
canine
incisor incisor incis or incisor
canine cellu lar cementum
premolar premolar molar molar molar
El ro re
I 01 Cl 81 A] [A [B IC
85 84 83 82 81 71 72 73 74 75
~
"' T s R Q p 0 N M L K
.5
-
..9::e
c
0
D Palmer
~ ~ 0 ~ a ~ ~ ~ ~
"'c: system
::lQJ
.g u
.,
'(3 D 0 l nternationa
system
"0
0 American
FIGURE 15.7
l second
molar
firs I
molar
4 44 C HAPTER 15 D i.!)rslillr Sysl<'tll /, Oml Cnvily n11rt Associated Stmct11res CHAPTER 15 Digrslillt Systr111 L Om/ Cn vity n111l Associntfll Stmctures 445
3 months
6 months
a b
9 months FIGURE 15.14
Ameloblasts in different stages of maturation. a. This black and
white microphotograph of an H&E-stained specimen shows matura-
tion-stage ameloblasts (MA) in demineralized tissue. The maturing
enamel has been lost during slide preparation, and the space below
FIGURE 15.13 the ameloblasts previously occupied by the enamel appears empty.
Enamel organ cells and odontoblasts in a developing tooth. Tl1is Maturation-stage ameloblasts with a striated border account for 80%
FIGURE 15.12
photomicrograph of an unstained plastic thick section viewed with of the cell population in the maturation zone. BV, blood vessels; CT,
Schematic diagrams of a partially formed tooth showing details of ing amelogenesis, enamel formation is influenced by the path of the
the phase contrast microscope shows enamel organ cells and odon- conn ective tissue; PL, papillary layer. X650. b. This photomicrograph
amelogenesis. a. The enamel is drawn to show the enamel rods ex- ameloblasts. The rod produced by the ameloblast forms in the wake
toblasts as they begin to produce enamel (E) and dentin (D), respec- shows smooth-end ed maturation-stage ameloblasts (MA), whicl1 ac-
tending from the dentinoenamel junction to the surface of the tooth. of the cell. Thus, in mature enamel, the direction of the enamel rod is
tively. Young enamel is deposited by secretory-stage ameloblasts (SA) count for 20% of the cell population in the mature zone. At the basal
Although the full thickness of the enamel is formed, the full thickness a record of the path taken earlier by the secretory-stage ameloblast.
onto the previously formed dentin. The enamel appears dark in the pole of the ameloblasts are the cells of the papillary layer (PL). A layer
of the dentin has not yet been established. The contour lines within c. At the apical pole of the secretory-stage ameloblasts are Tomes
illustration. At the top, the enamel surface displays a characteristic of stratum intermedium is no longer present during this stage of
the dentin show the extent to which the dentin has developed at a processes, surrounded by the developing enamel. Junctional com-
picket-fence pattern because of the sharp contrast between the lightly ameloblast maturation. x650.
particular time, as labeled in the illustration. Note that the pulp cav- plexes at the apical pole are also shown. Note the numerous matrix-
stained Tomes processes (TP) of the secretory-stage ameloblasts and
ity in the center of the tooth becomes smaller as the dentin develops. containing secretory vesicles in the cytoplasm of the processes.
the darkly stain ed young enamel product that partly surrounds the
(Based on Schour I, Massier M. JAm Dent Assoc 1936;23 :1948.) b. Our-
cell processes. The nuclei (N) at the right belong to cells of the stratum
intermedium. The nuclei (N) on the left belong to odontoblasts located
in the basal part of the cells. The odontoblast cytoplasm extends to
substance in the body. Amelogenins and ameloblastins are Collagen fibers that project out of the matrix of the ce- the dashed line. At this point, cytoplasmic processes (OP) extend into
removed during enamel maturation. Thus, mature enamel mentum and embed in the bony matrix of the socket wall the dentin. x 85.
contains only enamelins and tuftelins. Th e ameloblasts de- form the bulk of the periodontal ligament. These fibers are
generate after the enamel is fully formed, at about the time another example of Sharpey's fibers (Fig. 15 .15). In addi-
of tooth eruption through the gum . tion, elastic fibers are also a component of the periodontal
ligament. This mode of attachment of the tooth in its
socket allows slight movement of the tooth to occur natu-
Cementum
rally. It also forms the basis of orthodontic procedures
used to straighten teeth and reduce malocclusion of the bit-
Cementum covers the root of the tooth
ing and grinding surfaces of the maxillary and mandibular Because most parts of the tooth are highly mineralized, teeth
teeth. During corrective tooth movements, the a lveola r are prepared for histologic study by methods similar to those
The root is the part of the tooth that fits into its socket
bone of the socket is resorbed and resynthesized, but the used for bone, namely, by means of ground sections and
or alveolus in the maxilla or mandible. Cementum is a thin
cementum is not. stained demineralized sections. Ground sections are most of-
layer of bone-like material that is secreted by cemento-
ten used to study an extracted or exfoliated tooth. As in the
cytes, cells that closely resemble osteocytes. Like bone, ce- preparation of bone, the ground section displays mineralized
mentum is 65% mineral. The lacunae and cana liculi in the Dentin tissue but destroys soft tissue; demineralization removes min-
cementum contain the cementocytes and their processes, eral and retains soft tissue. Demineralized sections have the
respectively. They resemble those structures in bone that Dentin is a calcified material that forms most of the tooth advantage that th ey can be used to view a section of a tooth
contain osteocytes and osteocyte processes. substance to study its relationship to the adjacent supporting structures.
Unlike bone, cementum is avascular. Also, the canalic- In routinely demineralized sections of a mature tooth, how-
uli in cementum do not form an interconnecting network. Dentin lies deep to the enamel and cementum. It con- ever, the enamel is dissolved and lost. Therefore, diagrams of
a tooth showing features of both enamel and soft tissues are FIGURE 15.15
A layer of cementoblasts (cells that resemble the os- tains less hydroxyapatite than enamel, about 70 % , but Electron micrograph of Sharpey's fibers. Sharpey's fibers extend from
teoblasts of the surface of growing bone) is seen on the more than is found in bone and cementum. Dentin is se- composite diagrams that combine data derived from both
the periodontal ligament (right) into the cementum. They consist of
ground and demineralized sections (see Fig. 15.7).
o uter surface of the cementum, adjacent to the periodon- creted by odontoblasts that form an epithelial layer over collagen fibrils. Sharpey's fibers within the cementum are mineralized;
tal ligament. the inner surface of the dentin, i.e., the surface that is in those within the periodontal ligament are not mineralized. x 13,000.
450 CHAPTER 15 D irjrsliPr Syslrm 1: Oral C wity ""d Associntcd Stmctwes CHAPTER 15 /)igestiue Sys tem], Oml Cavity mzd Associnted Stmctzms 45 1
contact with the pulp (Fig. 15.16). Like amelo blasts, matrix are similar to those of bone, predentin contains two
odontoblasts are columnar cell s that contain a well- unique proteins:
developed rER, a large Golgi appara tus, and other or-
D e11tin phosphoprotein (DPP), which is rich in aspartic
ganelles associa ted with the synthesis and secretion of
acid and phosphoserine an d binds large amounts of cal-
large amo unts of protein (Fig. 15 .17). The apical surface
cium. DPP is involved in initiation of mineralization and
of the odontoblast is in contact with the forming dentin;
in control of mineral size and shape.
junctional complexes between the odontoblasts at that
De11ti11 sialoprotein (DSP), which is rich in aspartic acid,
level separate the dentina l compartment from the pulp
serine, glutamic acid, and glycine and is also involved in
compartment.
the mineralization process.
The layer of odontoblasts retrea ts as the dentin is laid
down, leaving odontoblast processes embedded in the An unusual fea ture of the secretion of collagen and hy-
dentin in narrow channels called de11tinal tubules (see Fig. d roxyapatite by odontoblasts is the presence, in Golgi vesi-
15.15). The tubules and processes continue to elongate as cles, of arrays of a formed filamentous collagen precursor.
the dentin continues to thicken by rhythmic growth. The Granu les believed to contain calciu m attach to these pre-
rhythmic growth of dentin produces certain "growth cursors, giving rise to structures called abacus bodies (Figs.
lines" in the dentin (incrementa l lines of von Ebner and 15.17 and 15.18). Abacus bodies become more condensed
thicker lines of Owen) that mark significant developmental as they mature into secretory gra nules.
times such as birth (11eonatalline) and w hen unusual sub-
stances such as lead are incorporated into the growing Dentin is produced by odontoblasts
tooth. Study of grow th lines has proved useful in forensic FIGURE 15.18
Golgi apparatus in an odontoblast. This electron micrograph shows a
medicine. Dentin is the first mineralized component of the tooth to
region of the Golgi apparatus containing numerous large vesicles.
Predenti11 is the newly secreted organic matrix, closest be deposited. The outermost dentin, which is referred to as Note the abacus bodies (arrows) that conta in parall el arrays of fila-
to the cell body of the odontoblast, which has yet to be mantle dentin, is formed by subodontoblastic cells that ments studded w ith granules. x52,000.
mineralized. Although most of the proteins in the organic produce small bundles of collagen fibers (von Korff's
Above the attachment of the epithelium to the tooth, a Acini are of three types: serous, m ucous, or mixed Serous demilunes are artifacts of the t raditional fixation Serous cells are protein-secreting cells
shallow crevice called the gingival sulcus, is lin ed with method
crevicular epithelium that is continuous with the attach- The basic secretory unit of salivary glands, the saliv01t, Serous cells have a pyramidal shape, wi th a relatively
ment epithelium. The term periodontium refers to all the consists of tJ1e acinus, in tercalated duct, and excretor y As noted above, each mixed acinus, such as those wide basal surface facing the basal lamina and a small api-
tiss ues involved in the attachment of a tooth to the duct (Fig. 15 .22 ). The acinus is a blind sac composed of fo und in the sublingual and subm andib ular g la nds, con- cal surface facing the lumen of the aci nus. They contain
mandible and maxilla. These include the crevicular and secretory cells. The term acinus [L., berry or grape] refers to the tains serous and mucus-producing cells. In routine large amounts of rER, free ribosomes, a prominent Golgi
junctional epithehum, the cementum, the periodo ntal liga- secretory unit of the saliva ry glands. The acini of sa livar y preparation for both light and electron m icroscopy, apparatus, and numero us spherical secretory granules
ment, and the alveolar bone. glands contain either serous cells (protein secreting), mu- serous cells have traditiona lly been regarded as the struc- (Fig. 15.24 ). As in most protein-secreting cells that store
cous cells (mucin secreting), or both. The r elative frequen- tures that make up th e demilune. Recent electron micro- their secretions in zymogen granules, the granules are lo-
cies of the three types of acin i is a prime characteristic by scopic studi es now cha llenge this classica l interpretation cated in the apical cytoplasm . .Nlost other organelles are lo-
which the major salivary glands are distinguished. Thus, of t he demilune. Rapid freezing of tJ1e tiss ue in liquid ni- cated in the basal or perinuclear cytoplasm. In H&E sec-
9 SALIVARY GlANDS thr ee types of acini are descr ibed: trogen, fo llowed by rapid freeze su bstitution with os- tions, the basal cytoplasm of the sero us cell stains with
mium tetroxide in cold acetone, reveals that both mu- hematoxylin because of the rER and the free ri bosomes,
The major salivary glands are paired glands w ith long ducts Serous acini, which contain only serous cells and are cous and serous cell s are a ligned in the same row to w hereas the apica l region sta ins with eosin, in large p art
that empty into the oral cavity genera.lly spherical surro und the lumen of the secretory acin us. No serous because of the secretory granules.
Mucous acini, w hich contain only mucous cells and are demilune is found. Secti o ns prepared from the sa me W hen examined with the transm.issio n electron m icro-
The ma jor sa li var y glands, as noted above, consist of usually more tubular speci men by conventional m eth o ds show swoll en mu - scope (TEM), the base of the serous cell may display in-
the paired pa rotid , subm and ib ular, a nd subling ual Mixed acini, which contain both serous and muco us cous cells with enlarged secretory granules. Th e serous foldings of the plasma mem brane and basal-lateral fo lds in
glands. The parotid and the s ubmandibular glands are cells. ]n routine H&E preparations, mucous acini h ave cells form typical demilun es and are positioned in the pe- tJ1e fo rm of processes that interdigitate with sim.ilar
actua lly located o utside the ora l cavity; their secretions a cap of serous cells that are thought to secrete into the riphera l r egion of the acinus with slender cytoplasmic processes of adjacent cells. The serous cells are joined near
reac h the cavity by ducts. The parotid gland is located highl y convoluted intercellula r space between the mu- processes interposed between the mucous cells. These their apical surfa ce by juncti o nal complexes to neig hbo r-
subcutan eo usly, below and in front of the ear in the tem- co us cells. Beca use of their appeara nce in histologic findings indicate that the demilune observed i.n light or ing cells of the acinus (see Fig. 15.24 ).
pora l r egion of the head, a nd the submandibul ar gland is sections, such caps are called serous demilunes [Fr., half- electron microscopy is an m1:ifact of the routine fixation
located under the floor of the mouth, in the sub- moon]. method (Fig. 15.23). The process of demi lune fo rmation Mucous cells are mucin- secreting cells
mandibular triangle of th e neck . The su blingual gland is can be explained by the expansion of mucinogen, a ma-
located in the floor of the m o uth anterio r to th e s ub- jor component of secretor y granu les, during routine fi x- As in other mucus-secreting epitbeha, the mucous cells of
mandibular gland . ation. This expansio n in creases the vo lume of th e mu- the muco us saliva ry acini undergo cyclic activity. During
The minor sa livary glands are located in the submucosa cous cells and displaces the serou s ce lls from thei r part of the cycle, mucus is synthesized and stored within the
of different parts of the oral cavity. They include the lin- original position, thus crea ting the demilune effect. A cell as mucinogen granules. When the product is d ischarged
gual, labial, buccal, molar, and palatine glands. en similar phenomenon is sometimes seen in the intestina l fo llowing hormonal or nemal stimulation, the cell begins to
::l
Each sali va ry gland arises from the developing oral cav- c
'[j mucosa, in w hich swo llen goblet cells displace adj acent resynthesize mucus. After discharge of most or all of the
ity epitheliu m. Initially, th e gla nd takes the form of a solid C1l
a bsorpti ve cells. mucinogen granules, the cell is difficult to distinguish from
cord of cells that enters th e mesench yme. The proliferation '0
Q) an inactive serous cell. However, most m ucous cells contain
of epit heha l cells eventually produces hi ghly branched ep- ca ....
- u large nw11bers of m ucinogen granules in their apical cyto-
C1l ::l
ithelial cords w ith bulbo us ends. Degeneration of the in- ~'0 plasm, and because the mucinogen is lost in H & E-stained
Q)
nerm ost cells of the cords and bulbous ends leads to their paraffin sections, the apical portion of the cell usually ap-
E
cana lization . The cords become ducts, and the bulbous pears empty. In TEM preparation, the rER, mitochondria,
ends become secretory acini. t5
::J
RAPID FREEZING CONVENTIONAL FIXATION and other compo nents a1e seen chiefly in the basal po rtion
'0
'0 of the cell; this part of the cell also contains the nucleus,
Q) serous
Cii demilune which is typica lly flattened against th e base of the cell (Fig.
Secretory Gland Acini ;::
U5 15.25). In rapid-freeze preparations (Fig. 15.26), cells are
rounded and clearly isolated from each other. The nuclei are
Secretory acini are organized into lobules round and centra ll y located. The apical portion of the mu-
cous cell contains numerous mucinogen granules and a large
mucous cell
The major sa livary glands are surrounded by a capsule Golgi apparatus, in wh.ich large amounts of car bohydrate
of moderately dense connective tiss ue from which se pta are added to a protein base to synthesize the glycoprotein of
divide the secr etory portions of the gland into lo bes a nd FIGURE 15.23 th e mucin. Mucous cells possess apical junctional co m-
salivon parotid submandibular sublingual Relationship of serous-secreting cells and mucous-secreting cells in
lob ules. The septa contain the larger blood vessels and ex- plexes, the same as those seen between sero us cells.
cretory ducts. The connective tissue associated with the FIGURE 15.22 the mixed acinus. a. This drawing indicates the relationship of the
Diagram comparing the components of the salivon in the three ma- mucous and serous cells as observed in the electron microscope fol-
gro ups of secretory acini blends im perceptibl y into the sur- Myoepithelial cells are contractile cells that embrace the basal
jor salivary glands. The four major parts of the sa livon, the acinus, in- lowing the rapid freezi ng method. The serous cells extend from the
rounding loose connecti ve ti ss ue. The mino r sa.livary aspect of the acinar secretory cells
tercalated duct, striated duct, and excretory duct, are color coded. The basal lamina to the lumen of the acinus. b. In this drawing, serous
glands do not have a ca psu le. three columns on the right of the salivon compare the length of cells are shown occupying the periphery of the acinus to form the so-
N umerous lymphocytes and plasma cells populate the the different ducts in the three salivary glands. The red-colored cells of called serous demilune. This feature is visible in routine preparations Myoepitheli al cells are contractile cells with numero us
conJlective tissue surrounding th e acini in both the major the acinus represent serous-secreting cells, and t he yellow-colored cells using immersion fixation. The swollen mucous cells have forced out processes. They lie between th e basal plasma membrane of
and m ino r saliva ry glands. Their significance in the secre- represent mucous-secreting cells. The ratio of serous-secreting cells to the serous cells, leaving small remnants of the cytoplasm between t11e the epithelial cells and the basal lamina of the epithelium
tion of salivary antibodies is described below. mucous-secreting cells is depicted in the acini of the various glands. mucous cells. (Fig. 15 .27). Myoep ithelia l cells a lso underlie th e cells of
4 56 CHAPTER 1 5 Digntivr Sy~t e m J, Om/ Cn11ity 1111d Assorinted Struclurr~
FIGURE 15.25
low-magnification electron micrograph of a mucous acinus. The mately discharge into the lumen (L) of the acinus. Myoepithelial cell
mucous cells contain numerous mucinogen granu les. Many of the processes (MyC) are evident at the periphery of the acinus. x 5,000,
granules have coalesced to form larger Irregular masses that will ulti
FIGURE 15.24
Electron micrograph of the apical portion of parotid gland serous apparatus (G)_ Immature secretory vesicles (IV) are present close to
cells. The cells are polarized, with their product package within these- the Golgi apparatus. At the apical pole of the cells are junctional com-
cretory vesicles (SV) near the lumen (L) of the acinus. The cells display plexes (JC)- The intercellular space (/C) is dilated, and profiles of sec-
rough endoplasmic reticulum (rER) and several profiles of the Golgl tioned lateral plications are seen. M, mitochondria. x lS,OOO.
the proximal portion of the duct sys tem . In both locations, Excret01y ducts, w hich are the large r ducts that empty
th e myoepithelial cells are instrumenta l in moving secre- into the ora l cavity
to ry products tow ard the excretory duct. Myoepithelia l
cells are sometimes difficult to identify in H &E sections. The degree of develo pment o f the intercalated ducts and
The nucleus o f t he cell is often seen as a small round pro- striated ducts varies, d epending on the nature of the acinar
fil e near the basement membrane. The contractile fi laments secretion (see Fig.l5 .22). Serous glands have well-
stain with eosin and are sometimes recogn ized as a thin d eveloped intercalated d ucts and striated ducts t hat modify
eosinophilic band adj acent to the baseme nt memb ra ne. the serous secretion by both absorption of specific compo-
nents from the secretion and secretion of add itional com-
ponents to form the fina l product. Mucous glands, in w hich
Salivary Ducts the secretion is not modlfied, have very poorly developed
The lu men of the sal ivary acinus is continuo us wi th that of interca lated ducts that may not be recogniza ble in H &E
a d uct system that may have as many as three seq uentia l sections. Moreover, they do not d isplay striated ducts.
segments. These are referred to as
Intercalated ducts are located between a secretory acinus and
b1tercalated duct, w hi ch leads from th e aci n us a larger duct
Striated duct, so-ca lled because of th e presence of "stri - FIGURE 15.26
ations," the infoldings of the basal plasma membrane of Intercalated ducts are lined by low cuboidal epithelial cells Electron micrographs of mixed acini. a. Low-magnification electron round the acinus lumen. Serous demilunes are not evident x 6,000.
the columnar cells that form th e du ct that usually lack any distinctive feature to suggest a fu nction micrograph of the sublingual gland, prepared by the rapid freezing b. Electron micrograph of the sublingual gland prepared by tradi-
and freeze-substitution method, shows til e arrangement of the cells tional fixation in forma ldehyde. Note the considerable expansion and
wltllin a single acin us. The mucous cells have well-preserved round coalescence of the mucinogen granules and the formation of a
mucinogen granules. The mucous and serous cells are aligned to sur- serous demilune. X lS,OOO. (Courtesy of Dr. Shohei Yamasl1 ina.)
- - ,_-- - ---
t'i8 CHAPTER 1 5 Digeslive Syslr111 I: Oml Ctll>ily nud Associalen Slmtlfl rrs C H A PTER 15 Digeslive Sy slr111 I: Ornl Cn11ily aud Associnletl Slruclflres 4 59
ity. T he epitheliu m of sma ll excretory d ucts is simple predomi nant mucous acini exhibit s~ro us demilu nes, but
cu boidal. lt gradua lly changes to pseudostratified colum- purel y serous acini are ra rely p resent (Fig. 15.28c). Inter-
nar or stratified cuboidal. As the d ia meter of the duct in- calated ducts and striated d ucts are sho rt, difficult to lo-
creases, stratified columnar epitheli um is often seen, and as cate, or sometimes a bsen t. The mucous secretory un its
the ducts approach the oral epithelium, stratified sq ua- may be more tubular than pu rely acinar.
mous epithelium may be presen t. The parotid duct
(Stensen's d uct) a nd t he submandibu lar duct (Wharton's
d uct) travel in the connecti ve tissue of the face and neck,
Saliva
respecti vely, for some distance from the gland before pen-
Saliva includes the combined secretions of all the major and
etrating th e oral mucosa.
minor salivary glands
Major Salivary Glands Most saliva is p ro duced by the salivary glands. A smaller
PAROTID GLAND amount is derived from the gingival sulcus, tonsillar cr yp ts,
and general transudation from the epithelial lining of the
The parotid glands are completely serous oral cavity. One of the unique features of sa liva is the large
and varia ble volum e produced. The volume (per weight of
The paired serous paro tid glands are the largest of the gland tiss ue) of sali va exceeds t hat of o ther d igestive secre-
ma jor sa liva ry glands. The parotid duct travels from t he tions by as much as 40 times. T he large volu me of saliva
gla nd, which is located below and in front of the ear, to en- produced is undoubtedly related to its many func tions, only
ter the o ral cavity op posite the second upper mo lar tooth. some of wh ich are concern ed with digestion.
The secretory units in the pa rotid are serous and surround
n umero us, long, narrow intercalated d ucts. St riated d ucts Saliva performs both protective and digestive functions
are large and conspicuous (Fig. 15 .28a) .
Large amounts of adipose tissue often occur in th e T he salivary glands produce about 1200 mL of sa li va a
parotid gland; this is one o f its d isting uishing feat ures. The day. Saliva has numero us functions r elating to metabolic
FIG URE 15.27 facia l nerve (crania l nerve VII) passes thro ug h the pa rotid and non metabolic activities. T hese include
Electron micrograph of the basal portion of an acinus. Th is electron contractile fi laments and densities (arrows) similar to those seen in g la nd; large cr oss sections of th is ner ve may be encoun-
micrograph shows the basal portion of two secretory cells from a sub- smooth muscle cells. The ceil on the left with the small nucleus is a M oisteni ng th e oral m ucosa
tered in routine H&E sectio ns of the gland and are useful
mandibular gland. A myoepithelial cell process is also evident. Note lymphocyte. Having migrated through the basal lamina, it is also Moistening dry foods to aid swa ll owing
in identi fying the paro tid. M umps, a viral infection of th e
the location of the myoepithelial cell process on the epithelial side of within the epithelial compartment. Arrowheads, cell boundries; aster-
parotid g la nd, can damage the fac ia l nerve. Providing a med iu m for d isso lved and suspended food
the basal lamina. The cytoplasm of the myoepithelial cell contains isks, basal-lateral folds. x 15,000.
m aterials that chemicall y stimu la te taste b ud s
Buffering the co ntents o f t he oral cavity, beca use of its
SUBMANDIBULAR GLAND
high concentration o f bica rbonate ions
o ther than that of a conduit. H owever, the cells of interca- interdig itated w ith those of adjacent cells. The oucleus typ-
D igesting car bohyd ra tes w ith the d igestive enzym e a-
lated ducts possess ca rbon ic anhydrase acti vity. In serous se- ically o ccupies a central (ra ther than basa l) location in t he The submandibular glands are mixed glands that are mostly
serous in humans
mnylase that brea ks 1-4 glycosidic bonds and co ntinues
creting g lands and mixed glands, they ha ve been shown to cell. Stria ted d ucts are t he s ires of
to act in the eso phagus and stomach
Secrete bicm-bonate ion into the acinar product Reabsorption of Na+ from the primary secretion The la rge, pa ired, mixed subma ndibu lar glands ar e lo- Controlling the bacterial flor a of t he oral cavity by use
Absorb chloride ion from the acinar p ro duct Secretioll o f K+ and H C03 - into the secretio n cated under either side of the fl oo r of t he mouth, close to of lysozyme (mu1'amidase}, an en zyme that lyses the mu-
the m a ndible. A du ct from each of th e two glands runs fo r- ramic ac id in certain bacteria (e.g., staphylococci) .
As noted above, interca lated ducts are m ost pro minent More Na + is resorbed than K' is secreted, so t he secre-
in t hose sa livary glands th at produce a watery serou s tio n becomes hypotonic. W hen secretion is very rapid, ward and mediaiJ y to a papilla located o n th e floor of t he
The unique composition of sa liva is summa ri zed 1n
secreti on . In mu cus-secreting sa li va ry gla nds, th e inter - more Na + and less f(+ appea r in th e final sa liva because the m ou th just latera l to t he fre11-ulum of the tongue. Some
Tabl e 15.1.
ca la ted ducts, when p resent, are s hor t a nd di fficult to rea bsorption and seconda ry secretion systems cannot keep muco us ac ini capped by sero us d emilunes are genera ll y
iden tify. up w ith th e ra te of primar y secretion. Th us, the sa liva m ay found among t he predomin ant ser o us acini. In tercalated Saliva is a source of calcium and phosphate ions essential for
become isoton ic to hyperton ic. d ucts are less extensive t han in th e pa rotid g lan d (Fig. normal tooth development and maintenance
Striated duct cells have numerous infoldings of the basal The dia meter of stri ated ducts o ften exceed s tha t o f the L5.28b).
plasma membrane secreto ry acinus. Striated ducts are located in the Calciu m an d p hospha te in th e saliva a re essen tial for t he
parenchyma of the glands (they are itttralobular ducts) bu t SUB LINGUAL GLAND minera lization of newly erupted teeth and for repa ir o f
Striated ducts ar e lined by a simple cu bo idal epitheli um may be surrounded by sma ll amounts of connective tiss ue precario us les io ns of t he enamel in erupted teeth. In ad d i-
that gradu ally becomes columnar as it appr oaches th e ex- in w hich blood vessels and nerves can be seen running in The small sublingual glands are mixed glands that are mostly tion, sa li va se rves several o ther r oles in p rotecting th e
creto ry d uct. T he info ldings o f the basal plasma membrane pa ra llel w ith the du ct. mucus-secreting in humans teeth . Proteins in sa liva cove r t he teeth with a protective
are seen in histologic sectio ns as "st riatio ns." Long itud i- coa t called t he acqui1ed pellicle. Antibodies and other an-
nalJ y oriented, elo ngated mitochondria are encl osed in the Excretory ducts travel in the interlobular and interlobar The su bling ual glands, the sm allest of the pai red ma jor tibacterial agents reta rd bacteria l action that would o ther-
ino ld ings. Basa l info ldings associated w ith elongated mi- connective tissue sa li va ry gla nds, a re located in the fl oor of t he mo uth an te- w ise lead to tooth d ecay. Pa tients w hose salivar y g land s are
toc ho nd ria a re a morphologic specializa tion associated rior to the submandibular glands. T heir multiple small irradiated, as in the treatment o f salivary gla nd t umors, fail
w ith rea bsorption o f fluid and electrolytes. T he striated Excretory ducts constitute the principal ducts o f each o f s ubli ng ua l d ucts empty into th e submandibu la r d uct as to prod uce normal a mounts of sa liva; these pa ti en ts typi-
duct cells also have numer o us basal-la tera l fold s that are the major glands. T hey ultimately connect to th e o ral cav- we ll as directly onto t he floor of t he mouth. Som e of th e call y d evelo p rampant ca ries. Anticho linergic drugs used
....
4 60 C HAPTER 1 5 Digestive Syste111 /, Om/ Ca11ity ami Associa ted Stmctu res C H AP TER 15 OigestiiJe Sys te111 lc Oral Ca11ity c111d Associated Structures 46 I
~
keratini zed e pide rmi s offace ski n c hanges to the thick parakeratinized ep-
itheli um of the oral mucosa. The transition zone, the red portion of the
Lips, is characterized by deep penetration of connective ti ssue papillae
~3
into the base of the stratified squamo us keratinized epithe lium. The blood
vessels and nerve e ndings in these papillae are responsible for both the
color and the exqu isite touch sensiti vity of the lips.
A H&E-stained sagittal secti on thro ugh the lip in thi s low-power ori-
; '
entation photomicrograph to the right (X8) reveals the skin of the face,
the red margin of the lip, and the transition to the oral mucosa. The num-
bered rectangles indicate representative areas of each of these sites,
shown at higher magnifications in Figures L, 3, and5, respectively, on the
adj acent plate. Note the change in thi ckness of the e pithe lium from the
exterior or facial portion of the lip (the vertical surface on the right) to the
interior surface of the oral cavity (the surface beginning with rectangle 5
!!)
and continuing down the le ft surface of the lip) in this mi crograph. 1
Figure 1, lip, human, H&E x 120. ciated with it are hair follicles (HF) and sebaceous glands
T he ep ithelium ( EP) of the face is relati vely thin and has (SGI).
the general features of thin skin fo und in o ther sites. Asso-
Figure 2, lip, human, H&E x 380. the pigment mel anin (M ), and the dark blue near the s utface
The circled area in Figure I is shown at higher magnifi- is the stratum granulosum (SG) w ith its deep-blue-stained
catio n he re. The reddish brown mate ri al in the basal cells is ke ratohyalin granules.
Figure 4, lip, human, H&E x 380. sory receptors. ln fact, each of the two deep papillae seen in
The sensitivity of the red margin to stimuli such as lig ht Fig ure 3 contains a Meissner's corpuscle, one o f which
to uc h is due to the presence of a n increased number of sen- (M C) is more clearly seen in thi s fig ure.
Figure 5, lip, human, H&E x 120. of the o ral mucosa is evident in thi s fig ure. Note how the
T he transitio n from the keratinized red margin to the stratum granulosum sudde nly ends. Th is is more clearly
fairly thick stra tifi ed squamous parake rati nized epithelium show n at hig her magnification in Fig ure 6.
Figure 6, lip, human, H&E X380. face (a rrows). The epithelium is also muc h thi cker at this
Beyond the site where the stratum granulosum cells dis- poi nt and remains so throughout the oral cavity.
appear, nucle i are seen in the superficial cells up to the s ur-
KEY
BV, venous blood vessels MC, Meissner's corpusc le arrowheads, connective tissue papillae
EP, e pithe lium SG, stratum granul osum anows, nuclei of superfi c ial cells up to s ur-
HF, hair foll icle SGI, sebaceous g land face
M , me lani n pig ment
462
C H APTE R 15 Digestive System L Oral Cavity a11d Associa ted S tructrms 465
R
Figure 1, tongue, monkey, H&E x 65; inset X130.
This figure shows the dorsal surface of the tongue with papilla) forms the center of the fungiform papilla, and
the filiform papillae (Fil P). They are the most numerous of smaller connective tiss ue papillae (seco ndary connective
the three types of papillae. Structurally, they are bent, con- tissue papillae) project into the base of the surface epithe-
ical projections of the epithelium, with the point of the pro- lium (a rmwhead). The connecti ve ti ssue of the papillae is
jection directed posteriorly. These papillae do not possess highly vasculari zed. Because of the deep penetration of
taste buds and are composed of stratified sq uamous kera- connective ti ssue into the epithelium, combin ed with a very
tinized epithelium. thin keratinized surface, the fungiform papillae appear as
The fungiform papillae are scattered about as isolated, small red dots when the dorsal sutface of the tongue is ex-
sli ghtly rounded, elevated structures situated among the fil- amined by gross inspection.
iform papillae. A fungiform papilla is shown in the inset. A
B
Figure 2, tongue, monkey, H&E x 65. T he connective tissue extends as far as the muscle with-
The undersurface of the tongue is show n in this figure. out changing character, and no submucosa is recognized.
The smooth surface of the stratified squamou s epithe lium The muscle (M) is striated and is unique in its organization ;
( Ep) co ntrasts with the irregular surface of the dorsum of i.e., the fibers travel in three planes. Therefore, most sec-
the tongue. Moreover, the epithelial surface on the under- tions wi ll show bundles of muscle fibers c ut longitudinall y,
side of the tongue is usually not keratinized. T he connective at right ang les to each other, and in cross section. Nerves
ti ssue (CT) is immediately deep to the epithelium; deeper (N) that innervate the muscle are also frequently observed
still is the striated muscle (M ). in the connective tiss ue septa between the mu scle bundles.
The numerous connective tissue papillae that project The surface of the tongue behind the vallate papillae (the
into the base of the e pithelium of botl1 ventral and dorsal root of the tongue) contains lingual tonsils (not shown).
surfaces give the epithelial-connective ti ssue j unction an ir- These are similar in structure and appea rance to the palatine
reg ular profile. Often, these con necti ve ti ssue papillae are tonsils illustrated in Plate 32.
cut obliquely and then appear as small islands of connective
tissue within the epithe lial layer (see Fig. I ).
KEY
CT, connective tissue Fil P, filiform papillae N, nerves
E p, epithelium M, striated musc le bundles arrowhead (Fig. 1, inset), secondary con-
nective tissue papi ll a
464
CHAPTER 15 Di!)es!i!>e Sy stem /, Om/ C wi!y n11rl Associn!ed Stmct11res 4 67
B
Figure 1, tongue, monkey, H&E X 55. ithelium (EP) that is on the free surface of the foliate papil-
The sides of the tongue contain a series of vertical ridges lae is thick and has a number of secondary connective tis-
that bear taste buds. When these tidges are cut at right an- sue papillae projecting into its undersurface.
gles to their long axis, they appear as a row of papillae. The connective tissue within and under the foliate papil-
These ridges are called foliate papillae. Foliate papillae are lae contains serous-type glands (Gl), called von E bner's
not always conspicuous in the adult human tongue but are glands, which open via ducts (D) into the cleft between
quite evident in the infant tongue. They can be distin- neighboring papillae. In add ition to von Ebner's glands,
guished immedi ately from fungiform papillae in a section which are e ntirely of the serous type, the tongue contains
because they appear in rows, whereas fungiform papillae mixed (serous and mucous) glands near the apex and mu-
(not illustrated) appear alone. Moreover, numerous taste cous glands in the root (not illustrated).
buds (TB) are present on adjacent walls of neighboring fo- The dense patches (arrows) with in the connective tissue Foliate Papillae
liate papillae. In contrast, fungiform papillae have taste consist of accumulations of lymphocytes in the form of dif-
buds on the dorsal surface. The foli ate papillae are covered fuse lymphatic tissue. They are typically seen just below
by stratified squamous epithelium that is usually not kera- the clefts of the papillae.
tinized or is only slightly keratinized. The part of the ep-
Figure 2, tongue, monkey, H&E X55; inset X640. The connective tissue near the circumvallate papillae also
KEY
CT, connective tissue Gl, serous (von Ebner's) glands arrowheads (inset), taste bud pore
D, ducts M, stri ated muscle bundles arrows (Fig. 1), ly mphocytes Vallate Papilla
EP, epithelium TB, taste buds asterisk (inset), mitotic fig ure
466
1 '
C HA PTER 15 Di!}estive Syste111 /, Oral Cavity aut! Associa ted Stmctures 469
B
Figure 1, submandibular gland, human, H&E The nature of the duct system of the submandibular
X160. gland is shown to advantage in this figure. The initial ducts
The submandibular glands contain both serous and mu- leading from the acinus, the intercalated ducts, are very
cous aci ni . In humans, the serous components predominate. small. They possess a flattened to cuboidal epithelium and
The rectangle reveals a cluster of mucous acini (MA ). The exhibit a distinct lumen. Intercalated ducts in the sub-
mucus-secreting cells of the aci ni are readil y di scernable at mandibular gland (and the parotid gland) tend to be rela-
tllis low magnification because of their light staining. The tivel y long; thus, they are frequently encountered in a sec-
remainder of the fi eld is composed largely of serous acini tion . They merge (arrows) to form the larger striated ducts
(SA ). A few adipose cells (A) and various ducts- excretory (StD ). These duc ts have an epithelium of low to tall colum-
(ED), stri ated (StD), and intercalated (JD)-are also evident nar cells and, at high magn ification, show basal striations
in the field. (see Plate 48).
6
Associated with the acinar epithelium are myoe pithelial
X400. cells. They are located between the basal aspect of the se-
When examined at lligher magnification, as in this figure, cretory cells a nd the basal lamina. However, myoepithelial
the individual mucous cells exhibit distinc t cell boundaries. cells are diffic ult to identify in H&E-stained preparations
The ir nuclei are flattened (except those that are tangentially of salivary glands, and none can be identified with assur-
sectioned). In contrast, the cytoplasm of the serous cells ance here.
stains deepl y, and the nuclei appear ovoid or round. This fi gure also provides a compari son between an in-
Serous cells are also found forming a cap known as a tercalated duct (ID) and a small striated duct (StD) from the
serous demi lu ne (SD) on the pe riphery of many of the mu- rectangle in Figure 1. Outside the lobule, the striated duct
cous acini (MA). Recent evidence indicates this is an artifact joins the excretory duct (ED) (Fig . 1, upper left). The ex-
of fixation in which the serous cells are squeezed out of their cre tory duct is characterized by a wider lumen and a taller
normal position by swelling of the mucous cells. Some acini columnar epithelium. As the excretory ducts increase in
that appear to be of the sero us type (SA) and particul arly the size, the epithelium becomes pseudostratified and, finally,
acini that appear as small spherical profiles may actually be stratified in the main excretory ducts.
demilunes of mucous acinus that have been cut in a plane
that excludes the mucous cells from the section.
KEY
A, adipose cell S A, serous aci ni a rrows (Fig. 1), in tercalated ducts joining
ED, excretory duct SD, serous dem il une to form a striated duct
ID, in tercalated duct S tD, striated duct astel"isks, lum ina of mucous acini
MA, mucous aci ni rectangle (Fig. 1), cluster of mucous acini
468
"""""'
E
Figure 1, parotid gland, human, H&E x 160. served. They exhibi t a sim ple columnar epithelium. The in-
The parotid gland in the human is composed entirely of tercalated ducts are s maller; at th e low mag nification of thi s
sero us acini (A ) and their ducts. However, numerous adi- figure, they are difficult to recognize. A few intercalated
pose ce lls (AC) are usually distributed thro ughout the ducts (/D ) are indicated. The lower po rtio n of the fig ure re-
g la nd. Both the serous acini and the ir duct system in the veals a n excretory duct (ED ) within a connective tissue sep-
parotid g la nd are comparable in s tructure and arrangeme nt tum (CT). The epithe liu m of thi s excreto ry duct exhibits
to the same components in the submandi bular g land. two layers of nuclei and is either pseudostratified or, possi-
Within the lobule, the striated ducts (StD) are readily ob- bly, alre ady true stratified epithe lium.
B
Figure 2, parotid gland, monkey, glutaralde- A cross-sectional profile of an intercalated duct (/D) ap-
hyde-osmium tetroxide fixed, H&E X640. pears on the left of the micrograph; note its simple cuboidal
The serous cells are optimally preserved in this speci- epi thelium. A single flattened nucleus is present at the top
men and reveal their secretory (zy mogen) granul es. The of the duct and may represent one of the myoepithelial cells
granules appear as fine dot-like o bjects w ithin the cyto- that are assoc iated with the beginning of the duct system as
plasm. The acinus in the upper rig ht of the figure has been well as wi th the acini (A). The large duct occupying the
cut in cross section and reveals the ac inar lume n (AL). The center of the micrograph is a striated duct (StD ). It is com-
small rectangle drawn in the ac inus represents a n area com- posed of columnar ep ithelium . The s triati ons (S) that give
parable to the e lectron mi crograph shown as Figure 15.24. the duct its name are evident. Also of sig nificance is the
The large acinar profile to the left of the s triated d uct (StD) presence of plasma cells (PC) within the connecti ve ti ssue
shows that the acini are not simple spheres but, rather, ir- surrounding the d uct. T hese cells produce the im-
regular e longate s tructures. Because of the s ma ll size of the munoglobulins taken up and resecre ted by the acinar cells,
ac inar lumen and the variability in sectioning an aci nus, the par ticularly secreto ry TgA (slgA).
lume n is seen infrequently.
KEY
A, aci nus CT, con nective tissue P C, plasma cells
AC, adipose cell ED, excretory duct S, striations of duct cells
AL, acinar lumen ID, intercalated d uct StD, striated duct
470
CHAPTER 15 Digrslivt Sys lrm /, Om/ Cavily mrd Associalrd Slruclrms 4 73
B
Figure 1, sublingual gland, human , H&E x 160. tioned in a plane that does not incl ude the mucous compo-
This figure shows a sublingual gland at low power. The nent of the acinus, thus giving the appearance of a serous
mucous acini (MA) are conspicuous because of thei r li ght aci nus.
staining. Critical examination of the mucous acini at this The ducts of the sublingual gland that are observed most
re latively low magnification reveals that they a re not spher- frequentl y in a section are the intralobul ar ducts. They are
ical structures but, rather, elongate or tubular structures the eq uivalent of the striated duct of the submandibular and
with branching outpockets. Thus, the acinus is rather large, parotid glands but lack the extensive basal infoldings and
a nd much of it is usuall y not seen within the plane of a sin- mitochondrial array that creates the striations. One of the
g le section. intralobular duc ts ( l nD ) is evident in thi s figure (upper
The serous compone nt of the gland is composed largely right). The area within the rectang le includes part of this
of demilunes, but occasional se rous acini are present. As duct and is shown at higher magnification in Figure 2 .
noted earli er, some of the serous demilunes may be sec-
Figure 2, sublingual gland, human, H&E X400. cap-like addition to the mucous end pieces. The cytologic
KEY
MA, mucous acinus I n D, inualobular duct arrowhead, mucous acinus jo ining interca-
MC, mucous cells SD, serous demilune lated duct
ID, intercalated duct arrows, plas ma cells
472
16 BOX 16.3. Clinical Correlations: ZollingerEIIi5on Syndrome 490
BOX 16.4. Functional Considerations: Digestive and Absorptive Functions of
Enterocytes 502
BOX 16.5. Functional Considerations: Immune Functions of the Alimentary
Canal 509
Gastrointestinal Tract T he portion of the alimentary cana l that extends from the
proxima l part of the esophagus to the distal pa rt of the
a nal cana l is a hollow tube of varying di ameter. This tube
tight junctions between the simple columnar epithelial cells
of the mucosa serve as a selectively permea ble barrier. Most
epithelial cells transpo rt products of digestion and other es-
has the same basic structu ral o rga niza tion rluougho ut its sential substances such as water through the cell and into
length . Its wa ll is formed by fo ur d istinctive la yers. From the extracellular space beneath the tig ht junctions.
OVERVIEW OF THE ESOPHAGUS AND GASTROINTESTINAl TRACT 475 the lumen o utwa rd (Fig. 16. 1 ), they are
Mucosa 475 The absorptive function of the mucosa allows the movement
Submucosa 477 Mucosa, consisting of a lining epitheliu m, an underlying of digested nutrients, water, and electrolytes into the blood
Muscularis Externa 477 connective tissue called the lamina propria, and the and lymph vessels
Serosa and Adventitia 478 muscularis mucosae, composed of smooth muscle
ESOPHAGUS 478 Submucosa, consisting of dense irregular connecti ve The absorption of digested nutrients, water, and elec-
tiss ue trolytes is possible beca use of pro jections of the m ucosa and
STOMACH 480
Muscularis extema, consisting 111 most pa rts of two submucosa into the lumen of the d igestive tract. T hese sur -
Gastric Mucosa 481
layers of smooth muscle face pr ojections greatly increase the surface area ava ilable
Fundic Glands of the Gastric Mucosa 482
Serosa, a sero us m embr ane consisting of a simple squa fo r absorptio n and vary in size and orientation. They con-
Cardiac Glands of the Gastric Mucosa 487
mo us epithelium, the mesothelium, and a small a mount sist of the following structural specia li zations (see Fig. 16. 1)
Pyloric Glands of the Gastric Mucosa 488
of underlying connecti ve tissue. An adventitia consisting
Epithelial Cell Renewa l in the Stomach 488
only of connecti ve tissue is fo und w here the wa ll of the
Plicae circulares are circumferentially oriented su bmu-
Lamina Propria and Muscularis Mucosae 490 cosal fo lds present a lo ng most of th e length of the small
tube is di rectly attached or fi xed to adjoin ing stru ctures
Gastric Submucosa 491 intestine.
(i.e., body wall an d certai n retroperitonea l organs).
Gastric Muscularis Externa 491 Villi are mucosal projecti ons that cover the entire surface
Gastric Serosa 491 of the small in testine, the principa l site of a bsorption of
Mucosa the products of digestio n.
SMAlliNTESTINE 491
Microvilli a re tightl y packed, microscopic projectio ns of
Submucosa 4 99 The stru cture of the esop hagus a nd gastrointesti na l tract
the apica l surface of intestin a l a bso rptive cells. They fur-
Muscula ris Externa 500 va ries co nsiderably fro m regio n to region; most of the
ther increase the surface avai lable for absorption .
Serosa 501 varia tion o ccurs w ithin the mucosa . The epithelium dif-
Epithelial Cell Renewal in the Small Intestine 501 fe rs througho ut the ali mentary canal and is adapted to the ln additio n, the glycocalyx consists of glycopr oteins that
specific fun ctio n of each part of the tube. The histo logic project from the apical plasma membrane of epitheli al ab-
LARGE INTESTINE 501
cha racte ri stics of these layer s a re described below in rela- sorptive cells. It provides add itional surface fo r adsorption
Mucosa 503
tion to specific reg ions of the diges tive tu be. The mucosa and includes enzy mes secreted by the absorptive cells that
Epithelial Cell Renewal in the Large Intestine 504
has three principal functions: protection, absorption, and are essential for the fin al steps of digestion of proteins and
Lamina Propria 504
secretion. sugars. The epitheliu m selectively absorbs the products of
Muscularis Externa 506
Submucosa and Serosa 507
d igestio n both for its own cells and for transport in to the
The epithelium of the mucosa serves as a barrier that vascul ar system for distribution to o ther tissues.
Cecum and Appendix 507
separates the lumen of the alimentary canal from the rest
Rectum and Anal Canal 507
of the organism The secretory function of the mucosa provides lubrication and
BOXES delivers digestive enzymes, hormones, and antibodies into the
T he epithelia l barrier separa tes the extern a l lumi nal en- lumen of the alimentary tube.
BOX 16.1. Clinical Correlations: Pernicious Anemia and Peptic Ulcer
Disease 487
vironment of the tu be from the tiss ues and organs of th e
body. The barrier aids in protection of the ind ividua l from Secretion is carried o ut la rgely by glands distrib uted
BOX 16.2. Functional Considerations: Enteroendocrine Cells, APUD Cells,
and Gastrointestinal Hormones 489 the entry of antigens, pathogens, and other noxio us su b- throughout the length of th e digestive tube. The vari ous se-
474 475
----------- - -
4/6 CHAPTER 16 Digrsliar System {/, Esoplwgus a111/ Gnslroi111rsli11nl Trncl CHAPTER 1 6 Digesliat Syslrm J/, EsopiMgus nrul Gns lroiulrsli11ai Tmcl 477
clition, in several parts of the alimentary canal (e.g., the serosa . The submucosa also contains lymphatic vessels and
esophagus and anal canal), the lamina propria contains ag- a nerve plexus. The extensive nerve network in the sub-
gregations of mucus-secreting glands. In general they lubri- mucosa conta ins visceral sensory fibers mainly of sym pa-
cate the epithelial surface to protect the mucosa from me- thetic origin, parasympathetic (termina l) ganglia, and pre-
chanical and chemical injury. These glands are described ganglionic and postganglionic parasympathetic nerve
below in relation to speciiic regions of t he digestive rube. fibers. T he nerve cell bodies of parasympathetic ganglia
In segments of the d igestive tract in w hich a bsorption and their postganglionic nerve fibers represent the enteric
occurs, principally the small and large intestines, the ab- nervous system, the third d ivision of the a uto nomic nerv-
sorbed products of digestion diffuse into the blood and ous system. This system is primarily responsible for inner-
lymphatic vessels of the lamina propria for distribution . vating the smooth muscle layers of the alimentary cana l
Typically, the blood capillaries are of the fenestrated type and can function totally inde pendent of the central nerv-
and collect most of the a bsorbed metabolites. In the small o us system. In the submucosa, the network of unmyeli-
intestine, lymphatic capillaries are numerous and receive nated nerve fibers a nd ganglion cells constitute the submu-
some absorbed Lipids and proteins. cosal plexus (Meissner's plexus).
The lymphatic tissues in the lamina propria function as As n oted, gla nds occur occasionally in the submucosa in
muscularis externa
an integrated immunologic barrier t hat protects against certain locations. For example, they are present in the
pathogens a nd other antigenic substances that could po- esophagus and the initial portion of the duodenum. In his-
tentiaiJy e nter through the mucosa from the lumen of the tologic sections, the presence of these glands often aids in
alimentary canal. The lymphatic tiss ue is represented by identifying the specific segment or region of the tract.
ing contraction, the teniae facilitate shortening of th e tube rive tiss ue, the adventitia, which blends with the connec-
to move its contents. tive tissue of the wall.
stomach esophagus
esophagus
FIGURE 16.4
Photomicrograph of an esophageal submucosal gland. This pho-
tomicrograph shows a mucicarmine-stained section of the esopha-
gus. An esophageal gland, deeply stained red by the carmine, and an
adjacent excretory du ct are seen in the submucosa. These small,
duodenum
FIGURE 16.6
compound, tubuloalveolar glands produce mucus that lubricates the FIGURE 16.5 Photomicrograph of esophagogastric junction. This low-magnifica-
epithelial surface of the esophagus. Note the stained mucus within Photograph of a hemisected human stomach. This photograph tion photomicrograph shows the j unction between the esophagus
the excretory duct. The remaining submucosa consists of irregular shows the mucosal surface of tile posterior wall of tile stomach. Nu- and stomach. At the esophagogastric junction, the stratified squa
FIGURE 16.3 dense connective tissue. The inner layer of the muscularis externa merous longitudinal gastric folds are evident. These folds or rugae al- mous epithelium of the esophagus ends abruptly, and the simple
Photomicrograph ofthe esophageal mucosa. This higher-magnifica- (bottom) is composed of circularly arranged smooth muscle. x 110. low the stomach to distend as it fills. Tile histologic divisions of the columnar epithelium of the stomach mucosa begins. The surface of
tion photomicrograph shows the mucosa of the wall of the esopha- stomach differ from the anatomic division. The former is based on the stomach contains numerous and relatively deep depressions
gus in a H&E preparation. It consists of a stratified squamous epithe- the types of glands found In the mucosa. Histologically, the portion of called gastric pits that are formed by the surface epithelium. The
lium, lamina propria, and muscularis mucosae. The boundary the stomach adjacent to the entrance of the esophagus is the cardiac glands in the vicinity of the esophagus, the cardiac glands, extend
o f t he food in t he stomach by its gastric secretions produces region (cardia) in w hich cardiac glands are located. A dashed line ap-
between the epithelium and lamina propria is distinct, although un- from the bottom of these pits. The fundic (gastric) glands similarly
even, because of the connective tissue papillae. The basal layer of the
a pulpy flu id mix ca lled chyme. The chyme then passes into proximates its boundary. A slightly larger region leading toward the arise at the base of the gastric pits and are evident in the remaining
epithelium stains intensely, appearing as a dark band because the th e small intestine for further digestion and absorption. pyloric sphincter, the pyloric region (pylorus), contains the pyloric part of the mucosa. Note the relatively thick muscularis externa. X40.
basal cells are smaller and have a high nucleus-to-cytoplasm ratio. glands. Another dashed line approximates its boundary. The remain-
Note that the loose connective tissue of the lamina propria is very cel- The stomach is divided histologically into three regions on the der of the stomach, tile fundic region (fundus), is located between ttie
lular, containing many lymphocytes. The deepest part of the mucosa basis of the type of gland that each contains two dashed lines and contains the fu ndic (gastric) glands.
is the muscularis mucosae that is arranged in two layers (inner circu-
rower regions of the stomach but poorly developed in the
lar and outer longitudinal) similar in orientation to the muscularis ex- Gross a natomists subd ivide th e stomach into fou r re-
terna. X240. upper portion (see Fig. 16.5). When the stomach is fully
gions. The cardia surrounds t he esop hageal o ri6ce; the Fundic region (fundus), the largest part of the stomach, distended, the rugae, composed of the mucosa and under-
fundus lies above t he level of a horizontal line drawn wh ich is situated between the cardia and pylorus and
lying submucosa, virtuall y disappear. T he rugae do notal-
through the esophageal (cardiac) or:i6ce; the body lies be- con tains the fundic o r gastric glands (see Fig. 16.6 )
smoo th muscle of t he lower part of the esophagus is in- ter total surface area; rather, they serve to accommodate
low t his line; and the pyloric part is the fun nel-shaped re-
nervated by visceral motor neu rons of the vagus (from the expansion and filling of the stom ach.
gio n t hat leads into the pylorus, the dista l, narrow sphinc-
dorsal motor nucleus). T hese motor neurons synapse w ith
teric region between the stomach and du oden um.
Gastric Mucosa A view of the stomach's surface with a hand lens shows
postganglionic neuro ns whose cell bodies are located in t he that smaller regions of the mucosa are formed by grooves o r
Hi.s tologists also subdi vide the stomach, but into only
wa ll of the eso phag us. Longitudinal submucosal folds, rugae, allow the stomach to shallow trenches that divide the stomach surface into bulging
t hree regions (Fig. 16.5). These su bdivisions are based not
distend when filled irregular areas called mamillated areas. These grooves pro-
o n loca tion but on the types of glands that occur in the
vide a slightly increased surface area for secretion.
gas tric mucosa . The histo logic regions are the
\/STOMACH The stomach has the same general structural plan At higher magnification, numerous openings can be ob-
Cardiac region (cardia), the part near the esophageal throughout, consisting of a mucosa, submucosa, muscu- served in the mucosal surface. These are the gastric pits, or
The stomach is an expanded part of the digestive tube that o ri fice, w hich conta ins the cardiac glands (Fig. 16.6) laris externa, and serosa. Examination of the inner surface foveolae. T hey can be read ily demonstrated w ith t he scan-
lies beneath the d iaphragm. It receives the bolus of mace r- Pyloric region (pylorus), the part p roximal to the py- of the empty stomach reveals a number of longitudi nal ning electron microscope {Fig. 16. 7 ). The gastric g lands
ated food from the esophagus. Mixing and partial d igestion loric sp hincter, w hich con tains the pyloric glands folds o r ridges called rugae. They are prominent in the nar- open into the bottom of the gastric pits.
48'2 CHAPTER 16 Digtstivr Systrw /1, Esophagus aud Gastroiutrstiual Tract
NECK
FIGURE 16.7
Mucosal surface of the stomach. a. Scanning electron micrograph b. Higher magnification showing the apical surface of the surface
showing the mucosal surface of the stomach. The gastric pits contain mucous cells that line the stomach and gastric pits. Note the elon-
secretory material, mostly mucus (arrows). The surface mucus has gate polygonal shape of the cells. x 3,000.
been washed away to reveal the surface mucous cells. x l ,OOO.
Surface mucous cells line the inner surface of the stomach and the epithelial surface; thus, it protects against abrasion
the gastric pits from rougher components of the ch yme. Additionall y, its
high bicarbonate concentration protects the epithelium
The epithelium that lines the surface and the gastric pits from the acidic content of the gastric juice. The bicarbon-
of the stomach is simple columnar. The columnar cells a re ate that makes the mucus a lkal ine is secreted by the surface
designated stt1face mucous cells. Each cell possesses a cells but is prevented from mi x ing rapidly with the con-
large, apica l cup of mucinogen granules, creating a glan- tents of the gastric lumen by its contai nment within the
dular sheet of cells (Fig. 16.8 ). The mucous cup occupies mucus coat. chief
most of the vo lume of the cell. It typically appears empty The lining of the stomach does not function in an a b- cells
in routine hematoxylin and eosin (H&E) sections because sorptive capacity. H owever, some water, salts, a nd lipid-
the mucinogen is lost in fixation and dehydration. When solu ble drugs may be absorbed; a lcoho l and certain drugs,
the mucinogen is preserved by appropriate fixation, how- e.g_, aspirin , enter the lamina propria by damaging the sur-
ever, the gran ules stain intensel y w ith toluidine blue and face epithelium.
GASTRIC GLAND b
with the periodic acid-Schiff (PAS) procedure. The to lui-
dine blue staining reflects the presence of many strongly FUNDIC GLANDS OF THE GASTRIC MUCOSA FIGURE 16.8
anionic groups in the glycoprotein of the mucin, among cells is different from that produced by the surface mucous cells as
Gastric glands. a. This photomicrograph shows the fundic mucosa
which is bicarbonate. The fundic glands produce the gastric jui ce of the stomach evidenced by tl1e ligl?ter magenta staining in this region of the
from an Alcian blue/ PAS preparation to visualize mucus. Note that
The nucleus and Golgi apparatus of th e surface mucous the surface epithelium invaginates to form the gastric pits. The sur- gland. x 320. b. Schematic diagram of a gastric gland, illustrating
cells are located below the mucous cup. The basal part of The fundic glattds, also called gastric glands, are pres- face mucous cells and the cells lining the gastric pits are readily the relationship of tile gland to the gastric pit. Note that the isthmus
the cell contains sma ll amounts of rough endoplasmic ent throughout the entire gastri c mucosa except for the identified in this preparation because the neutral mucus within region contains dividing cells and undifferentiated cells; the neck
reticu lum (rER) that may impart a light basophilia to the relatively small regions occupied by cardiac and pyloric these cells is stained inten sely. One of the gastric pits and its asso- region contains mucous neck cells, parietal cells, and enteroen-
cytoplasm w hen observed in well-preserved specimens. gla nds. The fundi c gla nds are simple, branched, tubular ciated fundic gland are depicted by the dashed lines. This gland rep- docrine cells, including amine precursor uptake and decarboxyla-
The mucous secreti on from the surface mucous cells is glands that extend from the bottom of th e gastri c pits to resents a simple branched tubular gland (arrows indicate the tion (APUD) cells. Parietal cells are large, pear-shaped acidophilic
described as visible mucus beca use of its cloudy appear- branching pattern). It extends from the bottom of the gastric pit to cells found throughout the gland. The fundus of the gland contains
the muscula ris mucosae (see Fig. 16-8). Located between
the muscularis mucosae. Note the segments of the gland: the short mainly cl1lef cells, some parietal cells, and several types of en-
ance. It fo rms a thick, viscous, gel-like coat that adheres to the gas tri c pit and the gland below is a short segment
isthmus, the site of cell divisions; tl1e relatively long neck; and a teroendocrine cells.
shorter and wider fundus. The mucous secretion of mucous neck
CHAPTER 16 01jjestioc System 1/, Es o~hngus n11d Gnsiroin testi11ni Tract 4 85
484 CHAPTER 16
Digeslive System II: EsopiJngus n11d Gnsiro illtesiillni Tmci
tides by splitting interior peptide bonds. Peptides are , the cell a basophilic appearance, whereas the apical cyto- g1on. Zymogen granules containin g pepsinogen and a weak lipase
further digested into amino acids by enzymes in the plasm is eosinophilic due to the presence of the secretory are not always adeq u_ately preserved, and thus tile staining in tile api-
granules, also called zymogen granules because they contain cal reg1on of the cell 1s somewhat variable. This cell produces and se
small intestine.
cretes the precursor enzyme of the gastric secretion. (Based on Lentz
Mucus, an acid-protective coating for the stomach se- enzyme precursors. The basophilia, in particular, allows easy
TL. Cell Fine Structure: An Atlas of Drawings of W/1oleCell structure
creted by several types of mucus-producing cells. T he identification of these cells in H &E sections. The eosino-
Philadelphia: WB Saunders, 1971.) .
mucus and bicarbonates trapped within the m ucous philia may be faint or absent when the secretory granules are
layer maintain a neutral pH and contribute to the so- not adequately preserved. Chief cells secrete pepsinoge11 and
called physiologic gastric mucosa barrie~: In addition, a weak lipase. On contact with the acid gastric juice, cell, the nu mber of microvilli in the canaliculi increases
mucus serves as a physical barrier between the cells of pepsinogen is converted to pepsin, a proteolytic enzyme. a~1d the tu bulovesicular system is xeduced significantly 0;
the gastric mucosa and the ingested material in the lu- disappears. The n_1embranes of the tubulovesicular system
men of the stomach. Parietal cells secrete HCI and Intrinsic factor se_rve as a reservOir .of plasma membrane containing active
Intrinsic factor, a glycoprotei n that binds to vita mi n B12 ?wton pumps. Th1s membrane material can be inserted
It is essential for absorption of vitamin B 12 , which occurs Parietal (oxyntic) cells are found in the neck of the mt~ the plasma membrane of the canaliculi to increase
in the distal part of the ileum. fund ic glands, among the mucous neck cells, and in tbe their s urfac~ area and .the number of proton pumps avai l-
deeper part of the gland. They tend to be most numerous ab le for aCid productiOn . N umero us mitochondria with
In addition, gastrin and other hormones and hormone- in the upper and middle portions of the neck. They are comple~ cristae and many matrix granu les supply the high
like secretions are produced by enteroendocrine cells in the large cells, sometimes binucleate, and appear somewhat levels of energy necessary for acid secretion.
fundic glands and secreted into the lamina propria where tr iangular in sections, with the apex directed toward the
they enter the circulation or act locall y on other gastric ep- lumen of the gland and the base resting on the basa l lam- HCI is produced in the lumen of the intracellular canaliculi
ithelia l cells. ina. The nucleus is spherical, and the cytoplasm stains with
eosin and other acidic dyes. Their size and distinctive stain- basal lamina
Pa rieta l cells have th ree different types of membrane re-
Fundic glands are composed of four functionally different cell ing chaJ:acteristics allow them to be easily distinguished c~ptors_ for substances that activate HCl secretion: gastrin, PARIETAL CELL
types from other cells in the fu ndic glands. lnstamzne Hz , and acetylcholine M 3 receptors. Activation FIGURE 16.10
When examined with the transmission electron micro- of the ~astnn t:eceptor ~y gastrin, a gastrointestinal pep- Diagram. of a parietal cell. Tile cytoplasm of the parietal cell stains
The cells that constitute the fundic glands are of four scope (TEM}, parietal cells (Fig. 16.10) are seen to have an t~de hormone, IS the ma Jor path for parietal cell stimul a- wtth eostn largely because of the extensive am ount of membrane
functional types. Each has a distinctive appearance . In ad- extensive intracellular canalicular system that communi- tiOn. Following stimulation, several steps occur in the pro- compri ~ ing the intracellular canaliculus, tubulovesicular system, mito
dition, undifferentiated cells that give r ise to these cells are cates with the lumen of the gland . N umerous microvilli duction of H CI (Fig. 16.11) : chondna, and tile relatively small number of ribosomes. This cell pro
also present . The various cells that constitute the gland are project from the surface of the canalicu li, and an elaborate duces HCI and intrinsic factor. (Based on Lentz TL. Cell Fine Structure:
tubulovesicular membrane system is present in the cyto- Production of H+ ~ons in the parietal cell cytoplasm by An Atlas of Drawings of Who/eCe/1 Structure. Plllla delphia: W B Sa unders
Mucous neck cells plasm adjacent to the canaliculi. In an actively secreting the enzyme carbomc anh ydrase. This enzyme hydrolyzes 1971 .) '
Chief cells
486 CH A PTER 16 D igcslive Sysle111 1/, Esof>IJn!}IIS ""'/ Cns lroiHirslilltli Trncl CHAPTER 16 Digeslit>f Sysleou 1/, EsofJiwgus mul CnslroiHiesliolfli Tmcl 487
TABLE
CHAPTER16 Digestiue System [[, Esophagus aud Gaslroiutrsli1ra/ Tra ct
Major Action
Hormone Site of Synthesis Stimulates Inhibits
Gastrin Stomach Gastric acid secretion
Cholecystokinin (CCK) Duodenum Gallbladder contraction Gastric emptying Enteroendocrine cells are present in most of the digestive tract,
Jejunum Pancreatic enzyme secretion including the ducts of the pancreas and liver, and in the respi-
Pancreatic bicarbonate ion secretion ratory system, another endodermal derivative that originates by
Pancreatic growth invagination of the epithelium of the embryonic foregut. The
Secretin Duodenum Pancreatic enzyme secretion Gastric acid secretion endocrine islets (of Langerhans) of the pancreas can be consid-
Pancreatic bicarbonate ion secretion ered specialized accumulations of enteroendocrine cells derived
Pancreatic growth from pancreatic buds that also arise from the embryonic
Gastric inhibitory peptide (GIP) Duodenum Insulin release Gastric acid secretion foregut. It has been estimated that the enteroendocrine cells
Jejunum collectively would constitute the largest endocrine "organ in the
Motilin Duodenum Gastric motility body. These cells have also been called gastroenteropancreatic
Jejunum Intestinal motility (GEP) endocrine cells and closely resemble neurosecretory cells
of the central netvous system that secrete many of the same
Adapted from Johnson LR, ed. Essential Medical Physiology. Philadelphia: Lippincott-Raven, 1998. hormones and regulatory agents. For that reason, they are also
described as constituting part of a diffuse neuroendocrine sys-
PYLORIC GLANDS OF THE GASTRIC MUCOSA spersed within the gland epithelium along with occasional tem. These endocrine cells are not grouped as clusters in any
parietal cells. The glands empty into deep gastric pits that specific part of the gastrointestinal tract. Rather, they are dis-
Pyloric gland cells are similar to surface mucous cells and help occupy about ha lf the thickness of the mucosa (Fig. 16.15). tributed singly throughout the gastrointestinal epithelium. Fig-
protect the pyloric mucosa ure 16.13 shows the parts of the gastrointestinal tract from
which the hormones are released into the blood.
Pyloric glands are located in the pyloric antrum (the part
Epithelial Cell Renewal in the Stomach Some enteroendocrine cells may be classifiable functionally
as amine precursor uptake and decarboxylation (APUD) cells.
of the stomach between the fundus and the pylorus). They Surface mucous cells are renewed approximately every 3 to 5 They should not, however, be confused with the APUD cells
are branched, coiled, tubular glands. The lumen is rela- days that are derived from the embryonic neural crest and migrate
tively wide, and the secretory cells are similar in appear- to other sites in the body. Enteroendocrine cells, as discussed
FIGURE 16.14
ance to the smface mucous cells, suggesting a relatively The relatively short lifespan of the surface mucous cells, 3 above, differentiate from the progeny of the same stem cells
Photomicrograph of cardiac glands. This photomicrograph shows
viscous secretion. Enteroendocrine cells are found inter- to 5 days, is accommodated by mitotic activity in the isth- the esophagogastric junction. Note the presence of the stratified squa- as all of the other epithelial cells of the digestive tract. The fact
mous epithelium of the esophagus in the upper right corner of the mi- that two different cells may produce similar products should
crograph. The cardiac glands are tubular, somewhat tortuous, and oc- not imply that they have the sa me origin.
Enteroendocrine cells produce not only gastrointestinal hor-
TABLE 16.2. Physiologic Action of Other Hormones in the Gastrointestinal Tract casionally branched. They are composed mainly of mucus-secreting
cells similar in appearance to the cells of the esophageal glands. Mu- mones such as secretin, gastrin, cholecystokinin (CCK), gastric
Major Action cous secretion reaches the lumen of the gastric pit via a short duct inhibitory peptide (GIP), and motilin but also paracrine sub-
segment containing columnar cells. x 240. stances (paracrines). A paracrine substance differs from a hor-
Hormone Site of Synthesis Stimulates Inhibits
mone in that it diffuses locally to its target cell instead of be-
ing carried by the bloodstream to a target cell. A well-known
Candidate hormones
mus, the narrow segment that lies between the gastric pit a11d substance that appears to act as a paracrine substance within
Pancreatic polypeptide Pancreas Pancreatic enzyme secretion the gastrointestinal tract and pancreas is somatostatin, which
Pancreatic bicarbonate secretion
the fundic gland (Fig. 16.16). This mitotic activity provides
inhibits other gastrointestinal and pancreatic islet endocrine
Peptide YY Ileum
continuous cell renewal. Most of the newly produced cells at
Gastric acid secretion cells. APUD cells secrete a variety of regu lator substances in
Colon Gastric emptying this site become surface mucous cells. They migrate upward tissues and organs including the respiratory epithelium, adre-
Glucagon-like peptide-1 (GLP-1) Ileum Insulin release Gastric acid secretion along the wall of the pit to the luminal surface of the stom- nal medulla, islets of Langerhans, thyroid gland (parafollicular
Colon Gastric emptying ach and are ultimately shed into the stomach lumen. cells), and pituitary gland.
Paracrine hormones In addition to the established gastrointestinal hormones,
The cells of the fundic glands have a relatively long lifespan several gastrointestinal peptides have not been definitely clas
Somatostatin Mucosa throughout Gl tract Gastrin release
sified as hormones or paracrines. These peptides are desig-
Gastric acid secretion
Release of other Gl hormones Other ceUs from the isthmus migrate down into the gas- nated candidate or putative hormones.
tric glands to give r ise to the parietal cells, chief cells, mu- Other locally active agents isolated from the gastrointestinal
Histamine Mucosa throughout Gl tract Gastric acid secretion
cous gland cells, and enteroendocrine cells that constitute mucosa are neurotransmitters. These agents are released from
Neurocrine hormones nerve endings close to the target cell, usually the smooth mus
the gland epithelium. These cells have a relatively long
Bombesin Stomach Gastric release cle of the muscularis mucosae, the muscularis externa, or the tu-
lifespan. The parietal cells have the longest lifes pan, ap-
Enkephalins Mucosa and smooth muscle Smooth muscle contraction Intestinal secretion nica media of a blood vessel. In addition to acetylcholine (not a
proximately 150 to 200 days. Although parieta l cells peptide), peptides found in nerve fibers of the gastrointestinal
tllrougl1out Gl tract
develop from the same Lmdifferentiated stem cells, their tract are vasoactive intestinal peptide (VIP), bombesin, and
Vasoactive inhibitory peptide Mucosa and smooth muscle Pancreatic enzyme secretion Smooth muscle contraction
(VIP) tl1roug!lout GI tract
lifes pan is distinctly different. R ecently, it has been hy- enkephalins. Thus, a particular peptide may be produced by en-
Intestinal secretion Sphincter contraction
pothesized that parietal cells may have evolved from a docrine and paracrine cells and also be localized in nerve fibers.
Adapted from Jot1nson LR, ed. Essential Medical P."JYsiology. Philadelphia: Lippincott-Raven, 1998. bacterium called Neurospora crassa that previously ex-
490 CHAPTER 16 Digestive Systew /L Esophagus nnd Gastroiutestiunl Tra ct CHA PTER 16 Digestive Systcw n Esop/;ngus aud Gastroi>.t<stiunl Tmct 49 I
terminal
junctional web
microvilli
FIGURE 16.21
Diagrams of an enterocyte in different
phases of absorption. a. This cell has a
striated border on its apical surface and
j unctional complexes that seal the lu-
men of the intestine from the lateral
intercellular space. The characteristic
complement of organelles is depicted in
the diagram. b. This cell shows the dis-
tribution of lipid during fat absorption
as seen with the TEM. Initially, lipids are
seen in association with the microvilli
of the striated border. Lipids are inter-
nalized and seen in vesicles of the
smooth endoplasmic reticulum (sER) In
the apical portion of the cell. The
membrane-bounded lipid can be traced
to the center of the cell, where many of
the lipid-containing vesicles fuse. The
FIGURE 16.19 lipid is t11en discharged into the inter-
Photomicrograph of an intestinal villus. The surface of the vi llus con- cellular space. The extracellular lipids,
sists of columnar epithelial cells, chiefly enterocytes with a striated recognized as chylomicrons, pass be-
border. Also evident are goblet cells that ca n be readily identified by yond the basal lamina for further trans-
the presence of the apical mucous cup. Located beneath the epithe- port. (Based on Lentz TL. Cell Fine Struc-
c hylomicrons
lium is the highly cellular loose connective tissue, the lamina propria. ture: An Atlas of Drawings of Whole-Cell
The lamina propria contains large numbers of round cells, mostly lym- Structure. Philadelphia: WB Saunders,
phocytes. In addition, smooth muscle cells can be Identified. A lym- 1971.) ABSORPTIVE CELLS
phatic capillary called a lacteal occupies the center of the villus. When
the lacteal is dilated, as it is in this specimen, It is easily identified.
X 160. circular fold
that drives Na+ and water across t he basa l la mi na into t he The la teral cell sur face of th e enterocytes exh ibits elabo-
Tight junctions establish a barrier between the intestinal lu- connective tiss ue. r ate, flattened cytoplasmic processes (plicae) tha t interdig-
men and the epithelial intercellular compartment In epithelia with more pe rmea ble right junctio ns, suc h as itate with those of adja cent cells (see Fig. 4.15). T hese fo lds
those in the duodenum an d jejunum, a sodium pump also increase the la tera l surface a rea of the cell, rhus increasing
T he ti ght junctions between the intestinal lumen a nd the FIGURE 16.20
c rea tes low intracellular N a+ concen tratio n. W hen t he the a mo unt of p lasma membrane containing transp o rt en -
connective tissue compartment of the bo dy a llow selective Photomicrograph of Peyer's patches. This photomicrograph shows a con tents tha t pass into t he du odenum a nd jejunum are hy- zymes. During active abso rption, esp ecially of solutes, wa-
retention of substances a bsorbed by th e e nterocytes. As longitudinal section through the wall of a human ileum. Note the ex- poto nic, however, considera ble absorptio n of wa te r, along ter, a nd lipids, these lateral plications separate, enlarging
no ted in the section on occluding juncti ons (see page 97), tensive lymphatic nodules located in the mucosa and t11e section of a w ith additio n al Na + and other sma ll solu tes, takes p lace the i ntercellula r compartment. The increased h yd rostatic
the "tightn ess" of these junctio ns ca n vary. circular fold projecting into the lumen of the ileum. Lymphatic nod- directly ac ross the tig ht junctions of the e nterocytes into press ure from the accu mulated solutes a nd solven ts causes
In rela tively impermeable tight junctions, as in the ules within the Peyer's patch are primarily located within. the lamina the intercellula r spaces. This mech a nism of a bsorption is a directional flow thr o ug h th e basal la m ina into th e lam ina
propria, although many extend into the submucosa. They are covered referred to as solvent drag. pro pria (see Fig. 4. 1 ).
ile um a nd colon, acti ve tr ansport is required to move
by the intestinal epithelium, which contains enterocytes, occasional Other tra nsport mecha nisms also increase the concentra-
solutes across the barrie r. In simplest terms, active tra ns- In addition to the membra ne specializations associa ted
goblet cells, and specialized antigen-presenting M cells. x 40.
port systems, e.g. sodium p umps (Na+fK+-ATPase ), lo- tio ns o f specific substances, such as suga rs, a mino acids, a nd w ith absorption and tra nspo rt, the enterocyte cytoplasm is
ca ted in t he la tera l plasma mem bran e tra nsie ntly reduce othe r solutes in the intercellular sp ace. These su bsta nces also specialized for these functions. Elonga ted mitocho ndria
the cytoplasmi c concentration o f Na+ by tra nsporting it then d iffuse or flow down thei r concentration gradients that provide energy fo r tra nsport a re co ncentrated in the
across the lateral p las ma membra ne into the extracellula r q uently, wa ter and Na + enter the cell a t its apical surface, within the intercellular space to cross the epithelial basal apica l cytoplasm between the terminal web and t he nucl eus.
space below the tight junction. This transport of Na+ cre- passi ng through t he cell, and exiting at the latera l plasma lamina and enter the fen estra ted capilla ries in t he lamina Tubules a nd cisternae of th e smooth endoplasmic retic uiLml
a tes a hi gh intercellular Na+ co ncentration, ca using water membra ne as lo ng as t he sodium p ump co n tinues to func- propria loca ted immedia tely benea th the epithelium. Sub- (sER ), w hich a re in vo lved in th e a bsorption of fa tty acids
from the cell to enter the inter cellula r sp ace, redu cing both tion. Increased osm olarity in the intercellular sp ace d raws stances that a re too la rge to enter the blood vessels, such as and glycero l a nd in the resynthesis of neutra l fa t, are fo und
t he wate r and Na + concentrations in th e cell. Conse- water into this space, esta blish ing a hydrostatic p ress ure lipoprotein particles, enter the lympha tic lactea l. in the api cal cytoplasm beneath the termina l w e b.
Digeslive System II: Esopbngus nud Gaslroiulesfi11nl Trncl
CHAPTER 1 6 Diyeslive Syslem ll: Esopbngus twd Gnslroiulesli1wl Trncl 49 7
496 C H APTER 1 6
the enkeph ali ns. The functions of these peptides are listed
in Table 16.2.
FIGURE 16.28 sive network of nerve fibers (N). A satellite cell (SC), also referred to as
Electron micrograph of the myenteric (Auerbach's) plexus. The an enteric glial cell, Is seen In proximity to the neuron cell bodies.
plexus Is located between the two smooth muscle (SM) layers of the These cells have structural and chemical features in common with
muscularis externa. It consists of nerve cell bodies (CB) and an exten- glial cells of the CNS. BV, Blood vessel. X 3,800.
~ ]1
Fe receptor
FIGURE 16.27
Photomicrograph of Brunner's glands in the duodenum. This pho-
sis, the second type of contraction, la rgely involves th e Enteroendocrine cells and Paneth cells are also derived
tomicrograph shows part of the duodenal wall in a H&E preparation. lo ngitudina l muscle layer and moves th e intestinal con- from the stem cells at the base of the intestinal gland. En-
LAMINA PROPRIA A distinctive feature of the duodenum is the presence of Brunner's tents distally. teroendocrine cells appear to divide on ly once before dif-
glands. The das/1ed line marks the boundary between the villi and the fere ntiating. They migrate with the absorptive and goblet
plasma cell
typical intestinal glands (crypts of Lleberki.ihn). The latter extend to cells but at a slower rate. Paneth cells do not migrate; they
the muscularis mucosae. Under the mucosa is the submucosa, which
Serosa
FIGURE 16.26 remain in the base of the intestinal gland near the stem cells
contains Brunner's glands. These are branched tubular glands whose The serosa of the parts of the sma ll intestine that are lo-
Diagram of immunoglobulin A (lgA) secretion and transport. Im- secretory component consists of columnar cells. Tile duct of the Brun- from which they are deri ved . T hey live for approximately 4
cated intra peritoneally in the abdominal cavity corresponds
munoglobulin A (lgA) is secreted by plasma cells Into the lamina pro- ner's gland opens into the lumen of the intestinal gland (arrow). x 120 weeks and are then replaced by differentiation of a nearby
pria. Here, it dimerizes and then binds to a transmembrane F, recep- to the general description at the beginning of the chapter.
"committed " cell in the intestinal gland. Cells that are r ec-
tor on tile membrane of the enterocyte. Tile extracellular portion of
ogniza ble as Paneth cells no longer divide.
the membrane receptor will remain with the lgA dimer and w ill later Epithelial Cell Renewal in the Small Intestine
become the secretory component of the lgA. The lgA- receptor com-
Muscularis Externa
plex enters the cel l by endocytosis and is ca rried to the apical sur-
face within the endocytotic vesicles (a process called transcytosis). T he muscularis extema consists of a n inn er layer of cir -
All of the mature cells of the intestinal epithelium are derived Q LARGE INTESTINE
from a single stem cell population
The vesicle fuses with t11e apical plasma membrane, releasing the cularl y a rranged smooth muscle cells a nd an outer layer
lgA- receptor com plex as secretory lgA (slgA). The lgA monomers and The large intestine comprises the cecum w ith its projecting
o f longitudina ll y a rra nged smooth muscle cells. The main Stem cells a re located in the base of the intestinal gland.
dimers, the F, recepto rs, and the endocytotic vesicles are greatly ex- vennifonn appendix, the colon, the rectum and the anal
components of the m yenteric plexus (Auerbach's plexus) The zone of cell replication is restricted to the lower one
aggerated in size for clarity. The actual sizes of the vesicles involved canal. The colon is furth er subdi vided on the basis of its
a re located between these two muscle laye rs (Fig. 16.28). ha lf of the gla nd. A cell destined to becom e a goblet cell or
approximate those shown in the adjacent enterocytes. anatomic locatio n into ascending colon, transverse colon,
Two kinds of muscul ar contraction occur in the small in- absorptive cell usually undergoes severa l add itio nal divi-
sio ns after it leaves the pool of stem cells. The epithelial
descending colon, a nd sigmoid colon. The fou r layers char-
testine. Loca l contractio ns dis place intestinal contents
acteristic of the ali menta ry canal are present throughout.
ate ions. This highl y a lkal ine secretio n proba bly serves to both proximally and dista ll y, thi s type of contraction is cells migrate upward in the intestinal gla nd onto the villus
However, several distinctive features exist at the gross level
protect the prox imal small intestine by neutralizing the called segmentati01t. T hese contractions pr imaril y in- a nd are shed at the tip of the villus. Autoradiographic stud-
(Fig. 16.32):
ac id-conta ining chyme delivered to it. It also brings the in- volve the circular m uscle layer. T hey serve to circulate the ies have shown that the renewal time fo r abso rptive and
testina l contents close to the optimal pH for the pancrea tic chyme locally, mi xing it with digestive juices and moving go blet cells in the human small intestine is 5 to 6 days (see Except for the rectum , a nal canal, and vermiform ap-
enzy mes that ar e a lso deli vered to the d uodenum. it into contact w ith the mucosa fo r abso rptio n. Peristal- Fig. 4.32) . pendi x, the o uter longitudinal layer of the muscularis
50'2 CHAPTER 16 Digrstive Syste1t1 lL Esophagus fwd Gnstmiutrs tiunl Tra ct CHAPTER 16 Digestive System II: Esophagus nud Gnstroiutestiunl Tra ct 50 3
The plasma membrane of the microvilli of the enterocyte plays a tine exclusively via capillaries that lead to the portal vein and
role in digestion as well as absorption. Digestive enzymes are an- the liver.
chored in the plasma membrane, and their functional groups ex- Carbohydrate final digestion is brought about by enzymes
tend outward to become part of the glycocalyx. This arrangement bound to the microvilli of the enterocytes {Fig. 16.30). Galactose,
brings the end products of digestion close to their site of absorp- glucose, and fructose are conveyed to the liver by the vessels of
the hepatic portal system. Some infants and a larger percentage of - 5%
tion. Included among the enzymes are peptidases and disacchari-
dases. The plasma membrane of the apical microvilli also contains adults cannot tolerate milk and unfermented milk products be-
the enzyme enteropeptidase (enterokinase), which is particularly im- cause of the absence of lactase, the disaccharidase that splits lac-
portant in the duodenum, where it converts trypsinogen Into tose into galactose and glucose. If given milk, these Individuals be-
trypsin. Trypsin can then continue to convert additional trypsino- come bloated because of the gas produced by bacterial digestion
gen into trypsin, and trypsin converts several other pancreatic zy- of the unprocessed lactose and suffer from diarrhea. The condition
mogens into active enzymes {Fig. 16.29). A summary of digestion is completely alleviated if lactose (milk sugar) is eliminated from
and absorption of the three major nutrients is outlined In the fol- the diet. For some individuals, milk intolerance may be also par-
lowing paragraphs. tially or completely alleviated by using lactose-reduced milk prod-
Trlglycerldes are broken down into glycerol, monoglycerides, ucts or tablets of lactase (enzyme that digests lactose). which are
and long- and short-chain fatty acids. These substances are available as over-the-counter drugs.
emulsified by bile salts and pass into the apical portion of the Protein digestion and absorption is shown in Figure 16.31. The
enterocyte. Here, the glycerol and long-chain fatty acids are major end products of protein digestion are amino acids, which
resynthesized into triglycerides. The resynthesized triglycerides are absorbed by enterocytes. However, some peptides are also ab-
appear first In apical vesicles of the sER (see Fig. 16.21 ), then in sorbed and are evidently broken down lntracellularly. In one dis-
the Golgi (where they are converted into chylomicrons, sma ll order of amino acid absorption (Hartnup's disease), free amino
droplets of neutral fat), and finally in vesicles that discharge the acids appear in the blood when dipeptldes are fed to patients but
chylomicrons into the intercellular space. The chy lomicrons are not when free amino acids are fed. This supports the conclusion
conveyed away from the intestine via both venous capi llaries that dipeptides of certain amino acids are absorbed via a pathway
and lacteals. Short-chain fatty acids and glycerol leave the intes- different from that of the free amino acids. FIGURE 16.30
Diagram showing the digestion and absorption of carbohydrates
by an enterocyte. Carbohydrates are delivered to tile alimentary
canal as monosaccharides (e.g., glucose, fructose, and galactose),
pancreatic zymogens disaccharides (e.g., sucrose, lactose, and maltose), and as polysac-
(inactive proenzymes) charides {e.g., glycogen and starch). Enzymes evolved in digestion
of carbohydrates are classified as salivary and pancreatic amy-
lases. Further digestion is performed at the striated border of the
FIGURE 16.31
enterocytes by enzymes breaking down oligosaccharides and
chymotrypsinogen Diagram showing the digestion and absorption of protein by an
polysaccharides into three basic monosaccharides {glucose, galac- -
proelastase elastase enterocyte. Proteins entering the alimentary canal are completely
procarboxypeptidase A VI"_ ,.. carboxypeptidase A lose, and fructose). Glucose and galactose are absorbed by the en-
digested into free amino acids and small dipeptide or tripeptide
procarboxypeptidase B carboxypeptidase B terocyte via an active transport utilizing Na+-dependent glucose
fragments. Protein digestion starts in the stomach with pepsin,
prophospholipase A 2 phospholipase A2 transporters (SG LTl ). These transporters are localized at the apical ,
which hydrolyzes proteins to large polypeptides. The next step oc-
cell membrane (brown circles with G and Na ' labels). Fructose enters
curs in the small intestine by the action of pancreatic proteolytic
the cell via facilitated Na+independent transport utilizing GLUTS
enzymes. The activation process is shown in Figure 16.29. Free
(gray circle with F label) and GLUT2 glucose transporters (orange oc-
amino acids are transported by four different amino acid trans-
tagon with G2 label). The three absorbed monosaccharides then
FIGURE 16.29 porters and several dipeptide and tripeptide transporters into the
pass through the basal membrane of tile enterocyte, utilizing
Diagram showing events in the activation of the proteolytic en- cell and then from the cell Into the underlying capillaries of the por-
GLUT2 glucose transporters, into the underlying capillaries of tile
zymes of the pancreas. The majority of pancreatic enzymes (pro tal circulation.
portal circulation to reach their final destination in the liver.
teases) are secreted as inactive proenzymes. Their activation is trig-
gered by the arrival of chyme into the duodenum. This stimulates
the mucosal cells to release and to activate the enterokinase {blue
box) within the glycocalyx. The enterokinase activates trypsinogen,
converting it into its active form, trypsin (green box). In turn, trypsin
activates other pancreatic proenzymes (red box) into their active externa ex hibi ts three th ickened, equa ll y spaced bands Mucosa
ente rocyte forms (purple box). The active proteases hydrolyze peptide bonds known as the teniae coli.
of proteins or polypeptides and reduce them to small peptldes and The external surface of the cecum and colo n exhibits The mucosa of the large intestine contains n umero us
amino acids. sacculations known as haustra that ar e visible between straight tubular intestinal glands (crypts of Lieberki.ih n)
the ten iae. The mucosa has a "sm ooth " surface; neither that ex tend thro ugh the full thickness of the mucosa (Fig.
plicae circul ares nor villi ar e present. 16.3 3a ). The g lands consist of simple co lum nar epithelium,
Small fatty projections of the serosa known as omental as does the intestinal surface from w hich they invaginate.
appendices are visible o n the outer intestina l surface. Examination of the lumina] surface of the large intestine at
504 CHAPTER 16 Digestive System IJ.. Eso{>hng11s n11d Gnstmi11testiua/ Tmct CH APTE R 1 6 Digestive Syste111 11: fso{>l>n.!}II S nud Gnst1oilltesliunl Tm ct 50 5
submucosa and as a network around the muscularis The muscularis externa of the large intestine produces of the rest of the colon; the appendix differs from it in hav-
externa. two major types of contraction: segmentation and peristal- ing a uniform layer of longitudinal muscle in the muscu-
sis. Segmentation is local and does not result in the propul- laris externa (Fig. 16.35). The most conspicuous feature of
sion of conten ts. Peristalsis results in the distal mass move- the appendix is the large number of lymphatic nodules that
Muscularis Externa
ment of the colonic contents. Mass peristaltic movements extend into the submucosa. In many adults, the normal
As noted, in the cecum and colon (the ascending, trans- occur infrequently; in healthy persons, they usually occur structure of the appendix is lost, and the appendage is
verse, descending and sigmoid colon), the outer layer of once a day to empty the distal colon. filled with fibrous scar tissue.
the muscularis externa is, in part, condensed into promi-
nent longitudinal bands of muscle, called teniae coli,
which may be seen at the gross level (see Fig. 16.32). Be- Submucosa and Serosa Rectum and Anal Canal
tween these bands, the longitudinal layer forms an ex- The submucosa of the large intestine corresponds to the The rectum is the dilated distal portion of the alimentary
tremely thin sheet. In the rectum, anal canal, and vermi- general description already given. Where the large intestine canal. Its upper part is distinguished from the rest of the
form appendix, the outer longitudinal layer of smooth is directly in contact with other structures (as on much of large intestine by the presence of folds called transverse
muscle is a uniformly thick layer, as in the small intestine. its posterior surface), its outer layer is an adventitia; else- rectal folds. The mucosa of the rectum is similar to that of
Bundles of muscle from the teniae coli penetrate the in- where, the outer layer is a typical serosa. the rest of t he distal colon, having straight, tubular intes-
ner, circular layer of muscle at irregular intervals along the tinal glands with many goblet cells.
length and circumference of the colon. These apparent dis- The most djstal portion of the a limentary canal is the
continuities in the muscularis externa allow segments of Cecum and Appendix anal canal. It has an average length of 4 em and extends
the colon to contract independently, leading to the forma- The cecum forms a blind pouch just distal to the ileocecal from the upper aspect of the pelvic diaphragm to the anus
tion of saccules (haustra) in the colon wall. valve; the appendix is a thin, finger-like extension of this (Fig. 16.36). The upper part of the anal cana l has longitu-
pouch. The histology of the cecum closely resembles that dinal folds cal led anal columns. Depressions between the
lymphatic nodules
transverse
rectal folds
rectum
colorectal zone L
FIGURE 16.34 anal canal
anal transitional zone L
Electron micrograph of dividing goblet cells. Tilis electron micro-
grapil demonstrates tilat certain cells of the intestine continue to di-
squamous zone L
vide even after tiley ilave differentiated. Here, two goblet cells (GC)
are silown in division. Typically, tile dividing cells move away from FIGURE 16.35
the basal lamina toward the lumen. One of t ile goblet cells silows mu- Photomicrograph of a cross section through the vermiform appen-
perianal skin L
[ -------------
cinogen granules (M) in its apical cytoplasm. The cilromosomes (C) of dix. The vermiform appendix displays the same four layers as those
the dividing cells are not surrounded by a nuclear membrane. Com- of the large intestine except t11at its diameter is smaller. Typically, lym-
pare with the nuclei (N) of the nondividing intestinal epithelial cells. phatic nodules are seen w ithin the entire mucosa and usually extend FIG URE 16.36
The lumen of the gland (L) is on the right. CT, connective tissue; and into the submucosa. Note the distinct germinal centers within the Drawing ofthe rectum and anal canal. The rectum and anal canal are columnar (or cuboidal) epithelium and then to a stratified squamous
E, eosinophil. x s,ooo. lymphatic nodules. The muscularis externa is composed of a rela- the terminal portions of the large intestine. They are lined by the col- epithelium. This transition occurs in the area referred as the anal tran-
tively thick circu lar layer and a much thinner outer longitudinal layer. orectal mucosa that possesses a simple columnar epithelium contain- sitional zone, which occupies the middle third of the anal canal be-
The appendix is covered by a serosa that is continuous with t11e ing mostly goblet cells and numerous anal glands. In the anal canal tween the colorectal zone and the squamous zone of t11e perianal
mesentery of the appendix (lower right). XlO. the simple columnar epithelium undergoes transition into a stratified skin.
508 CHAPTER 16 Digestive System If, Esopl)(rgus n11d Gnstroi11testillnl Tra ct CHAPTER 16 Digestive Sy stem IL Eso111Jag11s n111/ Gastroirllesti11nl Tract 5 09
BOX 16.5
Immunologists have shown that the GALT not only responds to recesses of the adjacent extracellular space (Fig. 16.38). Lym pho-
antigenic stimuli but also functions in a monitoring capacity. This cytes w ithin the deeply recessed extracellular space sa mple the lu-
function has been partially clarified for the lymphatic nodules of minal protein, including antigens, and thus have the opportunity
the intestinal tract. TheM cells that cover Peyer's patches and lym- to stimulate development of specific antibodies against the anti-
phatic nodules have a distinctive surface that might be misinter- gens. The destination of these exposed lymphocytes has not yet
preted in sections as thick microvilli. The cells are readily identified been fully determined. Some remain w ithin the local lymphatic tis-
with the scanning electron microscope because microfolds con- sue, but others may be destined for other sites in the body, such
trast sharply with the microvilli that constitute the striated border as the salivary and mammary glands. Recall that in the salivary
of the adjacent enterocytes. glands, cells of the immune system (plasma cells) secrete lgA,
It has been shown with horseradish peroxidase (an enzyme which the glandular epithelium then converts into slgA. Some ex-
used as an experimental marker) that the M cells pinocytose pro- perimental observations suggest that antigen contact necessary
tein from the intestin al lumen, transport tl1e pinocytotic vesicles for the production of lgA by plasma cells occurs in the lymphatic
through the cell, and discharge the protein by exocytosis into deep nodules of the intestines.
M cells
lymphocytes
FIGURE 16.37
Photomicrographs of the anal canal. a. This photomicrograph shows from the thicken ing of tile circular layer of the muscularis externa. A
a longitudinal section through the wall of the anal canal. Note the small portion of the externa l anal sphincter is seen subcutaneously.
three zones in the ana l cana l: the squamous zone (SQZ) containing X10. b. This high magnification of the area indicated by the rectangle
stratified squamous epithelium; the ana l transitional zone (ATZ) con- in a shows the area of the anal transitional zone (ATZ). Note the abrupt
taining stratified squamous, stratified cuboidal, or columnar epithe- transition between stratified cuboidal and simple columnar epithe- a
lium and simple columnar epithelium of the rectal mucosa; and the lium. The simple columnar epithelium of anal glands extends into the
colorectal zone (CRZ) containing only simple columnar epithelium like submucosa. These straight, mucus-secreting tubular glands are sur- FIGURE 16.38
the rest of the colon. Note the anal valve that demarcates the transi- rounded by diffuse lymphatic tissue. x 200. Diagram of M cells in a lymphatic nodule of the intestine. a. This ' RL, Nemanic PC, eds. Scanning Electron Microscopy. Vol II. O'Hare,
tion between the ATZ and SQZ. The internal anal sphincter is derived diagram shows the relationship of the M cells (microfold cells) and IL: AMF, 1978.) b. Scanning electron micrograph of a Peyer's patch
absorptive cells to the ly mphatic nodule. The M cell is an epithelial lymphatic nodule bulging into the lumen of the ileum. Note that
cell that displays microfolds rather than microvilli on its apical sur- the area of the follicle covered by M cells is su rrounded by the fin-
anal columns are called anal sinuses. The anal canal is di- Squamous zone, which is fo und in the lower third of the face. It has deep recesses within which lymphocytes come close to ger-like proj ections of the intestinal villi. The surface of the M cells
vided into three zones according to the cha racter of the ep- anal canal. This zone is lined with stratified squamous ep- the lumen of the small intestine. M cells have MHC II molecules on has a smooth appearance. The absence of absorptive cells and
ithelial lining: ithelium that is continuous with that of the perineal skin. their surface and are therefore considered antigen-presenting mucus-producing goblet cells in the area covered by M cells facili-
cells. Antigen from the intestinal lumen is presented to T lympho- tates immunoreactions to antigens. x 80. (From Owen RL, Johns
Colorectal zone, which is found in the upper third of the In the anal cana l, anal glands extend into the su bmu- cytes residing w ithin the recesses of the M cell. (Based on Owen AL. Gastroenterology 1974;66.)
anal canal and contai ns simple columnar epithelium cosa and even into the muscularis externa. These
with characteristics identical to that in the rectum branched, straight tubular glands secrete mucus onto the
Anal transitional zone (ATZ), which occupies the middle anal surface through ducts li ned with stratified columnar
third of the anal cana l. It represents a transition between epithelium. Sometimes the anal glands are surrounded by Hair follicles and sebaceous glands are also fou nd at this pertension). There are no teniae coli at the level of the rec-
the simple columnar epithelium of the rectal mucosa and diffuse lymphatic tissue. T hey often lead to the formation site. tum; the longitudinal layer of the muscularis externa forms
the stratified squamous epithelium of the perianal skin. of pathologic fistulas (a false opening between the anal The submucosa of the anal columns contai ns the termi- a uniform sheet. The muscularis mucosae disappears at
The ATZ possesses a stratified columnar epithelium in- canal and the perianal skin). nal ramifica tions of the superior rectal artery and the rec- about the level of the anal transitional zone (ATZ), where
terposed between the simple columnar epithelium and La rge apocrine glands, the circumanal glands, are ta l veno us p lexus. Enlargements of these submucosal veins the circular layer of the muscu laris externa thickens to
the stratified squamous epithelium, which extends to the fo und in the skin surrounding the anal orifice. In some an- constitute internal hemorrhoids, which are related to ele- form the internal anal sphincter. The external anal sphinc-
cutaneous zone of the anal canal (Fig. 16.37). imals, the secretion of these glands acts as a sex attractant. vated venous pressure in the portal circulation (portal h y- ter is formed by striated muscle of the pelvic floor.
C HA PTER 1 6 Digestive System IL Esof>lwgus mrd Gnstroi11testi11al Tract 51 1
B
Figure 1, esophagus, monkey, H&E x 60; inset ated muscle. Although the striations are not evident at this
X400. low magnification, the more de nsely stai ned eosinophilic
A cross section of the wall of the esophagus is shown areas (asterisks) prove to be striated muscle when observed
here. T he mucosa (Muc) consists of stratified squamous ep- at higher magnification. Reference to the inset, which is
ithelium (Ep), a lamina propria (LP), and muscularis mu- from an area in the lower half of the figure, substantiates
cosae (MM). The boundruy between the epithelium and this identification.
lamina propria is distinct, although uneven, as a result of The inset shows ci1cularly orie nted striated and smooth
the presence of numerous deep connective tissue papillae. muscle. The stliated muscle stains more intensely with
The basal layer of the epithelium stains inte nsely, appearing eosin, but of greater significance are the di stribution and
as a dark band that is relativel y conspicuous at low magni- number of nuclei. In the midarea of the inset, numerous
fication. This is, in part, due to the cytoplasmic basophilia elongated and uniformly oriented nuclei are present; this is
of the basal cells. That the basal cells rue small results in a smooth muscle (SM). Above and below, few elongated nu-
high nuclear-cytoplasmic ratio, which further intensifies the clei are present; moreover, they are largely at the periphery
hematoxylin staining of thi s layer. of the bundles. This is striated muscle (StM); the cross-
The submucosa consists of irregular dense connective tis- striations are just perceptible in some areas. The specimen
sue that contains the Iruger blood vessels and nerves. No shown here is from the middle of the esophagus, where
glands rue seen in the submucosa in this figure, but they are both smooth and striated muscle are present. The muscu-
regularly present throughout this layer and are likely to be in- laris externa of the distal third of the esophagus would con-
cluded in a section of the wall. Whereas the boundruy be- tain only smooth muscle, whereas that of the proximal third
tween the epithelium and lamina propria is striking, the would consist of striated muscle.
boundruy betwee n the mucosa (Muc) and submucosa (SubM) External to the muscularis externa is the adventitia (Adv)
is less well mmked, although it is readily discernable. consisting of dense connective tissue.
The muscularis externa (ME) shown here is composed
largely of smooth muscle, but it also contains areas of stri-
R
Figure 2, esophagus, monkey, H&E x 300. lillln of the upper regions of the esophagus may be p arak-
As in other stratified squamous epithelia, new cells are eratinized or, more rarely, kerati nized.
produced in the basal layer, from which they move to the As shown in this figure, the lamina propria (LP) is a very
surface. During this migration, the shape and orie ntation of cellular, loose connective tissue containing many lympho-
the cells change. This change in cell shape and orie ntation cytes (Lym), small blood vessels, and lymphatic vessels
is also reflected in the appearance of the nuclei. In the (LV). The deepest part of the mucosa is the muscularis mu-
deeper layers, the nuclei are spherical; in the more superfi- cosae (MM). That layer of smooth muscle defines the
cial layers, the nuclei are e longated and oriented parallel to boundary between mucosa and submucosa. The nucle i of
the surface. That nuclei can be seen throughout the epithe- the smooth muscle cells of the muscularis mucosae appear
lial layer, particularly the surface cells, indicates that the spherical because the cells have been cut in cross section.
epithelium is not keratinized. In some instances, the epithe-
KEY
Adv, adventitia Lym, lymphocytes StM, striated musc le
Ep, stratified squamous epithe lium ME, muscularis externa SubM, submuco sa
L, long itudi nal layer of muscularis externa MM, muscularis mucosae ar rows (Fig. 2), lymphocytes in epithelium
LP, lamina propria Muc, mucosa asterisks (Fig. 1), meas containing striated
LV, lymphatic vessels SM, smooth muscle muscle in the muscularis extern a
510
...
C H APTER 16 Digesti11e Systew II: Esophagus aud Gasl.-oiulestiual Tmcl 5 I3
Figure 1, esophagogastric junction, H&E x 100. agus and the stomach (see also Fig. 3), the stratified squa-
Figure 2, esophagogastric junction, H&E x260. The cardiac glands (GL) are limited to a narrow region
Figure 4, esophagogastric junction, H&E x440. occasionally seen. The g lands empty their secretions via
KEY
D, ducts of cardiac glands L, lymphocytes MSC, surface mucous cells
Ep, epithelium LP, lamina propria P, gastric pits
Gl (Figs. 1 and 4), cardiac glands MGC, mucous gland cells arrows, intraepitheli al lymphocytes
GL (Fig. 2), cardiac glands MM, muscularis mucosae
512
CHAPTER 16 Digrsli11r Syslr111 Jl, EsopiJagus a111l Gaslroillleslillal Tract 5 15
Figure 1, stomach, H&E. fold is shown here. It consists of mucosa and submucosa
As with other parts of the gastrointestinal tract, the wall (asterisks). The rugae a re not permanent folds; they disap-
of the stomach consists of four layers: a mucosa (Muc), a pear when the stomach wall is stretched, as in the distended
submucosa (SubM ), a muscul aris externa (M E), and a stomach. Also evident are mamillated areas (M ), which are
serosa. The mucosa is the innermost layer and reveals three slight elevations of the mucosa that resemble cobblestones.
distinctive regions (arrows). The most superficial region The mamillated areas consist only of mucosa without sub-
contains the gastric pits; the middle region conta ins the mucosa.
necks of the gla nds, whic h tend to stain with eosin; and the The submucosa and muscularis exte rna stain predomi -
deepest part of the mucosa stains most heavi ly with hema- nantl y with eosin; the muscularis externa appears darker.
toxylin . The cell types of the deep (he matoxylin-staining) The smooth muscle of the muscularis externa gives an ap-
portion of the fundic mucosa are considered in Figure 3. pearance of being homogeneous a nd uniformly solid. In
The cells of all three regions and their staining characteri s- contrast, the submucosa, being connective tissue, may con-
tics are considered in Figure I of Plate 53. tain areas with adipocytes and contains numerous profiles
The inner slllface of the empty stomach is throw n into of blood vessels ( BV). The serosa is so thin that it is not ev-
long fo lds referred to as rugae. One such cross-sectioned ident as a discrete layer at th is low magnification.
Figure 2, stomach, H&E. glands (CG) and f undi c glands (FG) is marked by the
This figure and Figure 3 show the juncti on between the dashed line in each figure. 1
cardi ac and fundic regio ns of the stomach. Thi s junction The full thickness of the gastri c mucosa is show n here,
can be ide ntified histologically o n the basis of the structure as indicated by the presence of the muscularis mucosae
o f the mucosa. The gastric pits (P ), some o f which are seen (MM) deep to the fu ndi c gla nds. The muscularis mucosae
opening at the slllface (a rrows), are simila r in both regions, under the cardi ac glands is obscured by a large infi ltration
but the glands are different. The boundary between cardiac of lymphocytes formi ng a lymphatic nodule (L N).
SM--
/
\
Figure 3, stomach, H&E. region of the fundic mucosa, most of the cells are chief
This figure provides a comparison between the cardiac cells. The basal portion of the chi ef cell contains the nu-
and fundic gla nds at higher magnifica ti on. T he cardi ac cleus and extensive ergastoplasm, thus, its basophilia. The
glands (CG) consist of mucous gland cells arranged as a apical cytoplasm, normall y occupied by secretory granules
;
si mple columnar epithelium; the nucleus is in the most that were lost during the preparati on of the tissue, stains
basal part of the cell and is somewhat fl attened. The cyto- poorly. Interspersed among the c hief cells are parietal cells
plasm appears as a faint network of lightly sta ined materia l. ( P ). These cells typically have a round nucleus that is sur-
The lumina (L) of the cardiac glands are relati vely wide. On rounded by eosinophili c cytoplasm. Among the cells of the
the other hand, the fundic g lands ( FC) (left o f the dashed lamina propria are some with pale elongate nuclei. These
line) are small, and a lumen is seen readil y onl y in certain are smooth muscle cells (SM ) that exte nd into the lamina
fortuitously sectioned glands. As a consequence, most of propria from the muscul aris mucosae.
the glands appear to be cords o f cells. Because this is a deep
KEY
BV, blood vessels M E, muscul aris externa arrows: Fig. I, three differently stained re-
CG, cardiac glands MM, muscul aris mucosae gions of fundic mucosa; Fig. 2, opening
FG, fu ndic g lands Muc, mucosa of gastric pits
L, lumen J>: Fig. 2, gastric pits; Fig. 3, parietal cells aste risks, submucosa in ruga
L N, lymphatic nodu le SM, smooth musc le cell s dashed line, boundary between card iac and
M, mamillated areas S ubM, submucosa fund ic glands
514
CHAPTER 16 Digcsli11c Sysle111 lf, Esopbagus aut/ Gaslroiulesliual Tract 5I7
PLATE 53. STOMACH II
The e pithelial lining of the alimentary canal is a regularly renewing epithe lium ; each portion has a characteristic turnover
time and stem cell location. In the stomach, stem cells are located in the mucous neck. Cells that migrate upward to form the
mucous cells of the gastric pit and surface have a turnover time of 3 to 5 days; cells that migrate downward to form the pari-
etal cells, chief cells, and enteroendocrine cells of the glands have a turnover time of about 1 year.
Figure 1, stomach, monkey, H&E x 320. mucous neck cells are also the stem cells that divide to give
Figure 2, stomach, monkey, H&E x 320. The submucosa consists of con nective tissue of moderate
Figure 3, stomach, silver stain x 160. argentaffin cells. The surface mucous cells (MSC) in the
Figure 4, stomach, silver stain x 640. sections, and according ly, in H&E-staine d paraffin sections
KEY
A, adipocytes MM, musculari s mucosae PC, parietal cells
BV, blood ve5sels MNC, mucous neck cells SubM, submucosa
CC, chief cells MP, Meissner's plexus a rrows, argentaffin cells
GC, ganglion cells MSC, surface mucous ce lls arrowheads, nuclei of satelli te cells
ME, muscularis externa N, neck of fundic glands
516
.....
Figure 1, stomach-duodenum, monkey, H&E x40. cosae; therefore, this structure serves as a useful landmark
The junction between the stomach and the duodenum is in identifying the glands. In the stomach, the mu scularis
shown he re. Most of the mucosa in the micrograph belongs mucosae is readily identified as nanow bands of muscular
to the stomach; it is the pyloric mucosa (PMuc). The py- tissue ( MM). It can be followed toward the ri ght into the
loric s phincter appears as a thickened regio n of smooth duodenum but is then intetTupted in the region between the
muscle below the pyloric mucosa. On the far right is the two asterisks.
duodenal mucosa, the first part of the intestinal mucosa This figure also shows the thickened reg ion of the gas-
(!Muc). The area marked by the rectangle is shown at tric musculari s externa, where the stomach ends. This is the
higher magnification in Figure 2. It provides a comparison pyloric sphincter (PS). Its thickness, mostly clue to the am-
of the two mucosal regions and also shows the submucosal plification of the circular layer of smooth muscle of the
glands (Brunne r's glands). muscularis externa, can be appreciated by comparison with
The submucosa of the duodenum contains s ubmucosal the muscularis externa in the duodenum (ME).
(Brunner's) glands. These are below the muscularis mu-
Figure 2, stomach-duodenum, monkey x 120. With respect to the mucosal aspects of gastroduodenal
Examination of this region at higher magnification reveals histology, as mentioned above, the glands of the sto mach
that in addition to intestinal glands (!Gl) within the mucosa, empty into gastric pits. These are depressio ns; accordingly,
there are glands within the duodenal submucosa. These are when the pits are sectioned in a plane that is oblique or at
submucosal (Brunner's) glands (BGl). Some of the glandular right angles to the long axis of the pit, as in thi s figure, the
elements (arrows) can be seen to pass from the submucosa to pits can be recognized as be ing depressions because they are
the mucosa, thereby intenupting the musculari s mucosae surrounded by lamina propria. In contrast, the inner surface 3
(MM). The submucosal glands empty their secretions into the of the small intestine has villi (V). These are projections into
duodenal lume n by means of ducts (D ). In contrast, the py- the lumen of slightly varying height. When the villus is
loric glands ( PGl) are relatively straight for most of their cross-sectioned or obliquely sectioned, it is surrounded by
length but are coiled in the deepest part of the mucosa and are space of the lumen, as is one of the villi shown here. In ad-
sometimes branched. They are restricted to the mucosa and dition, the villi have lamina propria (LP) in their core.
empty into deep gastric pits. The boundary between the pits
and glands is, however, hard to ascertain in H&E sections.
Figure 3, stomach-duodenum, monkey x 640. surface mucous cells (MSC). The s urface cells contain an
The rectangula r area in Fig ure 2 is considered at higher apical cup of mucous materi al that typically appears empty
mag nifi cation here. It shows how the epithelium of the in a H&E- stained paraffin section. In contrast, the absorp-
stomach differs fro m that of the intestine. ln both cases, the tive cells (AC) of the intestine do not possess mucus in their
epithehum is simple columnar, and the underlying lamina cytoplasm . Although goblet cells are found in the intestinal
propria (LP) is hig hly cellul ar because of the presence of e pithelium and are scatte red among the absorptive cells,
large numbers of lymphocytes. The boundary between gas- they do not form a complete mucous sheet. The intestinal
tri c and duode nal epithelium is marked by the arro w. On absorptive cells also possess a striated border, which is
the stomac h side of the arrow, the epithelium consists of show n in Plate 56.
KEY
AC, absorptive cells MM, musculari s mucosae arrows: Fig. 2, Brunner's gland element
BGI, Brunner's glands MSC, surface mucous cells that passes from the submucosa to the
D, ducts PGI, pyloric glands mucosa; Fig. 3, boundary between gastric
IGI, intestinal glands PMuc, pyloric mucosa and duodenal epithelium
IMuc, intestinal mucosa PS, pyloric sphincter aste.-isks, interruption in muscularis mu-
LP, lamina propri a V, villi cosae
ME, muscularis externa
518
CHAPTER 1 6 Oigrslive SysltHI [[, EsopiMgus a111/ Gas lroiulesli11al Tra ct 52 I
Figure 1, duodenum, monkey, H&E x 120. ger-like . One villus, however, displays the form of a leaf-
Figure 2, duodenum, monkey, H&E x240. ina propria surrounding the intestin al glands (IGI) similarly
KEY
BGI, Brunner's glands L, longitudinal (outer) layer of muscularis SubM, submucosa
C, circular (inner) layer of muscularis ex- externa V, villi
terna LP, lamina propria arrow, duct of Brunner's gland
D, duct of Bru nner's gland ME, muscularis externa asterisk, leaf-like villus
GC, goblet cells MM, muscu laris mucosae dashed line (Fig. 1), boundary between
l GI, intesti nal glands (crypts) Muc, mucosa base of villi and intestinal glands
S, serosa
520
...
CHAPTER 1 6 Digestive System lJ, EsotJhngus a11d Gnstmi11testi11nl Tmct 5 '2 3
Figure 1, jejunum, monkey, H&E x22. serosa cannot be distinguished at this magnification.) Most
Figure 3, jejunum, monkey, H&E x500. plasnlic processes fro m the enterocytes. These processes
KEY
EC, endothelial cell ME, muscularis externa SubM, submucosa
GC, goblet cell MM, muscul aris mucosae V, villi
GI, intestinal glands (crypts) Muc, mucosa arrow, basal processes of enterocytes
L, lacteal PC, plicae circulares asterisks, basal-lateral intercellular spaces
LP, lamina propria S, serosa dashed line, boundary between villi and in-
Ly, lymphocytes SB, striated border testinal glands
M, smooth muscle cell
522
CHAPTER 16 Digeslive Sy sleur II: Eso~llll!JIIS mod Gnslroiulesliunl Trncl 52 5
Figure 1, ileum, monkey, H&E x20. erally have circular orientation, but they may travel in a lon-
Figure 2, ileum, monkey, H&E x40. Ius were a fi nger-Iike projection, others clearly do not. In
Figure 3, ileum , monkey, H&E x1 00; inset x 200. close to the intestinal glands (Gl). C learly, the lymphocytes
KEY
Gl, intestinal glands MM, muscularis mucosae SM, submucosa
LN, lymphatic nodules MM??, presumptive location of muscul aris V, villi
ME, muscularis externa mucosae asterisks, leaf-like villus
524
C H APTER 16 Digrstive Systr111 /[, Esopl~ngus mod Gnstroiutestiunl Trnct 52 7
W
Figure 1, colon, monkey, H&E x30. the circular layer (ME[c]) except in three locations where
A cross section through the large intestine is shown at the longitud inal layer of smooth muscle is present as a thic k \ } ME(c)
low magnification. It shows the four layers that make up the band. One of these thick bands, called a tenia coli (TC), is
/ I ME(I)
wall of the colon: the mucosa (Muc), the submucosa
(SubM), the muscularis externa (M E), and the serosa (S).
shown in this figu re. Because the colon is cross-sectioned,
the te nia coli is also cross-sectioned. The three teniae coli ME
--s
Although these layers are the same as those in the small in-
testine, several differences should be noted. The large in-
extend along the length of the large intestine as far as, but
not into, the rectum. -----
testine has no villi , nor does it have plicae circ ulares. On the The submucosa consists of a rather dense irregular con- 1
other hand, the muscularis externa is arranged in a distinc- nective tissue. It contains the larger blood vessels (BV) and
tive manner, and this is evident in the photomjcrograph. areas of adipose tissue (see A, Fig. 2).
The longitudinal layer (ME[l]) is substantially thinner than
W
Figure 2, colon, monkey, H&E x 140. in the deepest part of the gland , where it is o fte n slightly di-
The mucosa, shown at higher magnification, contai ns lated (asterisks, Fig. 3). Be tween the g lands (Gl) is a lam-
straight, unbra nched, tubu lar glands (crypts of Lieberki.ihn) ina propria (LP) that contains considerable numbers of
that extend to the musculari s mucosae (MM). The arrows lymphocytes and other cells of the immune system. Two
identify the openings of some of the glands at the intes tinal rectangles mark areas of the mucosa that are examined at
surface. Genera lly, the lume n of the glands is narrow except hi gher magnifi cation in Figures 3 and 4.
W
Figure 3, colon, monkey, H&E x 525. muscle cells appear as more or less rounded eosinophilic
This figu re reveals the muscularis mucosae (MM) and areas. These smooth muscle cells have been cut in cross
the ce lls in the lami na propria (LP), many of whic h can be section. Just above these cross-sectioned smooth muscle
recognized as lymphocytes and plas ma cells. The smooth cells are others that have been cut longitudinally; they dis-
muscle cells of the musc ularis mucosae are arranged in two play e longate nuclei and elongate strands of eosinophilic
layers. Note that the smooth muscle cells marked by the ar- cytoplasm.
rowheads show rounded nucle i; however, other smooth
Figure 4, colon, monkey, H&E x 525. number. Other cells in the gland are enteroendocrine cells,
The cells that line the surface of the colon and the g lands not easily identified in routine H&E-stained paraffin sec-
are principally absorptive cells (AC) and goblet cells (GC). tions, and, in the deep part of the gland, undifferentiated
The absorptive cells have a thin striated border that is evi- cells of the replicative zone, derived from the stem cells in
de nt where the arrows show the openjng of the glands. In- the base of the crypt. The undiffe re ntiated cells are readily
terspersed among the absorptive cells are the goblet cells identified if they are undergo ing division, by virtue of the
(GC). As the absorptive cells are followed into the glands, mjtotic figures (M) they display (see Fig. 3).
they become fewer, whereas the goblet cells increase in
KEY
A, adipose tissue ME, muscularis externa SubM, submucosa
AC, absorptive cells ME(c), circular layer of muscularis externa TC, tenia coli
BV, blood vessels ME(I), longitudinal layer of muscularis ex- arrowheads, smooth muscle cells showing
GC, goblet cells lerna rounded nuclei
G l, intestinal glands MM, muscularis mucosae arrows, opening of intestinal glands
LP, lami na propria Muc, mucosa asterisks, lu men of illlestinal glands
M, mi totic figures S, serosa
526
....
CHAPTER 1 6 Digeslive Syslelll IJ, Esophagus a111/ GaslroiulesliHal Tracl 52 9
B
Figure 1, appendix, human, H&E x 25. men (L ), mucosa (Muc), s ubmucosa (Subm), muscularis ex-
Cross section of an appendi x fro m a preadolescent, terna (ME), and serosa (S) are identified.
showing the various structures compos ing its walL The lu-
Figure 2, appendix, human, H&E xSO; inset x200. vessels (BV) and ne rves. The muscularis externa (ME) is
KEY
BV, blood vessel L, lumen S, serosa
Cap, cap of lymphatic nodule LN, lymphatic nodule Subm, submucosa
GC, germinal center ME, muscularis externa arrows, muscularis mucosae at base of
Gl, gland Muc, mucosa glands
528
CHAPTER 16 Oi!}rsl ivr Sys lem II: Eso fl /Jngus n11d Gnsl.-aillleslillnl Tra cl 53 I
@
Figure 1, anorectal junction, H&E x40. Between the two diamonds in the rectangular areas
A view of the anorectal junction is show n at low magni- shown is epithelium of the lower part of the anal canal. Un-
fication. Mucosa characteristic of the large intes tine is seen der this epithe lium, the re is a lymphatic nodule that has a
on the upper left of the micrograph. This region is the up- well-formed germinal center. Isolated lymphatic nodules
per part of the anal canal, and the intestinal glands are the under mucous membranes should not be construed to have
same as those present in the colon. The muscularis mucosae fixed locations. Rather, they may or may not be present, ac-
(MM) is readily identified as the narrow band of tissue un- cording to local demands.
der the glands. Both the intestinal glands and the muscu- Also, at this low magnification, note the internal anal
laris mucosae terminate within the left rectangular area of sphincter muscle (l AS), i.e., the thicke ned, most distal por-
the field, and here, at the diamond, the re is the first major tion of the circula r layer of smooth muscle of the muscu-
change in the epithelium. This area is examined at hi gher laris externa. Under the ski n on the right is the external anal
magnification in Figure 2. The right rectangular area in- sphincter muscle (EAS). It is composed of striated muscle
cludes the stratified squamous epi thelium (StS) of the skin fibers, which are seen in cross section.
and is examined at higher magnification in Figure 3.
@
Figure 3, anorectal junction, H&E x 160. stratified squamous epithelium (StS) below the level of the
The final change in epithelial type that occurs at the diamond is not keratinized, and nucleated cells can be seen
anorectal junction is shown here. On the rig ht is the strati- all the way to the surface. Again, numerous lymphocytes
fied squamous epithelium of skin (StS(k)). The keratinized (Lym) are in the underlying connective tissue, and many
nature of the surface is apparent. On the other hand, the have migrated into the e pithelium in the nonkeratinized
area.
KEY
EAS, external anal sphincter SC, simple columnar epithelium StS(k), stratified sq uamous epithelium (ker-
lAS, internal anal sphincter ST, stratified epithelium ati nized)
IG, intestinal glands StC, stratified cuboidal epitheliu m arrow, terminati on of muscularis mucosae
LN, lymphatic nodules StCol, stratified columnar epithel ium diamonds, junctio ns between epithelial
Lym, lymphocytes StS, stratified squamous epithel iu m types
MM, musculari s mucosae
530
...
17
inferior vena
two large lobes (the right and left lobes) and two smaller
lobes (the quadrate and ca udate lobes) (Fig. 17.1). This DIAPHRAGMATIC
SURFACE
anatontic division has only topographic importance be-
cause it re lates lobes of the liver to other abdominal or- right lobe
gans. Division into functional/surgical segments that cor-
Digestive System Ill: responds to the blood supply and bile drainage is more
clinically important.
In the embryo, the liver develops as an endodermal
left lobe
Liver, Gallbladder, evagination from the wall of the foregut (specifically the
site that will become the duodenum) to form the hepatic
diverticulum. The diverticulum proliferates, giving rise to
ligamentum
teres
Prothrombin and fibrinogen, important components of mopexin is involved in the transport of free heme in th e Bile production is an exocrine function of the liver Insulin and glucagon, both pancreatic hormones. These
the blood-clotting cascade. blood. Iron is stored within the hepatocyte cytoplasm in hormones are degraded in many organs, but the liver
Nonimmune a- and (1-globulins, which also help main- the form of ferritin or may be converted to hemosiderin The li ver is engaged in numerous metaboJic conver- and kidney are the most important sites of their degra-
tain plasma colloid osmotic press ure and serve as carrier granules. R ecent studies indicate that hepatocytes are the s ions involving substrates delivered by blood frorn the dation.
proteins for various substances (see Chapter 9, page 216). major sites of long-term storage of iron. Iro n overload (as digestive tract, pancreas, and sp leen. Some of these prod-
in multiple blood transfusions) may lead to hemochro- ucts are involved in the production of bile, an exocrine
The liver stores and converts several vitamins and iron matosis, a form of liver damage characterized by excessive secr etion of the liver. Bile contains conjugated and de-
Blood Supply to the liver
amounts of hemosiderin in hepatocytes. graded waste products that are returned to the intestine To appreciate the myriad functions of the liver introduced
Several vitamins are taken up from the bloodstream and for disposa l, as well as s ubstances that bind to metabo- abo ve, one must first understand its unique blood supply
are then stored and/or biochemically modified by the liver. The liver degrades drugs and toxins lites in the intestine to aid in absorption. (Table 17.1) and how blood is distributed to the hepatocytes. The liver
They include Bile is carried from the parenchyma of th e liver by bile has a dual blood supply consisting of a venous (portal)
Hepatocytes are involved in degradation of drugs, tox- ducts that fuse to form the hepatic duct. The cystic duct supply via the hepatic portal vein and an arterial supply
Vitamin A (retinol), an important vitamin in vision . Vi- ins, and other proteins foreign to the body (xenobiotics) .
tamin A is the precursor of retinal, which is required for then carries the bile into the gallbladde1' where it is con- via the hepatic artery. Bo th vessels enter the Liver at a
Many drugs and toxins are not hydrophilic; therefore, they centrated. Bile is return ed, via the cystic duct, to the hilum or porta hepatis, the same site at which the common
the synthesis of rhodopsin in the eye. The liver plays a
cannot be eliminated effectively from the circulation by the common bile duct, which delivers bile from the liver and bile duct, carrying the bile secreted by the liver, and the
major role in the uptake, storage, and maintenance of kidneys. The liver converts these substances into more sol-
circulating levels of vitamin A. When the vitamin A lev- ga ll bladder to the duodenum (see Fig. 17.15). lymphatic vessels leave the li ver.
uble forms. This process is performed by the hepatocytes
els in the blood decrease, the liver mobilizes its storage
in two phases: The liver receives the blood that initially supplied the
sites in the hepatic stellate cells (see page 541). Vitamin The endocrine-like functions of the liver are represented by
A is then r eleased into the circulation in the form of Phase I, called oxidation, includes hydroxylation its ability to modify the structure and function of many intestines, pancreas, and spleen
retinol botmd to retinol-binding protein (RBP). The (adding an -OH group ) and carboxylation (adding a hormones
liver also synthesizes RBP; RBP synthesis is regulated by -COOH group) to a foreign compound . This phase is The liver is unique among organs beca use it receives its
pl.asma levels of vitamin A. Night blindness and m ulti- performed in the hepatocyte smooth endoplasmic r etic- The liver modifies the action of hormones released by major blood s upply (about 75%) fro m the hepatic portal
ple skin disorders are related to vitamin A deficiency. ulum (sER) and mitochondria. It involves a series of bio- other organs. The liver's endocrine-like actions invoive vein, which carries venous blood that is largely depleted of
Vitamin D (cholecalciferol), an important vitamin in chemical reactions with proteins collectively named cy- oxygen. The blood delivered to the liver by the hepatic
calcium and phosphate metabolism. Vitamin D is ac- tochrome P450. portal vein comes from the digestive tract a nd the major
Vitamin D, which is converted by the liver to 25-
quired from dietary vitamin D 3 and is also produced in Phase II, or conjugation, includes conjugation with glu- a bdominal organs, such as the pancreas and spleen.
hydroxycholecalciferol, the predominant form of circu-
the skin during exposure to ultraviolet light by conver- curonic acid, glycine, or taurine. This pwcess makes the The portal blood carried to the Liver contains
lating vitam in D (page 534).
sion of 7-dehydrocholesterol. Unlike vitamin A, vitamin product of phase I even more water soluble so that it can
Thyroxine, a hormone secreted by the thyroid gland as Nutrients and toxic m ate.rials absorbed in the intestine
D is not stored in the liver but is distributed to skeletal be easily r emoved by the kidney.
tetraiodothyronine (T4), which is converted in the liver Blood cells and breakdown products of blood cells from
muscles and adipose tissue. T he liver plays an important to the biologically active form, triiodothyronine (T3), by
role in vitamin D metabolism by converting vitamin D 3 The liver is involved in many other important metabolic the spleen
pathways
deiodination. Endocrine secretions of the pancreas and enteroen-
to 25-hydroxycholecalciferol, the predominant form of Growth hormone (GH), a hormone secreted by the
circulating vitamin D. Further conversion takes place in docrine cells of the gastrointestinal tract
The li ver is important in carbohydrate metabolism as it pituitary gland. The action of GH is modified by
the kidney to 1,25-hydroxycholecalciierol, which is 10 liver-produced growth hormone-releasing hormone Thus, the li ver stands directl y in the pathway of blood
ma intains an adequate supply of nutrients for cell
times more active than vitamin D 3 . Vitamin D is essential (GHRH) and inhibited by somatostatin, which is secreted vessels that convey substances absorbed from the digestive
processes. In glucose metabolism, the liver phosphorylates
for development and growth of the skeletal system and by enteroendocrine cells of the gastrointestinal tract. tract. While the liver is the first organ to receive metabolic
absorbed glucose from the gastroi11testinal tract to glucose-
teeth. Deficiency of vitamin D is associated with rickets
6-phosphate. Depending on energy requirements, glucose-
and disorders of bone mineralization.
6-phospbate is either stored in the liver in the form of glyco-
Vitamin K, which is important in hepatic synthesis of
gen or used in the glycolytic pathways. During fasting, TABLE 17.1. Composition of Bile
prothrombin and several other clotting factors. Like vi-
glycogen is broken down by glycogenolysis, and glucose is
tamin D, it is derived from two so urces: dietary vitamin Component Function
released into the bloodstream. In additi on, the liver func-
K and synthesis in th e small intestine by intestinal bac-
tions in lipid metabolism. Fatty acids derived from plasma Water Solute in whicl1 other components are carried
terial flora. Vitamin K is transported to the liver with
are consumed by hepatocytes using {3-oxidation to provide Phospholipids (i.e., lecithin) and cholesterol Metabolic substrates for otl1er cells in the body; precursors of membrane components
chylomicrons, where it is rapidly absorbed, partially and steroids; largely reabsorbed in tile gut and recycl ed
energy. The liver also prod uces ketone bodies that are used
used, and then partially secreted with the VLDL frac- Bile salts (also called bile acids): primary Emulsifying agents that aid in ti1e digestion and absorption of lipids from the gut and
as a fuel by other organs (the liver ca nno t use them as an en-
tion. Vitamin K deficiency is associated with hypopro- (secreted by liver): cl1olic acid, help to keep the cholesterol and phospholipids of tile bile in solution, largely recycled,
ergy source) . The involvement in cholesterol metabolism
thrombinemia and bleeding disord ers. chenodeoxycholic acid; secondary going back and forth between the liver and gut
(synthesis and uptake from the blood) is also an impo rtant (converted by bacterial flora in the intestine):
In addition, the liver functions in the storage, metabo- functio n of the liver. Ch olesterol is used in for mation of bi.le deoxycholic acid, lithocholic acid
lism, and homeostasis of iron. It synthesizes almost all of sa lts, synthesis of VLDLs, and biosynthesis of organelles. Bile pigments, principally the glucuronide Detoxify bilirubin, the end product of hemoglobin degradation, and carry it to the gut
the proteins involved in iron transport and metabolism, in- The liver synthesizes most of the urea in the body from of the bilirubin produced in the spleen, bone for disposal
cluding transferrin, haptoglobin, and hemopexin. Trans- ammonium ions derived from protein and nucleic acid marrow, and liver by the breakdown
ferrin is a plasma iron-transport protein. Haptoglobin degradation. Fi.nalJ y, the li ver is involved in the synthesis of hemoglobin
binds to free hemoglobin in the plasma, from which the en- and conversion of nonessential amino acids into essential
Electrolytes: Na+, K, Ca>+, Mg21 , cr-. and HCO,- Establish and maintain bile as an isotonic fluid; also largely reabsorbed in tile gut
tire complex is removed by the liver to preserve iron. He- amino acids.
536 CHAPTER 17 Digrs iive Sysiem II f: Li11cr, GaltiJiaclder, 1111cl Pn11crrns CHAPTER 1 7 Digesiir>e Sys!en1 Ill: Livrr; Gnllliladder, aud Paucrtas 53 7
terminal hepatic venule (central vein) LIVER LOBULES cells radiate from the central vein to the periphery of the
lobule, as do the s inusoids. At the angles of the hexagon
There are th ree ways to describe the structure of the liver
are the portal areas (portal canals), loose stromal connec-
in terms of a functional unit: the classic lobule, the po1-tal
tive tissue characterized by the presence of the portal tri-
lobule, and the liver acinus. The classic lobule is the tradi-
ads. This connective tissue is ultimately continuous with
tional way to describe the orga niza tion of the li ver
the fibro us capsule of the liver. The portal canal is bor-
parenchyma, and it is relatively easy to visualize. It is based
dered by the outermost hepatocytes of the lo bule. At the
on the distribution of the branches of the portal vein a nd
edges of the portal canal, between the connective tissue
capillary
hepatic artery within the organ and the p athway that
stroma and the hepatocytes, is a small space called the
arteriosinusoidal branch blood from them follows as it ultimately perfuses the liver
terminal branch of hepatic artery cells.
space of Mall. This space is thought to be one of the sites
where lymph originates in the liver.
terminal branch of portal vein lymphatic vessel In some species, e.g., the pig (Fig. 17.4a), the classic lob-
The classic hepatic lobule is a roughly hexagonal mass of tissue
ule is easily recognized because the portal areas are con-
nected by relati vely thick layers of com1ective tissue. In
The classic lobule (Fig. 17.3) consists of stacks of anas-
humans, however, there is normally very little interlobular
tomosing plates of hepatocytes, one cell thick, separated
connective tissue, an d it is necessa ry, when examining his-
by the anastomosing system of sim tsoids that perfuse the
tologic secti ons of liver, to draw imaginary lines between
cells with the mixed portal and arterial blood. Each lobule
portal areas surrounding a central vein to get some sense
measures a bout 2.0 X 0. 7 mm. At the center of the lobule
of the size of the classic lo bule (Fig. 17.4b).
is a relatively large venule, the terminal hepatic venule
(central vein), into which the sinusoids drain. The plates of
The portal lobule emphasizes the exocrine functions of the
FIGURE 17.2 liver
Blood supply to the liver: the portal triad. The portal triad is com- capillary network in the perivascular connective tissue surrounding
posed of the branches of the hepatic artery, portal vein, and bile duct. each hepatic triad within the portal canal. Also note the periportal terminal hepatic venule The major exocrine function of the li ver is bile secretion.
Blood from the terminal branches of the hepatic artery and portal space of Mall, located between the portal cana l and the outermost (central vein)
Thus, the morphologic axis of the portal lobule is the in-
vein enters the hepatic sinusoids. The mixture of venous and arterial hepatocytes. This space is also filled with a small amount of connec-
terlobular bile duct of the portal triad of the "classic" lob-
blood is transported by the sinusoids toward the terminal hepatic tive tissue in which lymph drainage begins. From here, blind-ended
ule. Its outer margins are imaginary lines drawn between
venule (centra l vein). From here, blood drains into the sublobular lymphatic capillaries form larger lymphatic vessels that accompany
veins, the tributaries of the hepatic vein. Note the small vessels and branches of the hepatic artery. the three centra l vei ns that are closest to that portal triad
portal (Fig. 17.5). These lines define a roughly triang ular block of
vein tissue that includes those portions of three classic lobules
th at secrete the bile that drai ns into its axia l bile duct. T his
concept allows a description of hepatic parenchymal struc-
substrates and nutr ients, it is a lso the first exposed to toxic Structural Organization of the Liver hepatic
ture comparable to that of other exocrine glands.
artery
substances that ha ve been absorbed. As introduced above, the structural com ponents of the
T he hepatic artery, a branch of the celiac trunk, carries liver include The liver acinus is the structural unit that provides the best
oxygenated blood to the liver, providing the remain ing correlation between blood perfusion, metabolic activity, and
25% of its blood suppl y. Beca use blood from the two Parenchyma, consisting of orga nized plates of hepato- liver pathology
so urces is mixed just befo re it perfuses the hepatocytes of cytes, w hich in the adult are normally o ne cell thick and
the liver parenchyma , the li ver cells are never exposed to are separated by sinusoidal capillari es. ln yo ung individ - The li ver aci nus is lozenge sha ped and represents the
fully oxygenated blood. uals up to 6 years of age, the liver cells are arranged in smallest functio na l unit of the hepatic parenchyma . The
Within the liver, the distributing branches of the portal plates two cells thick. short axis of the acinus is defined by the termina l
vein and hepatic artery, which suppl y the sinusoidal capil- Connective tissue stroma that is continuous with the fi - branches of the porta l t ri a d that li e a long the border be-
laries (sinusoids) that bathe the hepatocytes, and the brous capsule of Glisson. Blood vessels, nerves, lym- tween tw o cl ass ic lobu les. Th e long axis is a line drawn
draining branches of the bile duct system, which lea d to phatic vessels, and bi le ducts travel within the connec- FI GURE 17.3
between the two centra l veins closest to the short axis.
the commo n hepatic duct, course together in a relati o nship tive tissue stroma. Diagram of a "classic" liver lobule. A classic" liver lobule can be
Therefore, in a two-dimensiona l view (Fig. 17.6) the
termed the portal triad. Although a convenient term, it is schematically diagramed as a six-sided polyhedral prism with portal
Sinusoidal capillaries (sinusoids), the vascular channels li ver acinus occupies parts of adjacent classic lo bules.
triads (hepatic artery, portal vein, and bile duct) at each of the corners.
a misnomer because one or more vessels of the lym phatic between the plates of hepatocytes. This concept a llows a descripti o n o f the exocrine secre-
The blood vessels of the portal triads send distributing branches
drainage system of the live r always travel with the vein, a r- Perisinusoidal spaces (spaces of Disse), w hich lie tory function of the liver comparab le to th at of the por-
along the sides of the lobule, and these branches open into the he-
tery, and bile duct. (Fig. 17.2) between the sinusoida l endo theliu m a nd the hepa- patic sinusoids. Tl1e long axis of the lobule is traversed by the termi- ta l lobule.
The sinusoids ar e in intima te contact with the hepato- tocytes. nal hepatic venule (central vein), which receives blood from the he The hepatocytes in each liver acinus are described as be-
cytes an d provide for the exchange of substances between patic sinusoids. Note that a wedge of the tissue has been removed ing arranged in three concentric elliptical zones surro und-
the blood and li ver cells. The sinusoids lead to a central With this inform atio n as background, one can now con- from the lobule for better visualization of the terminal hepatic venule. ing the sho rt axis (see Fig. 17.6).
vein t hat in turn em pties into the sublobular veins. Blood sider several ways to describe the o rgani zation of these Interconnecting sheets or plates of hepatocytes are disposed In a ra-
leaves the liver through the hepatic veins, which empty structural elements in o rd er to understand the maj or func- dial pattern from the terminal hepatic venule to the periphery of the Zone 1 is closest to the short axis and the blood supply
into the inferior vena cava. tions of tbe li ver. lobule. from penetrating branches of the porta l vein and hepatic
........
538 CHAPTE R 17 Digestive System II/, Liver, Ga/1/,/adder, alld Pa llcrcas C HAPTER 1 7 Digestive Sy stem lfl: Liver, Gallbladder, mtd Pa11crcas 539
long axis
FIGURE 17.6
The liver acinus. The liver acinus is a functional interpretation of liver
organization. It consists of adjacent sectors of neighboring hexagonal
fields of classic lobules partially separated by distributing blood ves-
Vl sels. The zones, marked 1, 2, and 3, are supplied with blood that is
x most oxygenated and richest in nutrients in zone 1 and least so in
cO
1:: zone 3. The terminal hepatic venules (central veins) in this interpreta-
0
..c tion are at the edges of the acinus instead of in the center, as in the
Vl
classic lobule. The vessels of the portal canals, namely, terminal
branches of the portal vein and hepatic artery that, along with the
smallest bile ducts, make up the portal triad, are shown at the corners
of the hexagon that outlines the cross-sectioned profile of the classic
lobule.
~ ""'-portal
vein vein
FIGURE 17.7
""-portal ""'- portal Photomicrograph of centrilobular necrosis in human liver. This
canals canals canals photomicrograph shows a routine H&E liver biopsy specimen from
an individual with congestive heart failure. Pathologic changes (re-
CLASSIC LOBULE PORTAL LOBULE LIVER ACINUS ferred to as ischemic necrosis) are most severe in hepatocytes in
zone 3. This zone surrounds the terminal hepatic venule (central
FIGURE 17.5 vein). This type of necrosis is referred to as centrilobular necrosis.
Comparison of the classic liver lobule, portal lobule, and liver acinus. the lobule. The portal lobule has a portal canal at the center of til e
Note the presence of multiple round vacuoles, which indicates ex-
The area indicated in blue shows the territory of each of the three units lobule and terminal hepatic venules (central veins) at the peripheral
tensive lipid accumulation. No noticeable changes are seen in the
relating to liver organization and function. The classi c lobule has the angles of the lobule. The liver acinus has distributing vessels at the
periphery of the lobule, i.e., zone 1 and much of zone 2. x 320.
terminal hepatic venu le (central vein) at the center of the lobule and equator and terminal l1 epatic venules (central veins) at each pole.
the portal canals containing portal triads at the peripheral angles of
54 0 CHAPTER 17 Digestir>e System ur Live,., Gnllblnddct; mtd Pt111Cret!S CH APTER 1 7 Digestir>c Sy sle111 f/1, Li11er, Gallbladder, n11d Pn11c,.rns .5 4 1
artery. This zone corresponds to the peripher y of the portal vein Large gaps are present between neighboring endo thelial Kupffer cells belong to the mononuclear phagocytotic system
classic lobules . bile duct cells.
Z one 3 is farthest from the short axis and closest to the Kupffer cell Like other member s of the mononuclear phagocytotic
Hepatic sinusoids differ from other sinusoids in that a system , K upffer cells are derived from monocytes. The
terminal hepatic vein (central vein ). This zone corre-
second cell type, the stellate sinusoidal macrophage, or scanning electron microscope (SEM ) and tra nsmission
spo nds to the most central part of the classic lobule that
Kupffer cell (Fig. 17.9), is a regular part of the vessel lining. electron microscope (TEM) clearly show that the Kupffer
surrounds the terminal hepatic vein.
Zone 2 lies between zones 1 and 3 but has no sharp cells form part of the lin ing of the sinusoid . Previously,
boundaries.
The zonation is important in the description and inter-
-. they had been described as lying on the luminal surface of
the endothelial cells. T his older histologic description was
probably based on the fact that processes of the Kupffer
pretation of patterns of degeneration, r egeneration, and cells occasionally overlap endothelial processes on the lu-
specific toxic effects in the liver parenchyma relative to the minal side. Kupffer cells do not form junctions w ith neigh-
degree or quality of vascular perfusion of the hepatic cells. boring endothelial cells.
As a result of the sinusoidal blood flow, the oxygen gradi- hepatic Processes of Kupffer cells often seem to span the sinu -
ent, the m etabolic activity of the hepatocytes, and tbe dis- sinusoid soidal lumen and may even partia lly occlude it. The pres-
tr ib ution of hepatic enzymes va ries across the three zones. ence of red cell fragments and iron in the form of fe rritin
The distribution of liver damage du e to ischemia and ex- in the cytoplasm of Kupffer cells suggests that they may be
posure to toxic substances can be ex plained using this ~nvolved in the final breakdown of some damaged or senile
zonal interpretation. red blood cells that reach the liver from the spleen. Some
Cells in zone 1 are the fust to receive oxygen , nutrients, of the ferritin iro n may be converted to hemosiderin gran-
and toxins from the sinusoidal blood and are the first to ules and stored in the cells. This function is greatly in-
FIGURE 17.8
show morphologic changes follow ing bile duct occlusion creased after splenectomy and is then essential for red
Diagram of the flow of blood and bile in the liver. This schematic di-
(bile stasis). These cells are also the last to die if circulation agram of a part of a classic lobule shows the components of the por- blood cell disposal.
is impaired and the first to regenerate. On the other hand, tal triads, hepatic sinuses, terminal hepatic venule (central vein) and
cells in zone 3 are the first to show ischemic necrosis (cen- associated plates of hepatocytes. Red arrows indicate the direction of
trilobular necrosis) in situations of reduced perfusion and the blood flow in the sinusoids. Note that th e direction of bile flow PERISINUSOIDAL SPACE (SPACE OF DISSE )
the first to show fat accumulation . They are the last to re- (green arrows) is opposite that of the blood flow.
spond to toxic substances and bile stasis. Normal varia- hepatic The perisinusoidal space is the site of exchange of materials
- stellate cell -----;~,:;:
tions in enzyme activity, the number and size of cytoplas- (Ito cell) between blood and liver cells
mic organelles, and the size of cytoplasmic glycogen larger portal canals return the blood to the interlob ular
deposits are also seen between zones 1 and 3. Cells in zone veins before they empty into the sinusoid. The perisinusoidal space (space of Disse) lies between
2 have functional and morphologic characteristics and re- The central vein is a thin-walled vessel receiving blood th e basal surfaces of hepatocytes and the basal s urfaces of
sponses intermediate to those of zones 1 and 3. from the hepatic sinusoids. The endothelial lining of the endothelial cell s and Kupffer cells that line the sinusoids.
central vein is surro unded by small amounts of spirally Small, irregular microvilli project into th is space from the
arranged connective tissue fibers. The centra l vein, so basal surface of the hepatocytes (Fig. 17.10).
BLOOD VESSELS OF THE PARENCHYMA named beca use of its central position in the classic lobule, T he microvilli increase the surface area availa ble for ex-
is actua lly the terminal venule of the system of hepatic change of materials between hepatocytes and plasma by as
The blood vessels that occupy the portal canals are called
veins and, thus, is more pr operly called the terminal he- much as 6 times. Because of the large gaps in the end o the-
interl o bular vessels. Only the interlobular vessels that form
patic venule. The sublobular vein, the vessel that r eceives lial layer and the a bsence of a continuo us basal lamina, no
the sm a llest portal triads send blood into the sinnsoids.
blood from the terminal hepatic venules, has a distinct hepatic significant barrier exists between the blood plasma in the
The larger interlo bular vessels branch into distributing ves-
layer of connective tissue fibers, both collagenous and elas- sinusoid sinusoid and the hepatocyte plasma membrane. Proteins
sels that are located at the peripher y of the lo bule. These
tic, just external to the endotheliu m. The sublob ul ar veins and lipoproteins synthesized by the hepatocyte are trans-
distributing vessels send inlet vessels to the sinusoids (Fig.
as well as th e hepatic veins into which they drain, travel ferred into the blood in the perisinusoida l space; this path-
17.8). In the sinusoids, the blood flows centripetally to-
alone. Because they are solitary vessels, they can be r eadily way is for li ver secretions other than bile.
ward th e centra l vein. The central ve in courses through the
distingui shed in a histologic section from the porta l veins In the feta l liver, the space between blood vessels and
central axis of the class ic liver lobule, becoming lar ger as it
that are members of a triad. There are no valves in hepatic hepatocytes contains islands of bl ood- form ing cells. In
progresses tluough the lobule and empties into a sublobu-
veins. cases of cluonic anemia in the adult, blood-forming cells
la r ve in. Several sublobular veins converge to form larger
hepatic veins that empty into the inferior vena cava . FIGURE 17.9 . may aga in appea r in the perisinusoidal space.
Hepatic sinusoids are lined with a thin d iscontinuous Electron micrograph of two hepatic sinusoids of t he liver. One he-
The structure of the porta l vein and its branches within
endothelium pati c sinusoid (top) displays a stellate sinusoidal macr'Opl1age (Kupffer The hepatic stellate cells (Ito cells) store vitami n A; however, in
the liver is typical of veins in general. The lumen is much
cell). The remainder of the sinusoid as well as the other sinusoid is pathologic conditions, they differentiate into myofibroblasts
larger than that of the artery associated with it. The str uc-
The discontinuo us sinusoidal endothelium has a d iscon- lined by thin endothelial cell cytoplasm. Surrounding each sinusoid is
ture of the hepatic artery is like that of other arteries, i.e., and synthesize collagen
tinuous basal lamina that is absent over large areas. The the perisinusoidal space (space of Disse), which contains numerous he-
it has a thick muscular wall. In additio n to providing arte- patocyte microvilli. Also present in the perisinusoidal space is a he-
discontinuity of the endothelium is evident in two ways: The other cell type fo und in the perisin usoida l space is
rial blood directly to the sinusoids, the hepatic arter y pro- patic stellate cell (Ito cell) with a large lipid droplet and several smaller
vides arteria l blood to the connective tissue and other Large fenestrae, witho ut diaphragm s, are present within droplets. Its nucleus conforms to the curve of the lipid droplet. the hepatic stellate cell (commo nly called an Ito cell).
structures in the larger por tal canals. Capillaries in these th e end oth elia l cells. X6,600. T hese cells of mesenchymal origi n are the primary stmage
542 CHAPTER 17 Digcsti11e Sys tem lJ[; Uoer. Gnllhlarlrler, a11rl Pa11crcas CHAPTER 1 7 Digeslioe System [{[, Liuer, Gallb/nrlrler, mrd Pn11crens 543
Lymphatic Pathway
droplets increases after injection or ingestion of certain tion similar to that of mitochondria. They contain a
hepatotoxins, including ethanol. large amount of oxidase that generates toxic hydrogen
Lipofuscin pigment within lysosomes seen with routine peroxide, H 2 0 2 The enzyme catalase, also residing
H&E staining in various amounts. Well-delineated brown within peroxisomes, degrades hydrogen peroxide to oxy-
granules can also be visualized by the PAS method. gen and water. These types of reactions are involved in
As noted above, the liver cell is polyhedral; for conven- many detoxification processes occurring in the liver, e.g.,
ience, it is described as having six smfaces, although there detoxification of alcohol. In fact, about one half of the
may be more. A schematic section of a cuboida l hepatocyte ethanol that is ingested is converted to acetaldehyde by
is shown in Fig. 17.12. Two of its surfaces face the perisi- enzymes contained in liver peroxisomes. In humans,
nusoidal space. The plasma membrane of two surfaces catalase and o-amino acid oxidase, as well as alcohol
faces a neighboring hepatocyte and a bile canaliculus. As- dehydrogenase, are found in peroxisomes. In addition,
suming that the cell is cuboidal , the remaining two sur- peroxisomes are a lso in volved in breakdown of fatty
faces, which cannot be seen in the diagram, would also acids (f3-oxidation) as well as gluconeogenesis and me-
face neighboring cells and bile canaliculi. The surfaces that tabolism of purines.
face the perisinusoidal space correspond to the basal sur-
face of other epithelial cells; the surfaces that face neigh- sER can be extensive in hepatocytes
boring cells and bile canaliculi correspond to the lateral
and apical surfaces, respectively, of other epithelial cells. The sER in hepatocytes may be extensive but varies with
metabolic activity (see Fig. 17.13 b). The sER contains en-
Peroxisomes are numerous in hepatocytes zymes involved in degradation and conjugation of toxins
and drugs as well as enzymes responsible for synthesizing
H epatocytes have as many as 200 to 300 peroxisomes cholesterol and the lipid portion of lipoproteins. Under
per cell. They are relatively large and vary in diameter conditions of hepatocyte challenge by drugs, toxins, or
from 0.2 to 1.0 pm (see Fig. 17.13a). Peroxisomes are a metabolic stimulants, the sER may become the predomi-
major site of oxygen use and in this way perform a func- nant organelle in the celL In addition to stimulating sER
bile
canaliculus
rER mitochondria actiVIty, certain drugs and hormones induce synthesis 6f tine histologic specin1ens. Heavy-metal preparations
new sER membranes and their associated enzymes. The (Golgi stains) of thick sections of liver give an indication
sER undergoes hypertrophy following administration of of the extent of the Golgi network. As ma ny as 50 Golgi
alcohol, drugs (i.e, phenobarbital, ana bolic steroids, and units, each consisting of three to five closely stacked cis-
progesterone), and certain chernotherapeutic agents used ternae, plus man y large and small vesicles, are found in
to treat cancer. hepatocytes. These " units" are actua lly branches of the
Stimulation of the sER by ethanol enhances its ability to tortuou s Golgi apparatus seen in heavy-metal prepara-
detoxify other drugs, certain carcinogens, and some pesti- tions. Elements of the Golgi apparatus concentrated near
glycogen
cides. On the other hand, metabolism by the sER can ac- the bile canaliculus are believed to be associated with the
LUMEN OF HEPATIC SINUSOID tually increase the hepatocyte-damaging effects of some exocrine secretion of bile. Golgi cisternae and vesicles
toxic compounds, such as carbon tetrachloride (CCI 4 ) and near the sinusoidal surfaces of the ceiJ , however, contain
FIGURE 17.12
Schematic diagram of a plate of hepatocytes interposed between
3,4-benzpyrene. electron-dense granules 25 to 80 nm in diameter that are
plasmic vacuoles containing vitamin A. Tile sparse collagen fibers
hepatic sinusoids. This diagram sl1ows a one-cell-thick plate of llepa found in the perisinusoidal space (of Disse) are produced by the he- believed to be VLDL and other lipoprotein precmsors.
tocytes interposed between two sin usoids. If it is assumed that tile cell patic stellate cells (Ito cells). In certain pathologic conditions, these cells The large Golgi apparatus in hepatocytes consists of as many These substances are subsequently released into the circu-
is cuboida l, two sides of each cell (shown) would face hepatic sinu- lose their storage vacuoles and differentiate into myofibroblasts that as 50 Golgi units lation as part of the endocrine secretory funct ion of the
soids, two sides of each cell (shown) would face bile canaliculi, and the produce collagen fibers, leading to liver fibrosis. Observe that the stel- hepatocytes. Similar dense globules are seen in dilated
additional two sides (not shown) would face bile canaliculi. Note the late sinusoidal macrophage (Kupffer cell) forms an integral part of t11e Examination of hepatocytes with the TEM shows the portions of the sER and, occasionally, in the dilated ends
location and features of a 11epatic stellate cell {Ito cell) filled w ith cyto- sinusoidal lining. Golgi to be much more ela borate than those seen in rou- of rER cisternae where they are synthesized.
546 CHA PTER 17 Oi!}estii/C Sys tem II L Livn, Gnllblndtler, n11tl Pn11crrns C H AP TER 1 7 Oi!}<'stive Sy stem IlL Liver, Gnllblnddei, n11d Pn11cr-rns 54 7
Lysosomes concentrated near the bile canaliculus correspond The bile canaliculus is a small canal formed by apposed FIGURE 17.14
to the peri biliary dense bodies seen in histologic sections grooves in the surface of adjacent hepatocytes Photomicrograph of bile canaliculi. This high-magnification pho-
tomicrograph shows several onecellthick plates of hepatocytes sep
Hepatocyte lysosomes are so heterogeneous that they Bile canalicu li form a complete loop around four sides arated by hepatic sinusoids. The plane of section in certain areas is
can only be positively identified, even at the TEM level, by of the idealized six-sided hepatocytes (Fig. 17.14). They parallel to the bile canaliculi. In this plane, the canaliculi reveal their
histochemical means. In addition to normal lysosomal en- arrangement on fou r sid es of tile hepatocytes (arrows). Arrowheads in-
are a pprox imately 0.5 J.lm in luminal diameter and are iso- sphincter
zymes, TEM reveals other components: lated from the rest of the intercellular compartment by dicate those bile canaliculi that appear only in cross-sectional profile. of comm on __!_~~--:\\\\
Xl ,240. bile duct
Pigment granules (lipofuscin} tight junctions, which are part of junctional complexes
(of Boyden)
Partia lly digested cytoplasmic organelles that a lso include zonulae adherentes and desmosomes .
M yelin figures Microvilli of the two adjacent hepatocytes extend into the
canalicular lumen. Adenosine triphosphatase (ATPa se} hepatopancreatic
H epatocyte lysosomes ma y also be a normal storage site
and other a lkaline phosphatases can be localized on the ameter a nd are lined by an epithelium that is cuboidal near ampulla (of Vater}
for iron (as a ferritin complex} and a site o f iron accumu-
la tion in certa in storage diseases . plasma membranes of the canaliculi, suggesting that bile the lobules and gradua lly becomes columna r as the ducts
The number of lysosomes increases in a variety of patho- secretion into this space is a n active process. Bile flow is near the porta bepatis. The co lumnar cells have well-de- sph incter of hepatopancreatic ampulla
centrifuga l, i.e., from the region of the central vein toward veloped microvilli, as do those of the extrahepatic bile (of Oddi}
logic conditions, ranging fro m simple obstructi ve bile sta-
sis to vira l hepatitis and anemia. However, although the the portal canal (a direction opposite to the blood flow }. ducts and gall bladder. As the bile ducts get larger, they FIGURE 17.15
range of normal liver function-particularly the rate of N ear the portal cana l but still within the lobule, bile gradually acquire a dense connecti ve tissue investment Diagram showing the relationship of hepatic, pancreatic, and gall-
bile secretion-is quite wide, no statistica lly significant canaliculi join to form th e short intrahepatic ductules, the containing numerous elastic fibers. Smooth muscle cells bladder ducts. The gallbladder is a blind pouch joined to a single cys-
morphologic changes take place in the Golgi apparatus or canals ofHet'ing (see Fig. 17.11a }, wh ich a re lined w ith appear in this connective tissue as the ducts approach the tic duct in w llicll numerous mucosal folds form the spiral valve (of
cuboidal nonhepatocytic cells. This ductule epithelium is hilum. Interlobular ducts join to form the right and left he- Heister). Tile cystic duct joins with the common hepatic duct, and to-
lysosomes of the peribiJiary cytoplasm to correlate with gether they form th e common bile duct that leads into the duode
the rate of bi le secretion. subtended by a complete basal lamina, as is the rest of the patic ducts, which in turn join at the hilum to form the
num. At the entry to the duodenum, the common bile duct is joined
dista l biliar y tree. common hepatic duct (Fig. 17.15}.
by the main pancreatic duct to form the hepatopancreatic ampulla
In some individuals, the ducts of Luschka are located
Biliary Tree (of Vater), and together they enter the second part of tile duodenum.
Intrahepatic bile ductules carry bile to hepatic ducts in the connective tissue between the liver and the gall-
Sphincters can be found at the distal part of these ducts. The spllinc-
The biliary tree is the system of conduits of increasing di- bladder, near the neck of the ga llbladder. These ducts ters of the common bile duct (of Boyden), the main pancreatic duct,
ameter that bile flows through from the hepatocytes to the The du ctules have a diameter of about 1.0 to 1.5 pm and connect with the cystic duct, not w ith the lumen of the and the hepatopancreatic ampu lla (of Oddi) control the flow of bile
gallbladder and then to the intestine. The smallest carry bile through the boundary of the lobule to the intet- gallbladder. They are histologica lly similar to the intra- and pancreatic secretion into t11e duo denum. When tile common bile
branches of thi s systern are the canaliculi into which the lobulm- bile ducts that form part of the portal triad (see hepatic bile ducts and ma y be remnants of aberrant em- duct sphincter contracts, bile cannot enter the duodenum; it ba cks up
hepatocytes secrete bile. Fig. 17.11 b ). These ducts range from 15 to 40 fJ-111 in di- bryonic bile ducts. and flows into the gallbladder, where it is concentrated and stored .
548 CHA PTE R 1 7 Oigestiue Systwz IlL Lirm; Gnlll>lndder, 111111 Pn11crens CHAPTER 17 Oigrslivr Systrm IlL Livrr, Gnl/blnrlrlrr, mrrl Pmrcrens 54 9
The adult human liver secretes, on average, about 1 L of bile a is a secondar y deriva ti ve of the em bryonic fo regut, ar ising
day as an evagination o f the primitive bile duct that connects
the embryonic liver to the developing intestine.
T he com position of bile and the fu ncti ons of most of its
components are listed in Table 17.1. As noted in the table, The gallbladder concentrates and stores bile
many components of the bile are recycled via the portal
circulati o n. The gallbladder is a blind pouch that leads, via a neck,
Abo ut 90% of the bile salts, a component of bile, is re- to the cystic duct . Thw ugh this d uct it receives dilute bile
a bso rbed by the gut and transported back to the li ver in fro m the hepatic duct. H ormo nes secreted by the en-
th e portal blood. The bile salts a re then r ea bsorbed a nd teroendocrine cells of the small intestine in response to the
resecreted by hepatocytes. H epa tocytes also synthesize presence of fat in the proxima l du o denum , stimulate con-
new bile salts to replace those that are lost. tractions of the sm ooth muscle of the gallbladder. As a r e-
Cholesterol a nd phospholipid lecithin, as well as most of sult of these contracti ons, concentrated bile is discharged
the electrolytes and water deliver ed to the gut with the into the corru110n bile duct, which carries the bile to th e
bile, a re also reabsorbed a nd recycled. d uodenum.
Bilirub in glucuro nide, the detoxified end product of he- Mucosa of the gallbladder has several characteristic features
moglo bin breakdow n, is not recycled. It is ultimately ex-
creted with the feces and gives them their colo r. Failure to The empty or partially fi lled ga ll bladder has n umerous
a bsorb bili rubin or fa ilure to conjuga te it o r secrete gl u- deep mucosal fo lds (Fig. 17.16). T he mu cosal surface con-
curonide can produce jaundice. sists of simple columnar epith elium. T he tall epi thelial cells
Bile flow fro m the liver is regulated by hormo na l and exhibit the fo llowing fea tures:
neura l control. T he rate of blood fl ow to the li ver and the
concentratio n of bile salts in the blood exert regu latory ef- N umerous well-developed apical microvilli
fects on the bile fl ow. Bile flow is increased w hen hormones Apical junctional complexes that jo in adjacent cells and
such as cho lecystokinin (CCK ), gastrin, and motilin a re re- form a barrier betwee n the lu men and the intercellular
leased by enteroendocrine cells during digestion. Steroid compartment
ho rmo nes (i.e., estrogen during pregnancy) decrease bile se- Loca lized concentrations of mitochond1ia in the apical
cretio n fr om the liver. In addi tio n, parasympathetic stimu- and basal cytoplasm
latio n increases bile flow by prompting contraction of the Complex lateral plications (Fig. 17.1 7)
gallbladder an d relaxation of the sphincter of O ddi. Bile These cells closely resemble the absorpti ve cells of the
that leaves th e live r via the conunon hepatic d uct flows intestine.
thro ugh the cystic duct to the gallbladder. The gallbladder Both cells share the a bove characteristics, as well as lo-
stores and ca n increase the concentra tio n of bile up to 10- calization of Na +JK-activa ted ATPase o n their lateral FIGURE 17.16
fold. Following stimulatio n, the gallbladder contracts and plasm a m embranes a nd secretory vesicles fil led with g lyco- Photomicrograph of the wall of the gallbladder. The mucosa of the submucosa. The smooth muscle bundles of the muscularis externa are
deli vers the bile to the duodenum via the commo n bile duct. proteins in their apical cytoplasm.
gallbladder consists of a lining of simple columnar epithelial cells and randomly oriented. External to the muscle is an adventitia containing
a lamina propria of loose connective tissue, w hich typically exhibits adipose tissue and blood vessels. The portion of the gallbladder not
T he lamina propria of the m ucosa is particularly r ich attached to the liver displays a typical serosa instead of an adventitia.
T he liver has both sympathetic and parasympathetic numerous deep folds in the mucosa. Beneath this layer is a relatively
in fenestTated capill ar ies and sma ll ven ules, but there thick layer, the muscularis externa. There is no muscularis mucosae or Xl 75.
innervation
are no lympha tic vessels in this layer. The lamina propria
T he li ver (and ga tlbladder ) receives nerves fro m both is a lso ve ry cell ular, conta ining la rge numbers of lym-
sympatheti c and parasympathetic divisio ns of the auto- phocytes and plas ma cells. The cha racteristi cs of th e
no mic nervo us system . The nerves enter the li ver at the lamina propri a resem ble those o f the colon, another bundl es of smooth muscle cells. Despite its o rigin fro m a this layer is referred to as the adventitia. T he unattached
po rta hepatis a nd r amify thro ug h the li ver in th e porta l or gan specialized fo r the a bso rptio n of e lectro lytes a nd for eg ut-deri ved tube, the gallbladder does not have a mus- surface is covered by a serosa or viscera l periton eum con-
cana ls alo ng with the members of the porta l tri ad. Sym pa- wa ter. cul aris mucosae or submucosa. T he smooth muscle bun- sisting of a layer of mesothelium a nd a thi n layer of loose
thetic fi ber s a re believed to in nervate blood vessels; Mucin-secreting glands are sometimes present in the d les a re somewhat r andomly oriented, unlike the laye red connective tissue.
par asym pathetic fi bers are assumed to in nervate the large lamina propria in th e no rma l human gall bladder, espe- o rgan iza tio n of the intestine. Contraction o f the smooth In addition, deep d iverticula of the mucosa, ca lled Rok i-
d ucts (those that conta in smooth m uscle in their wa lls) and cially near the neck of the o rga n, but they a re mo re com- muscle red uces th e vo lume of the bladder, fo rcing its con- ta1tsky-Aschoff sinuses, sometimes extend through the
possibly blood vessels. The cell bodies of parasympathetic monly fo und in infla med ga ll bladders. Cells that ap pear tents out thro ugh the cystic duct. m uscularis extern a (Fig. 17.18). T hey are tho ught to
neurons are often present near the porta hepatis. identica l to enteroendocrine cells of the intestine are also Extern al to the muscularis externa is a thick laye r of presage p atho logic changes. Also, bacter ia may accu mu-
fou nd in these glands. dense connective tissue (see Fig. 17. 16). T his layer conta ins late in th ese sinuses, ca using chro nic infla mmation.
la rge blood vessels, an extensive lymphatic network, an d
\1 GALLBLADDER The wall of the gallbladder lacks a muscularis mucosae and the a utono mic nerves that inner va te the muscularis ex- Concentration of the bile requires the coupled transport of salt
submucosa terna and the bloo d vessels (cell bod ies of parasympa thetic and water
T he gallbladder is a pea r-shaped, distensible sac with a vol- neurons are fo und in the wa ll of the cystic d uct). T he co n-
ume of abo ut 50 mL in humans (see Fig. 17.15 ). It is at- Extern al to the lami na prop ri a is a muscularis externa nective tiss ue is also rich in elastic fi bers an d ad ipose tis- The epithelia l cell s of th e ga llbl adder act ive ly transport
tached to the viscera l surface of the li ve r. T he gallbladder that has numero us collagen and elastic fi bers among the sue. W here th e ga ll bladd er attaches to the liver surface, both Na+ and Cl- (a nd H C03- ) from the cytoplasm into
5 50 CHAPTER 17 Digestive System fiL Liver. Gallbladder, a11d Pa11creas CHAPTER 17 Digestive System 1//, Li11er, Caii!Jlndder, mrd Pa11crcas 55 I
\1 PANCREAS
Overview
The pancreas is an elongate gland described as having a
head, body, and tail. The head is an expanded portion that
lies in the C-shaped curve of the duodenum (Fig. 17.19). It
is joined to the duodenum by connective tissue. The cen-
trally located body of the pancreas crosses the midline of
the human body, and the tail extends toward the hilum of
the spleen. The pancreatic duct (of Wirsung) extends
through the length of the gland and empties into the duo-
cystic duct
FIGURE 17.18
Photomicrograph of the Rokitansky-Aschoff sinuses in the wall of
the gallbladder. This photomicrograph shows deep invaginations of
the mucosa extending into the muscularis externa. These invagina-
tions are referred to as RokitanskyAschoff sinuses. x 120.
denum at the hepatopancreatic ampulla (of Vater) The acinar cells are characteri zed by distinct basophilia
through w hich the common bile duct from the liver and in the basal cytoplasm and by acidophilic zymogen gran-
gallbladder also enters the duodenum. The hepatopancre- ules in the apical cytoplasm (see F ig. 17.20a). Zymogen
atic sphincter (of Oddi) surrounds the ampulla and not gra nules are most numerous in the pancreas of fasting in-
onl y regulates the flow of bile and pancreatic juice into the dividuals. The squamous centroacinar cells lack both er-
duodenum but also prevents reflux of intestinal contents gastoplasm and secretory g ra nules; thus, they sta in very
into the pancreatic duct. In some individuals, an accessory lightly with eosin. This weak staining helps identify them
pancreatic duct (of Santorini) is present, a vestige of the in routine histologic sections.
pancreas's origin from two embryonic endoderma l primo r-
dia that evaginate from the foregut. Zymogen granules contain a v ariety of d igestive enzymes in an
A thin layer of loose connective tissue forms a capsule inactive form
ar o und the gland. From this capsule, septa extend into the
gland, dividing it into ill-defined lobules. Wi thin the lob- Pancreatic enzymes can digest most food substances.
ules, a stroma of loose connective tissue su rrounds the The inactive enzymes, or proenzymes, contained in pan-
parenchyma l units. Between the lobules, larger amounts of creatic zymogen granules are listed below alo ng with the
connective tiss ue surround the lar ger d ucts, blood vessels, specific substances they digest when activated.
and nerves. Moreover, in the connective tissue surround ing
Proteolytic endopeptidases (trypsinogen, chymotrypsin-
the pancreatic d uct, there are small mucous gla nds that
ogen) and proteolytic exopeptidases (procarboxypepti-
empty into the duct.
dase, proaminopeptidase) digest proteins by cleaving
their internal peptide bonds (endopeptidases) or by
The pancreas is an exocrine and endocrine gland
cleaving amino acids fro m the carboxyl o r amino end of
Unlike the liver, in which the exocrine and secretory (en- the peptide.
docrine) functio ns reside in the same cell, the dual func- Amylolytic enzymes (a-amylase) digest ca rbohydra tes
tions of the pancreas are relegated to two structura ll y dis- by cleaving the glycosidic linkages of glucose polymers
ti nct compo nents. Lipases digest lipids by cleaving ester bonds of triglyc-
erides, producing free fa tty acids.
The exocrine component synthesizes and secretes en- Nucleolytic enzymes (deoxyribonuclease and ribonu-
zymes into the duodenu m that ar e essential for digestion clease) digest nucleic acids, producing mo nonucleotides.
in the intestine. intralobular collecting duct
The endocrine component synthesizes and secretes the The pancreatic digestive enzymes are activated only after
acinar cells intercalated duct
hormones insuli11 and glucagon into the blood. T hese they reach the lumen of the small intestine. Initially, the
hormo nes regulate glucose, lipid, an d protein metabo- proteolytic activity of enzymes (enterokinases) in the glyco-
zymogen granules
lism in the body. calyx of the microvilli of the intestinal absorptive cells con-
verts trypsinogen to trypsin, a potent proteolytic enzyme.
T he exocrine pancreas is found throughout the orga n; Trypsin then catalyzes the conversio n of the other inactive
b
wi thin the exocrine pancr eas, distinct cell masses called enzymes as well as the digestio n of proteins in the chyme. FIGURE 17.20
islets of Langerhans are dispersed an d constitute the en- The cytoplasmic basophilia of the pancreatic acina r cells Pancreatic acinus and its duct system. a. In this photomicrograph of mal cells. x 860. b. In this schematic diagram, observe the beginning
docrine pancreas. when o bserved with the TEM a ppears as an extensive ar- a thin, HfiE-stained plastic section, an intercalated duct can be seen of the intercalated duct. Note the location and shapes of the cen-
beginning within a pancreatic acinus. The cells forming the duCt troacinar cells w ithin the acinus. They represent the initial lining of
ray of r ER and free ribosomes. T he presence of these nu-
within the <'Cinus are the centroacinar cells. The eosinophilic zymo the interca lated duct, which drains into an intralobular collecting duct.
Exocrine Pancreas merous o rga nelles correlates with the high level of protein
gen granules are clearly seen in the apical cytoplasm of the parenchy-
synthetic activity of the acinar cells (Fig. 17 .21 ). A well-de-
The exocrine pancreas is a serous gland veloped Golgi apparatus is present in the a pical cytoplasm
and is involved in concentration and packaging of the se-
The exocrine pancreas closely resemb.les the parotid cretor y produ cts. M itochondri a a re small and, a lthough centra ll y placed, fla ttened nucleus and attenuated cyto- ing ducts. T here are no striated (sec retory) ducts in the
gland, with which it can be confused . T he secretory units found th ro ugho ut the cell, are concentrated among the plasm, w hich is typical of a squa mous cell. pancreas.
are acina r or tubu loacinar in shape and are for med by a rER cisternae. Aci na r cells are joined to one ano ther by T he complex, branching network of intralobular ducts
simple epithelium of pyramidal sero us cel ls (Fig. 17.20a). ju nctional complexes at their apica l poles, thus fo rm ing an Centroacin ar cells are intercalated duct cells locat ed drains into the larger interlobular ducts, which ar e lined
T he cells have a narrow free (lumi nal) surface an d a broad isolated lumen into which sma ll microvilli extend fr om the in the acinus with a low colu mna r epithelium in which enteroendocrine
basal surface. Periacinar connective tissue is minimal. apical surfaces of the ac inar cells and into which the zy- cells and occasio na l goblet cells ma y be fo und. T he inter-
T he serous secretory cells of the acin us prod uce the di- mogen granules are released by exocytosis. Centroacinar cells a re continuo us with the cells of the lobula r du cts, in turn, drain directl y in to the main pancre-
gesti ve enzyme precursors secreted by the pancr eas. Pancre- short interca lated duct tha t lies o utside the aci nus. The atic duct, which r uns the length of the gland par allel to its
atic acin i are unique among glandular acini; the initial duct structura l unit of the acinus and centroacina r cells resem- lo ng axis, giving th is porti o n of the duct system a herring-
Duct System of the Exocrine Pancreas
that leads from the acinus, the intercalated duct, actuall y bles a sm all balloon (the acinus) into which a drinking bone-like appea ra nce (see Fig. 17.1 9). A second lar ge duct,
begins within the acin us (Fig. 17.20b) . T he duct cells located The centroacina r cells (see Fig. 17.20a) are the beginning straw (the intercala ted duct) has been pus hed. The in ter- the accessory pancreatic duct, arises i11 the head of the
inside the acinus are referred to as centroacinar cells. of the duct system of the exocrine pancreas. They have a calated d ucts are short and drai n into intralo bular co l.lect- pancr eas.
CHAPTER 1 7 Digrslillr Syslew 111. Li11rr, Gallhladtlrr. aud Paucreas 55 5
554 CH APTER 17
Digrslivr Sysleut Ill: Uurr, Galll!laddrr, arul Paumas
serves to neutralize the acidity of the ch yme that enters the
duodenum from the stomach and to establish the optimal
pH for th e activity of the major pancreatic enzymes.
B
Figure 1, liver, human, H&E X65; inset X65. the sunounding connective tissue of the portal canal. The
At the low magnification shown here, large numbers of vein is typically thin walled; the artery is smaller in diame-
hepatic cells appear to be uniformly disposed throughout ter and has a thic ke r wall. The bile ducts are composed of a
the s pecimen. The hepatic cells are arranged in o ne-cell- simple cuboidal or columnar epi thelium, depending on the
thick plates, but when sectioned, they appear as intercon- size of the duct. Mul tiple profiles of the blood vessels and
necting cords one or more cells thick, de pending on the bile ducts may be ev ident in the canal because of either
plane of section. The sinusoids appear as li ght areas be- branching or thei r passage o ut of the plane of section and
tween the cords of cells; they are more clearly shown in then back in again.
Figure 2 (asterisks). The vessel through which blood leaves the liver is the he-
Also present in this figure is a portal cana l. It is a con- patic vein. Tt is readily identified because it travels alone (in-
nective tissue septum that carries the branches of the hepatic set) and is stmounded by an appreciable amount of connec-
artery (HA ) and portal vein (PV), bile ducts (BD ), and lym- tive tissue (CT). If more than one profile of a vein is present
phatic vessels and nerves. The artery and vei n, along with within this connective tissue, but no arteries or bile ducts are
the bile duct, are collectively refeJTed to as a portal triad. present, the second vessel will also be a hepatic vein. Such is
The hepatic artery and the portal vein are easy to iden- the case in the inset, where a profi le of a small hepatic vein is
tify because they are fo und in relation to one another w ithin seen just above the larger hepatic vein ( HV).
B
The limits of the lobule are defi ned, in part, by the por-
The termi nal hepatic venules o r centra l veins (CV) are
tal canal. In other directi ons, the plates of the lobule do not
the most d is tal radicals of the he patic vein, and like the he-
appear to have a li mit; i.e., they have become contiguous
patic vein, they al so travel alone. Their di stinguis hing fea-
with plates of an adj acent lobule. One can estimate the d i-
tures are the sinusoids that penetrate the wa ll of the vein
mensions o f the lobule, however, by approximating a c ircle
and the pauc ity of surrounding con nective ti ssue. These
with the centra l ve in as its cente r and incorporating those
characteristics are s hown to advantage in Plate 62.
plates that exhibit a radia l arrangement up to the point
It is best to examine low-magnification views of the liver
where a portal canal is present. If the lobule has been cross-
to define the boundaries of a lobul e. A lo bule is best identi-
sectioned, the radia l li n'lit is set by the location of one or
fied when it is cut in cross sectio n. The centra l vein then ap-
more of the po rtal cana ls as indicated by the bile ducts ( BD)
pears as a circ ul ar profile, and the hepatic cells appear as
in this figure.
cords rad iating from the central vein. Such a lobule is o ut-
lined by the dashed line in Figure I.
KEY
BD, bile duct HV, hepatic vein asterisks (Fig. 2), blood si nusoid s
CT, connective tissue L , lymphatic nodu le dotted line (Fig. 1), approx imates the limits
CV, central vei n (terminal hepatic venule) PV, portal vein of a lobu le
HA, hepatic artery
560
CHAPTER 17 Digcslitlc System I [f Live,., Gnllblntltle,., n11tl PnHc,.ens 563
B
Figure 1, liver, human, H&E X 500; inset X800. The cells that line the sinusoids (S) show little, if any,
The central vein and surrounding hepatocytes from Fig- cytoplasmic detail in routine preparations. Perisinusoidal
ure 2 of Plate 61 are shown here at higher magnification. macrophages (Kupffer cells [ K C]) are generally recognized
The cytoplasm of the hepatocytes in this specimen has a by their ovoid nuclei and the projection of the cell into the
foamy appearance because of extraction of glycogen and lumen. The endothelial cell, in contrast, is a squamous cell
lipid during tissue preparation. The boundaries between in- that has a smaller, attenu ated or elongated nucleus. Some
dividual he patocytes are discernable in some locations but nuclei of this descripti on are evident in the micrograph.
not between those cells where the knife bas cut across the The termination of two of the sinusoids and their union
boundary in an oblique plane. Frequentl y, when cell bound- with the central vein (CV) is indicated by the curved ar-
aries are observed at still higher magn ificati on (inset), a rows. Note that the wall of the vein is strengthened by con-
very small circ ular or oval profile is observed midway necti ve ti ssue, mostly collagen, whic h appears as homoge-
along the boundary. These profiles represent the bile canali- neous eosin-stained material (asterisks). Fibroblasts (F)
culi (BC). wi thin this connective tissue can be ide ntified and distin-
guished from the endothelial cell (EN) lining of the vein.
Figure 2, liver, rat, glutaraldehyde-osmium this specimen is the clear representation of the bile cana-
KEY
BC, bile canaliculus KC, Kupffer cell asterisks, connecti ve tissue of central vein
CV, central vein L, li pid droplet curved anows, o pen ing of si nusoid into
EN, endotheJjaJ cell S, sinusoid central vein
F, fibrobl ast arrows (Fig. 2), g lycogen
562
C HA PTER 17 Digestive System 1II Liver, Cni/J,/rulder, 1111d Pmzcrens 565
Figure 1, gallbladder, H&E x45. the larger blood vessels ( BV) travel and , more peripherally,
The gallbladder is a holl ow, pear-shaped organ that con- of varying amounts of adipose tissue (AT).
centrates and stores the bile. The full thi ck ness of its wall is T he mucosa is thrown into numerous folds that are partic-
shown here. It is composed of a mucosa (Mu c), muscularis ularly pronounced when the muscularis is highly contracted.
(Mus), and adventitia (Adv) and , o n its free surface (not This is the usual histologic appearance of the gallbladder un-
shown), a serosa. T he mucosa is considered at higher mag- less, of course, steps are taken to fix and preserve it in a dis-
nification in Fig ure 2. T he muscularis consists of interlac- tended state. Occasionally, the section cuts tluough a recess in
ing bundles of smooth muscle (SM) . The adventitia (Adv) a fold, and the recess may then resemble a gland (arrows). The
consists of irregular den se connective tissue through which mucosa, however, does not possess glands, except in the neck
region, where some mucous glands are present (see Fig. 4).
Figure 2, gallbladder, human , H&E x 325. ways evide nt in routi ne H &E- stained sections. The cyto-
The mucosa consists of a tall simple columnar absorp- plasm stains rather uniformly with eosin. This is re lated to
tive epithelium (Ep) resting on a lami na propria of loose ir- its absorptive function and is in contrast to the staining of
regular connective tissue (CT). T he epithelium has c harac- cells that are engaged in the productio n of protein. Lastly,
teristics that di stinguish it from the absorptive epithelium of with respect to its absorptive function, the epithelial cells
other organs, s uc h as the intestines. O nly o ne cell type, tall frequently ex hibi t diste nded inte rce llular spaces at their
columnar cells, is present in the epithelial layer (see Fig. 3). basal aspect (see Fig . 3, arrows ). Thi s is a feature associ-
T he nuclei are in the basal portion of the cell. T he cells pos- ated with the transport of fluid across the epithelium and , as
sess a thin apical striated border. However, this is not al- note d above, co mmo nly seen in intestinal absorptive cells.
Figure 3, gallbladder, human, H&E x550. mation. ) Another feature of note in the lamina propria is the
T he lamina propria underlyi ng the epithelium is usuall y presence of several glands and gland-like profiles (GI) other
very cellular. In thi s specimen, in addition to lymphocytes than those seen in the mucosa and noted above. These are
(L), a relati vely common finding, a large number of plasma readily apparent in Figure l. Two of these structures,
cells ( PC) is also present w ithin the lam ina propria. (The marked by asterisks in Figure I , are shown at higher mag-
hi gh co ncentratio n of plasma cells suggests chronic in flam- ni fi catio n in Figure 4 .
Figure 4, gallbladder, human, H&E x 550. is onl y partially incl uded in the micrograph has rounded or
The smaller of the two gland-like structures is composed ovoid nuclei. This epitheli al-lined structure is not a true
of mucous cells (MC) and represents a section tluough a gland but represents an invagination of the mucous mem-
mucous gland . This specimen was take n fro m a site near the brane that extends into and often throug h the thickness of
neck of the ga llbladder where mucous glands are often the muscularis. T hese invaginatio ns are know n as Rok itan-
present. Note the c haracteri stic flatte ned nuclei at the base sky-Aschoff sinuses. T heir role or sig nificance, if any, is
of the cell and the lightly stained appearance of the cyto- unknow n. (Some autho rities contend that they result from
plasm, features characteristic of muc in- secreting cells. In di sease, but they are also fo und in small numbers in g~ill
contrast, the epithelium of the large gland-li ke profile that bladders that appear normal in all o ther respects.)
KEY
Adv, adventitia L , lymphocytes SM, smootb muscle
AT, adipose tissue MC, mucous cell s arrows: Fi g. I, recess in luminal surface;
BY, blood vessel Muc, mucosa Fig. 3, intercel lular spaces
CT, connective tissue, lamjna propria Mus, muscularis aster isks (Fig. 1), gland or gland-like struc-
Ep, epithelium PC, plasma cell s ture
Gl, gland or gland- like structu re
564
CHAPTER 17 Diges tive System II L Liver, Gallbladder, a11d Pa11creas 567
B
Figure 1, pancreas, H&E X160; inset X360 This figure shows an islet of Langerhans (l L) among the
The pancreas is surrounded by a delicate capsule of far more numerous acini. (Islets are most numerous in the
moderately de nse connective tissue. Septa from the capsule tail of the pancreas and least numerous in the head). Cells
di vide the pancreas into lobules, one of which is shown within the islets are arranged as irregular cords. In routine
here, bounded by connective tissue (CT). Larger blood ves- preparations, it is not possible to identify the various cell
sels (BV) travel in the connecti ve tissue septa; nerves also types within the islets. Note, however, that B cells are the
travel in the septa, but they are seen infrequently. Within the most numerous; these produce insulin. The next most nu-
lobule are the numerous acini of the exocrine component, merous are A cells; these produce glucagon. The inset also
an intralobular duct (lnD), intercalated ducts (not readil y shows numerous capillaries (arrows). The labels A and B
eviden t at this low magnification), and islets of Langerhans are not intended to identify specific cells but rather to show
(IL). Also within the lobule are the small blood vessels and those parts of the islets where A and B cells are fou nd in
the connective ti ss ue serving as a stroma for the parenchy- greatest number.
mal elements of the gland.
Figure 2, pancreas, H&E X600. duct ( ID ), which is seen in cross section at the furthest dis-
KEY
A, region with most A cells CT, connective tissue lnD, intralobular duct
B, region with most B cells E1, ergastoplasm arrows, capil laries
BV, blood vessels ID, intercalated ducts asterisks, lumen of acin i
CC, centroacinar cells IL, islets of Langerhans
566
as well as regu lation of immune responses to inhaled The passages extern a l to the lungs consist of
antigens. Nasa( cavities (a nd, during forced breathing, the oral
The lungs develop in the embryo as a ventral evagination cavity )
of the foregut; thus, the epithelium of the respiratory system Nasopharynx and orophmynx
is of endodermal origin. This initial respiratory diverticu-
Lmynx
lum grows into the thoracic mesenchyme. The bronchial Trachea
Respiratory System
cartilages, smooth muscle, and the other connective tissue Paired m ain (primmy) bronchi
elements ar e derived from the thoracic mesenchyme.
Within the lungs, the main bronchi undergo extensive
The air passages of the respiratory system consist of a br anching to give rise ultimately to the distributing bron-
conducting portion and a respiratory portion chioles. The bronchioles represent the termina l part of the
conducting passages. Collectively, the internal bronchi and
OVERVIEW OF THE RESPI RATORY SYSTEM 568 The conducting portion of the respiratory system con- the bronchioles constitute the bronchial tree.
sists of those air passages that lead to the sites of respira - The respimtory portion is that part of the respira tory
NASAL CAVITIES 569
tio n within the lung where gas exchange takes place. The tract in which gas exchange occurs. Sequentially, it in-
Vestibule of the Nasal cavity 570
Respiratory Segment of tl1e Nasal Cavity 570 conducting passages include those located o utside as well cludes
Olfactory Segment of the Nasal Cavity 571 as within the lungs. Respimtory bronchioles
Paranasal Sinuses 573 A lveolar ducts
PHARYNX 573 A lveolar sacs
Alveoli
LARYNX 573
Blood vessels en ter the lung with the bronchi. The arter-
TRACHEA 575 ies bra nch into smaller vessels as they follow the bronchial
Tra cheal Epithelium 575 tree into the substance of the lung. Capillaries come into in -
Ba sem ent Membrane and Lamina Propria 577 timate contact with the terminal respirato ry units, the alve-
BRONCHI 579 oli. This intimate relationship between the alveolar air
spaces and the pulmonary capillaries is the structu ral basis
BRONCHIOLES 580
for gas exchange within the lung parenchyma. T he essential
Bronchiolar Structure 581
features of the lung blood supply are described on page 590.
Bronchiolar Function 582
Air passing through the respiratory passages must be
ALVEOLI 583 conditio ned before reaching the terminal respiratory units.
BLOOD SUPPLY 590 Conditioning of the air occurs in the conducting portion
of the system and includes warming, moistening, and 1'e-
LYMPHATIC VESSELS 590 moval of particulate materials. Mucous and serous secre-
NERVES 590 tions play a major role in the conditi oning process. These
secretions moisten the a ir and also trap particles that have
BOXES managed to slip past the special short thick hairs, ca lled
BOX 18.1. Clinical Correlations: Metaplasia 575
vib1issae, in the nasa l cavities. Mucus, augmented by these
serous secretions, also prevents the dehydratio n of the un-
BOX 18.2. Clinical Correlations: Cystic Fibrosis 582
derlying epithelium by the moving air. Mucus covers al -
BOX 18.3. Clinical Correlations: Emphysema and Pneumonia 588 most the entire luminal surface of the cond ucting passages
and is continuously p roduced by goblet cells and mucus-
secreting glands in the walls of the passages . The mucus
and other secretions are moved toward the pharynx by
sacs means of coordinated sweeping movements of cilia and are
respiratory
9 OVERVIEW OF THE RESPIRATORY Three pri ncipa l func tions are performed by this sys- bronchioles then norma lly swa llowed.
SYSTEM tem: air conduction, air filtration, and gas exchange (res-
FIGURE 18.1
piration). The latter occurs in the alveoli. In addition, air Diagram of respiratory passages. The nasal cavities, nasopllarynx,
The respiratory system consists of the paired lungs and a passing through the larynx is used to produ ce speech , oropl1arynx, larynx, trachea, bronchi, and bronchioles constitute the
9 NASAL CAVITIES
series of air passages that lead to and from the ltmgs. and air passing over the olfactory mucosa in the nasal conducting portion of tile respiratory system. Th e respirat01y portion
Within the lu ng, the air passages branch into increasingly cavities carries stim uli for the sense of smell. The respi- of tile system, where gas exchange occurs, is composed of respira- The nasal cavities are pa ired chambers sepa ra ted by a
smaller tubes until the very smallest ai1 spaces, ca lled alve- ratory system also participates to a lesser degree in en- tory bronchioles, alveolar ducts, alveolar sacs, and alveoli. (Based on bony and cartilaginous septum. Each cavity or cha mber
oli, are reached (Fig. 18.1). docrin e functions (hormon e production and secr etion), Boileau G. A Method of Anatomy. Baltimore: Williams a Wilkins, 1980.) comm un icates anteriorly with the externa l environment
568 569
5 70 CHAPTER 1 8 Respirnlo1y Syslem CHAPTER 18 Res/Jim lory Syslem 57 I
through the nares (nostrils) and posteriorly with the na- Respiratory Segment of the Nasal Cavity Small granule cells that r esemble basal cells but contain This connective tiss ue contains numerous blood and lym-
sop harynx through the choanae (Fig. 18.2). The chambers secreto ry gran ules phatic vessels, unmyelinated olfactor y nerves, myelinated
are divided into three regions: The r espirator y segment constitutes most of the volume of
Basal cells, stem cells from w hich the o ther cell types nerves, and olfactor y glands.
the nasal cavities . It is lined with a ciliated, pseudostrati-
Vestibule anse The o lfactory epithelium, li ke the epithelium of the res-
fied column ar epithelium. The underlying lamina propria
Respiratmy segment piratory segment, is also pseudostrati.fied, but it conta ins
is attached to the pei'iosteum of the adjacent bone. The epithelium of the respiratory segment of the nasal
Olfactory segment ver y different cell types. Also, it lacks goblet cells (Fig.
The medial wall of the res piratory segment, the nasal cavity is essentia lly the same as the epithelium lining most of 18.3 ). The olfactory epithelium is composed of the follow-
septum, is smooth, but the lateral wa lls a re tluown into the parts that follow in the conducting system. Because the ing cell types:
Vestibule of the Nasal Cavity folds by the presence of three shelf-like, bony projecti ons respiratory epithelium of the trachea is studied and exam-
called turbinates or conchae. The turbinates play a dua l ined in preference to that of the nasal cavity, the above cell
The vestibule communicates anteriorly with the external en- Olfactory cells, bipolm' neurons that span the thickness
role. They increase s urface area as well as cause turbu- types are discussed in the section on the trachea (page 575).
virotm1ent. It is lined with stratified squamous epithelium, a of the epithelium
lence in airflow to allow more efficient conditioning of in-
continuation of the skin of the face, and contains a variable Supporting or sustentacular cells, columnar cells that
spired air. The mucosa of the respiratory segment warms, moistens, and
number of stiff hairs, vibrissae, that entrap large particulate provide mechanical and meta bolic support to the o lfac-
The ciliated, pseudostratified columnar epithelium of the filters inspired air
matter before it is carried in the air stream to the rest of the tory cells
respiratory segment is composed of five cell types :
cavity. Sebaceous glands are also present and their secreti ons Basal cells, stem cells fro m w hich new o lfactory cells
assist in the entrapment of particulate matter. Posteriorly, Ciliated cells, ta ll columnar cells w ith cilia that pr oject The lamina propria of the respirator y segment has a and supporti ng cells di fferen tiate
w here the vestibule ends, the stratified sq uamo us epithelium into the mucus covering the surface of the epitheli um rich, vascular netwmk that includes a complex set of cap- Bntsh cells, the same cell type that occurs in the respira-
becomes thinner and undergoes a transition to the pseudos- Goblet cells that synthesize and secrete mucus illary loops. The arrangement of the vessels allows the in- tory epithelium
tratified epithelium that characterizes the respiratory seg- Brush cells, a general name for those cells in the respira- haled air to be wa rmed by blood flowing through the part
ment. At this site, sebaceous glands are absent. tory tract that bear short, blunt m icrovilli of the loop closest to the su rface. The ca pillaries that reside Olfactory cells are bipolar neurons that possess an apical
near the surface are arranged in rows; the blood flows per- projection bear ing cilia
pendicular to the airflow, much as one would find .in a me-
chanical heat-excha nge system. These same vessels may be- The apical (luminal) pole of each olfactory cell is a den-
come engorged and leaky during allergic reactions or viral dritic process that projects above the epithelial surface as a
infections such as the common cold. The lamina propria knob-like structure called the olfactory vesicle. A number of
then becomes distended with fluid , resu lting in marked cilia (10 to 23) with typical basal bodies arise from the ol-
olfactory mucosa
swelling o f the muco us membrane with conseq uent restric- facto ry vesicle and extend radia lly in a plane parallel to the
ti o n of the air passage, making breathing difficult. The epithelial surface (see Fig. 18.3). The cil ia are usually up to
lamina propria also contains mucous g lands, many ex- 200 ~J.m long and may overlap with cilia of adjacent o lfac-
hibiting sero us demilunes. Their secretions supplement tory cells. The cilia a re regarded as nonmotile, altho ugh
that of the goblet cells in the respirator y epithelium. some research suggests tbat they may have limjted motility.
By increasing surface area, the turbinates increase the ef- The plasma rnembrane of the cilia contains odorant-bind-
vestibule ficiency with which the inspired air is warmed. The ing proteins that act as olfactory r eceptors. Incoming odor-
tu rbinates also incr ease the efficiency of filtration of in- ant mo lecules a re solubilized in th e o lfactory mucus and in-
spired air through the process of turbulent precipitation. teract w ith the olfactory receptors to generate an action
The air stream is broken into eddies by the tur binates . Pa r- potential. The basal pole of the cell gives rise to an axona l
ticul ate matter suspended in the air stream is thrown out process th at leaves the epithelia l com partment to enter the
of the stream and adheres to the mucus-covered wall of the connecti ve tissue, w here it joins with axons from other ol-
nasal cavity. Particles trapped in this layer of mucus are factory cells to fo rm the olfactory nerve (cranial nerve 1).
transported to the pharynx by means of coordinated Autoradiographic studies show that o lfactory cells have a
sweeping movements of cilia and ar e then swallowed. lifespan of about 1 month. If injured, they are quickly re-
placed. O lfactor y cells (a nd some neurons of the enteric di -
vision of the auto no mic nervous system) appear to be the
Olfactory Segment of the Nasal Cavity
only neLuons that a re readil y replaced during postnatal li fe.
T he olfactory segment is loca ted on part of the dome of
each nasal cavity and, to a variable extent, the contiguous Supporting cells provide mechanical and metabolic support for
la tera l and med ial nasal walls. It is lined with a specialized the olfactory cells
olfactory mucosa. In livi ng tissue, this mucosa is distin-
guished by its slight yellowish brown color caused by pig- Supporting cells a re the most numerous cells in the o l-
ment i11 the olfactmy epithelium and the assoc iated olfac- factOry epitheli um . The nu clei of these ta ll colum nar or
FIGURE 18.2
Diagram of the relationship of the pharynx to the respiratory and the larynx (i.e., epiglottis, thyroid cartil age, and cricoid cartilage). Note
tory glands. In humans, the tota l surface area of the sustentac ular cells occupy a more apica! positio n in the ep-
digestive systems. Th e pharynx is divided into three parts: nasophar tile ventricular and voca l folds in the middle of tile larynx, approxi olfactory mucosa is only a few square cen timeters; in an i- ithelium than d o those of the other cell ty pes, th us aiding
ynx, oropt1 arynx, and laryngopharynx. It is located posterior to the rnately at tile level of tile thyroid ca rtilage. This part of the larynx rep- mals wi th an acute sense of smell, the tota l surface area of in their identification in the light microscope (see Fig.
nasal and oral cavities and extends inferiorly past tile larynx. The resents tile narrowest portion of tile respiratory system and is re- t he olfactory mucosa is considerably more extensive. 18.3). T hey have n umerous microvilli on their a pical su r-
pt1arynx serves both respiratory and digestive systems. This mid- sponsible fo r producing sound by audible vibration of t11e vocal folds. The lam ina propria of th e olfactory mucosa is djrectly face, and abundant mitochondria . N umerous profiles of
sagittal section also transects tile cartilages forming tile skeleton of contiguo us with the periosteum of the underlying bone. smooth endo plasmic reticulum (sER) and, to a mo re lim-
5 72 CHAPTER 18 Respiratory Systrt11 CHAPTER 18 R.es firntory System 57 3
In human respiratory mucosa, ciliated pseudostratlfled epithe- impaired. To compensate, the individual begins to cough, thereby
lium may change to stratified squamous epithelium. This trans- facilitating tile expulsion of accumulated mucus in the airway,
formation is a normal occurrence on the rounded, more exposed particularly in the trachea. With time, the number of ciliated cells
portions of the turbinates, on the vocal folds, and in certain other decreases because of chronic coughing. This reduction in ciliated
regions. Changes in the character of the respiratory epithelium cells further impairs the normal epithelium and results in its re
may, however, occur in other ciliated epithelial sites when the placement with stratified squamous epithelium at affected sites in
pattern of airflow is altered or when forceful airflow occurs, as in tile airway.
chronic coughing. Typically, in chronic bronchitis and bronchiec- Epithelial alterations of this kind are referred to as metaplasia,
tasis, the respiratory epithelium changes in certain regions to a i.e., a reversible change from one type of fully differentiated adult
stratified squamous form. The altered epithelium is more resist- cell to a different type of adu lt cell. A given mature cell does not
ant to physical stress and insult, but it is less effective function- cl1ange to another type of mature cell; rather, basal cell prolifer-
ally. In smokers, a similar epithelial change occurs. Initially, tile ation gives rise to the new differentiated cell type. These cellular
cilia on ciliated cells lose their synchronous beating pattern due changes are considered to be controlled and adaptive.
to noxious elements in smoke. As a result, removal of mucus is
The epitheliu m serves to protect the mucosa from abrasion tween the free ends of the C-shaped cartilages at the pos-
caused by the rapidly moving air stream . The rest of the terior border of the trachea, adjacent to the esophagus.
vocal is voealis
muscle muscle lar ynx is lined with the ciliated, pseudostratified columnar
epithelium that characterizes the respiratory tract (see Fig. Tracheal Epithelium
18.4). T he connecti ve tissue of the la rynx contains mixed
m ucosero us glands that secrete tluough ducts onto the la- Tracheal epithelium is similar to respiratory epithelium in
ryngeal surface. other parts of t he conducting airway
bone
tissue
/ fibroelastic
membrane
trachea
bone
tissue
~
FIGURE 18.5
Photomicrograph of a section of the trachea and esophagus. a. This cartilage, whereas the lighter-staining material has been replaced by
specimen, obtained from an elderly individual, shows the relationship bone tissue. The very light areas (arrows) are marrow spaces. x 3.25.
between the trachea and the esophagus at the base of the neck. The b. This high-magnification photomicrograpl1 shows an area of
cartilaginous tracheal rings, which keep the trachea patent, have a c- the tracheal ring that has partially transformed into bone. The top
shaped appearance. The cartilage gap, where the trachea is adjacent of the micrograph shows the tracheal mucosa and submucosa. Below
to the esophageal wall, is spanned by a fibroelastic membrane. It con- is part of the tracheal ring. In this particular region, however, a sub-
tains the trachealis muscle and numerous seromucous glands. In this stantial portion of the cartilage has been replaced by bone tissue and
specimen, the tracheal ring has been transformed, in part, to bone, a marrow. The bone tissue exhibits typical lamellae and osteocytes. The
process that occurs in aging. The darker-staining material represents cartilage tissue, in contrast, exhibits nests of chondrocytes. x 100.
number of mucous cells increases durjng chronic inita- mjcroscope (TEM), a thin, tapering cytoplasmic process is
tion of the a ir passages. sometimes observed extending to the lumen. Also, with the
Brush cells have the same general features as those de- TEM, the cytoplasm exhibits numerous, membrane-
scribed for the respiratory epithelium of tbe nasal cavity bounded, dense-core granules. In one type of small granule
(Fig. 18.9a). They are columnar cells that bear blunt mi- cell the secretion is a catecholamine. A second cell type pro-
crovilli. The basal surface of the cells is in synaptic contact duces polypeptide hormones such as serotonin, calcitonin,
with an afferent nerve ending (epitheliodendr itic synapse) . and gastrin-releasing peptide (bombesin). Some small gran- FIGURE 18.6
Thus, the brush cell is regarded as a receptor cell. ule cells appear to be innervated. The fLmction of these cells Electron micrograph of human trachea. This electron micrograph basal cells, which are confined to the basal portion of the epithelial
Small granule cells are respiratory representa tives of the shows t11e three main cell types of this respiratory epithelium. They layer near the connective tissue. x 1,800. (Courtesy of Dr. Johannes A.
is not well understood. Some are present in groups in asso-
are represented by ciliated epithelial cells extending to the surface, G. Rl1odin.)
general class of enteroendocri.ne cells of the gut and gut de- ciation with nerve fibers, forming neuroepithelia l bodies,
where they possess cilia; goblet cells with mucinogen granules; and
ri vatives (Fig. 1 8.9b). T heir presence is explained by the de- which are thought to function in reflexes regulati1~g the air-
velopment of the respiratory tract and lungs fro m an evagi- way or vascular ca liber.
nation of the primitive foregut. Small gra nule cells usually Basal cells serve as a reserve cell population that main-
occur singly in the trachea and are sparsely dispersed tai ns individual cell replacement in the epjthelium. Basa l Basement Membrane and Lamina Propria usually appears as a glassy or homogeneo us light-staining
among the other cell types. Tbey are difficult to distinguish cells tend to be prominent because their nuclei form a layer approximately 25 to 40 IJ.m th ick (see Fig. 18.8 ).
from basal cells in the light microscope without specia l row in close prox imity to the basal lamina. Although A thick "basement membrane" is characteristic of tracheal Electron microscopy reveals that it consists of densely
techniq ues such as silver staining, which reacts with the nuclei of other cells reside at this same general level epithelium packed collageno us fibe rs that lie immediately under the
granules. The nucleus is located near the basement mem- with in the epithelium, they are relatively sparse. Thus, epithelia l basal lamina . Structurally, it can be regarded as
brane; the cytoplasm is somewhat more extensive than that most of the nuclei near the basement membrane belong Located beneath the tracheal epithelium is a distinctive an unusually thick and dense reticular la mina and , as such,
of the smaller basal cells. With the transmission electron to basal cells. layer typically referred to as a " basement membrane." lt is part of the lamina propria. In smokers, particularl y
578 CHAPTER 18 Rrs/Jirnlory Syslem CHAPTER 18 Res/Jirnlory Syslrm 5 79
The boundary between mucosa and submucosa is defined by ter. In the trachea, the submucosa is a relatively loose con-
an elastic membrane nective tissue similar in appearance to the lamina propria,
which makes it difficult to determine where it begins. Dif-
Interspersed among the collagenous fibers are numerous fuse lymphatic tissue and lymphatic nodu les characteristi-
elastic fibers. Where the lamina propria ends, the elastic cally extend into this layer from the lamina propria . The
material is more extensive, and in specimens stained for submucosa contains the larger distributing vessels and
these fibers, a distinct band of elastic material is seen. This lymphatics of the tracheal wall.
band or elastic membrane marks the boundary between Submucosal glands composed of mucus-secreting acini
the lamina propria and submucosa . In H&E preparations, with serous demilunes are also present in th e submucosa.
however, the boundary is not obvious. Their ducts consist of a simple cuboidal epithelium and ex-
The submucosa is unlike that of most other o rgans, tend through the lamina propria to deliver their product,
where this connective tiss ue typically has a dense charac- largely glycoproteins, on the epithelial surface. The glands
are especially numerous in the cartilage-free gap on the
posterior portion of the trachea. Some penetrate the mus-
cle layer at this site and, therefore, also lie in the adventi-
tia. The submucosal layer ends where its connective tissue
junctional fibers blend with the perichondrium of the cartilage layer.
complex
glycogen
The tracheal cartilages and trachealis muscle separate
submucosa from adventitia
(
.
.
FIGURE 18.8
Photomicrograph of tracheal epithelium. Three major cell types are
evident in t11e tracheal epithelium (Ep): ciliated columnar cells; mucus-
~
\}BRONCHI
'
FIGURE 18.7 secreting goblet cells (G) interspersed between the ciliated cells; and
Scanning electron micrograph of t he luminal surface of a bronchus. basa l cells, which are close to the basement membrane (BM). The cil-
T he trachea divides into two branches forming the main
The nonciliated cells are the goblet cells (G). Their surface is charac- iated columnar cells extend from t he basement membrane to the sur- (primary) bronchi. Anatomically, these divisions are more
terized by small blunt microvilli that give a stippled appearance to the face. At their free surface they contain numerous cilia that, toget11er, frequently described as simply the right and left main
cell at this low magnification. The cilia of the many ciliated cel ls oc- give the surface a brush-like appearance. At the base of the cilia is a bronchi, terms that are more useful beca use of the physi-
cupy the remainder of the micrograph. Note how all are synchro- dense eosinophilic line. This is due to the linear aggregation of struc- cal difference between the two. The right bronch us is
nously" arrayed (i.e., uniformly leaning in the same direction) appear- tures referred to as basal bodies, located at the proximal end of each
b wider and significantly shorter than the left. On entering
ing just as they were when fixed at a specific moment during their cilium. Although basement membranes are not ordinarily seen in H&E mitochondria the hilum of the lung, each main bronchus divides into the
wave-like movement. x 1,200. preparations, a structure identified as such is seen regularly under the lobar bronchi (secondary bmnchi). The left lung is divided
epithelium in the human trachea. The underlying lamina propria (LP) into two lobes; the right lung is divided into three lobes.
FIGURE 18.9
consists of loose connective tissue. The more deeply located submu- Diagram of a brush cell and small granule cell. a. The brush cell, as il- Thus, the righ t bronchus divides into three lobar bronchial
cosa (SM) contains dense irregular connective tissue with blood and lustrated here, is interposed between type I and type II alveolar cells
those who experience chron ic coughing, this layer may be branches, and the left into two lobar bronchial branches,
lymphatic vessels, nerves, and numerous mucus-secreting tracheal of an alveolus. Blunt microvilli are distinctive features of the brush
considerably thicker, a response to mucosal irritation. glands. x 400.
with each branch supplying one lobe. The left lung is fur-
cell. The cytoplasm typically shows a Golgi apparatus, lysosomes, mi-
The lamina propria, excluding that part just designated ther divided into 8 bronchopulmonary segments and the
tochondria, and glycogen inclusions. b. This small granule cell is
as basement membrane, appears as a typical loose connec- right lung into 10 such segments. Thus, in the right lung
shown located between two Clara cells, as in a terminal or respiratory
tive tissue. It is very cellular, containing numerous lym- in the lamina propria and submucosa of the tracheal wall. bronchiole. Tile cell contains small secretory vesicles, most of which
the lobar bronchi give rise to 10 segmental bronchi (terti-
phocytes, many of which infiltrate the epithelium. Plasma It is a lso present in other parts of the respiratory system in- are in the basal portion of t11e cell. In addition to the vesicles, the most
ary bronchi); the lobar bronchi of the left lung give rise to
cells, mast cells, eosinophils, and fibrobl.a sts are the other volved primarily with air conduction. This lymphatic tis- conspicuous organelles of the cell are rough-surfa ced endoplasmic 8 segmental bronchi.
cel l types readily observed in this layer. Lymphatic tissue, sue is the developmental and functional equivalent of the reticulum (rER), a Golgi apparatus, and mitochondria. A nerve termi- A segmenta l bronchus and the lung parenchyma that it
in both diffuse and nodular forms, is consistently present bronchus-associated lymphatic tissue (BALT) . nal is shown within the epithelium adjacent to the cell. supplies constitute a bronchofJubnonary segment. The sig-
580 CHAPTER 18 R.esf>i,.nlo,.y Syslew CHAPTER 1 8 Respimlo>-y Sysle"' 58 I
nificance of the bronchopulmonary segment in the human Adventitia is moderately dense connective tissue that is duct narrows. Goblet cells are still present in the largest
lung becomes apparent when considering the need for sur- continuous with that of adjacent structures, such as pul- bronchioles but are not present in the terminal bronchioles
g ica l resection, which may be required in certain disease monary artery and lung parenchyma. that follow. An exception is in smokers and others exposed
states. The segments, each with its own blood supply and to irritants in the air. There are no subepithelial glands in
connective tissue septa, are convenient subunits that facil- bronchioles. Cartilage plates, characteristic of bronchi, are
itate surgical resection. 9 BRONCHIOLES absent in bronchioles. Instead, small elements of cartilage
Initially, the bronchi have the same general histologic may be present, particularly at branching points. A rela-
structure as the trachea. At the point where the bronchi en- The bronchopulmonary segments are further subdivided tively thick layer of smooth muscle is present in the wall of
ter the lungs to become intrapulmonary bronchi, the struc- into pulmonary lobules; each lobule is supplied by a bron- all bronchioles.
ture of the bronchial wall changes. The carti lage rings are chiole. Delicate connective tissue septa that partially sep- Sma ll bronchioles have a simple cuboidal epithelium.
replaced by cartilage plates of irregular shape. The p lates arate adjacent lobules may be represented on the surface The smallest conducting bronchioles, the terminal bron-
are distributed in a linear array around the entire circum- of the lung as faintly outlined polygonal areas. Pulmonary chioles, are lined with a simple cuboidal epithelium in
ference of the wa ll, giving the bronchi a circular or cylin- acini are smaller units of structure that make up the lob- which Clara cells are interspersed among the ciliated cells
drical shape in contrast to the ovoid shape with a flattened ules. Each acinus consists of a terminal bronchiole and (see Fig. 18.11). Clara cells increase in number as the cili-
posterior wall of the trachea. As the bronchi decrease in the respiratory bronchioles and alveoli that it aerates (see ated cells decrease along the length of the bronchiole. Oc-
size because of branching, the cartilage plates become Fig. 18.10). The smallest functional unit of pulmonary casional brush cells and small granule cells are also pres-
smaller and less numerous. The plates ultimately disappear structure is thus the respiratory bronchiolar unit. It con- ent. A small amount of connective tissue underlies the
at the point where the airway reaches a diameter of about epithelium, and a circumferential layer of smooth muscle
1 mm, whereupon the branch is designated a bronchiole. und erlies the connective tissue in the conducting portions.
Clara cells are nonciliated cells that have a characteristic
Bronchi can be identified by their cartilage plates and a circular rounded or dome-shaped apical surface projection. They
layer of smooth muscle
display TEM characteristics of protein-secreting cells (Fig.
18.12). They have a well-developed basal rER, a lateral or
The second change observed in the wa ll of the intrapul- supranuclear Golgi apparatus, secretory granules that stain
monary bronchus is the addition of smooth muscle to form for protein, an d numerous cisternae of sER in the apical
a complete circumferential la yer. The smooth muscle be-
comes an increasingly conspicuous layer as the amount of
cartilage diminishes. Initially, the smooth muscle is
arranged in interlacing bundles forming a continuous
secretory vesicles
layer. In the smaller bronchi, the smooth muscle may ap-
FIGURE 18.11
pear discontinuous. Scanning electron micrograph of a terminal bronchiole. This scan-
Beca use the smooth muscle forms a separate Ia yer, ning photomicrograph shows a longitudinal section throughout the
namely, a muscularis, the wall of the bronchus can be re- terminal bronchiole and surrounding alveoli (A). Note that the apical
garded as having five layers: surfaces of the Clara cells possess no cilia and have a characteristic
dome-shaped appearance. x 150. The inset shows some of the Clara
Mucosa, composed of a pseudostratified epithelitun with cells at a higher magnification and the cilia of a neighboring ciliated
the same cellular composition as the trachea. The height cell, which are present in very small numbers at this level. Note the
of the cells decreases as the bronchi decrease in diame- relatively few cilia present on these small cells. Xl ,200.
ter. In H &E specimens the "basement membrane" is
conspicuous in the primary bronchi but quickly dimin-
sists of a single respiratory bronchiole and the alveoli that
ishes in thickness and disappears as a discrete structure.
it supplies.
The la mina propria is simi lar to that of the trachea but
is reduced in amount in proportion to the diameter of
the bronchi. Bronchiolar Structure mitochondrion
Muscularis, a continuous layer of smooth muscle in the Bronchioles are air-conducting ducts that measure 1 mm
larger bronchi. It is more attenuated and loosely organ- FIGURE 18.10
or less in diameter. The larger bronchioles represent
ized in smaller bronchi, w here it may appear discontin- Photomicrograph showing the respiratory portion of the bronchial ~v..~;fr,';:;J,;-,'t.J',:.!!i'i'ilai):,.<. :,;:;..:;,,,,;!.C:il:=1::t.';c!IJ,;,\#!,;o>1oii'h"'''ii>;'8:}/\;;11ML,<'.;.:<.\")!g;:;;;
branches of the segmental bronchi. These ducts branch re-
uous because of its spiral course. Contraction of the tree. In this photomicrograph a terminal bronchiole (TB) is shown lon- . basallamina
gitudinally sectioned as it branches into two respiratory bronchioles
peatedly, giving rise to the smaller terminal bronchioles
muscle maintains the appropriate diameter of the air-
(RB). The terminal bronchiole Is the most distal part of the conducting that also branch. The terminal bronchioles finally give rise
way. FIGURE 18.12
portion of the respiratory system and is not engaged in gas exchange. to the l'espimtory bmnchioles.
Submucosa remains as a relatively loose connective tis- Diagram of a Clara cell between bronchiolar ciliated epithelial cells.
The respiratory bronchiole engages in gas exchange and is the be- Tile nucleus is in a basal location. Rough-surfaced endoplasmic retic-
sue. Glands are present as well as adipose tissue in the Cartilage plates and glands are not present in bronchioles
ginning of the respiratory portion of tile bronchial tree. Respiratory ulum (rER), a Golgi apparatus, and mitochondria are chiefly in basa l
larger bronchi.
bronchioles give rise to alveolar ducts (AD), whicll are elongate air- and paranuclear locations of tile cell. Smooth-surfaced endoplasmic
Cartilage layer consists of discontinuous cartilage plates ways that have almost no walls, only alveoli surrounding the duct The larger-diameter bronchioles initially have a ciliated, reticul um (sER) and secretory vesicles are cl1iefly in the apical cyto-
that become sma ller as the bronchial diameter dimin- space. Alveolar sacs (AS) are spaces at the termination of the alveolar pseudostratified colu mnar epithelium that gradually trans- plasm. One of the secretory vesicles is st1own discharging its contents
ishes . ducts that, likewise, are surrounded by alveoli. x 120. forms into a simple ciliated columnar epithelium as the onto the surface of the cell.
58'2 CHAPTER 18 Respiratory System CHAPTER 18 Resf>iratory System 58 3
C lara cells predo minate. O ccasional brush cells a nd dense- of smooth mu scle are present in the kn ob-like interalve-
core gran ule cells a re a lso present a long the le ngth of the olar septa (see below).
respiratory bronch iole. Scattered , t hin-wa lled o utpocket- Alveolar sacs are spaces s urrounded b y cluster s of alve-
ings, alveoli, extend from t he lumen of t he respiratory o li. The surroun ding a lveoli open into these s paces.
Cystic fibrosis (mucoviscidosis) is a chronic obstructive pulmonary decreased a- secretion and Increased Na + and water reabsorption
disease of children and young adults. It is an autosomal recessive from the lumen (Fig. 18.13). As a result, the ' mucociliary escalator' bronchioles (see Fig. 1 8. 10). A lveo li are the sites a t w hich Alveolar sacs usually occu r at the terminatio n of a n alve-
disorder that affects the viscosity of the secretion of the exocrine malfunctions, with consequent accumulation of an unusually thick, air leaves and enters t he bronchi o le to a llow gas exchange. olar duct but may occu r anywhere a long its length. Alveoli
glands. Almost all exocrine glands secrete abnormally viscid mucus viscous mucous secretion. The pulmonary lesion is probably initi- are surrounded and separated from o ne a nother by a n ex-
that obstructs the glands and their excretory ducts. The primary ated by obstruction of the bronchioles. Bronchiolar obstruction ceedingly thin connective tissue layer that contains blood
cause of cystic fibrosis is a genetic defect in the Cl- channel protein, blocks the airways and leads to thickening of the bronchiole walls \}ALVEOLI capillaries. The tiss ue between adjacent a lveo la r air spaces
which results in abnormal epithelial transport of o-. and to other degenerative changes In the alveoli. Because fluids re-
is called the alveolar septum or septal wall (Fig. 18.15 ).
The course of the disease is largely determined by the degree of main trapped in the lungs, individuals with cystic fibrosis have fre Alveoli are the site of gas exchange
pulmonary Involvement. At birth, the lungs are normal. However, quent respiratory tract infections. The recent cloning of the cystic fi-
the defective o- channel protein in t11e bronchial epithelium causes brosis gene could lead to the use of gene therapy in the future. Alveolar epithelium is composed of type I and II alveolar ce lls
The surface a rea available for gas exchange is increased and occasional brush ce lls
by the lung alveoli. Alveoli ar e the termi na l air spaces of
normal mucus
t he respira tory system a nd are the actual s ites of gas ex- The a lveola r su rface fo rms a vu lnera ble bio logic inter -
change between the air a nd th e blood. Each a lveo lus is sur- face that is subject to many destabiliz ing s urface forces a nd
rounded by a network of capillaries that brings b lood into to continuous exposu re to inhaled particles, pathogens,
close prox imity to inha le d air inside the a lveolus. About and toxins. T he a lveola r e pithelium is composed of sever al
150 to 250 mi llion a lveoli a re fo und in each adu lt lung; specialized cells a nd their products, some of w hich play de-
their combined internal surface area is approx ima tely 75 fensive and protective ro les:
m 2 , rough ly the size of a tenn is court. Each a lveolus is a
thi n-walled polyhedral chamber approximately 0.2 mm in Type I alveolar cells, a lso known as type I p11-eumocytes,
dia m eter that is con flue nt with a n a lveolar sac (Fig. 18.14). are extremely thin squa m o us cells t hat line most (95%)
of the surface of the a lveo li (see Fig. 18.15). These cells
Alveolm ducts are e lon gate airways that have a lmost no are joined to one a n other a nd to the o ther cells of the
walls, only a lveoli, as their perip heral boundary. Rings a lveolar epitheli um by occl uding junctio ns (Fig. 1 8. 16).
T he junctions fo rm a n effective ba rrier b etween the a ir
space a nd th e compo ne nts of th e septal wa ll. Type I
a lveo lar cells are not capa ble of cell d ivision.
Type II alveolar cells, a lso called type II pneumocytes or
septal cells, a re secretory cells. These cuboidal cells are in-
tersp ersed among the type I cells but tend to congregate at
septal junctions. Type II cells are as numerous as type T
cells, but because of their different shape they cover o nly
ABSORPTIVE CELL IN CYSTIC FIBROSIS GOBLET CELL NORMAL ABSORPTIVE CELL about 5% of the a lveolar a ir surface. Like C la ra cells, type
FIGURE 18.13 ll cells tend to bulge into the a ir space (see Fig. 18.16).
Schematic diagram of pathology in cystic fibrosis. In cystic fibro- the cell. As a result, the mucous layer within the bronchial tree be- T heir apica l cytoplasm is fi lled w ith granules that are re-
sis, secretion of o- anions into the lumen of the bronchial tree is comes dehydrated and viscous. This thick mucus is difficult to solved w ith the TEM (Fig. 18.17) as stacks of parallel
markedly decreased because of a defective or nonexistent chlo- move by the mucoci liary escalator mechanism, and it clogs the lu- membrane lamellae, the lamellar bodies. They are rich in
ride channel protein. Na+ resorption from the lumen of the men of the bronchial tree, obstructing airflow.
a mixture of p hospho lipids, neutral lipids, and p roteins
bronchial tree is then increased, causing movement of water into
th at is secreted by exocytosis to form an a lveola r lining,
sur face-active agent called surfactant. In a dd it io n to secre-
tion of surfactant, type ll a lveolar cells are progenitor cells
for type I a lveolar cells. Foll owing lung injury, they p rolif-
erate and restore both types of a lveolar cells within the
cytoplasm. C la ra cells secrete a s urface-active agent, a Bronchiolar Function a lveolus. H yperplasia of type II a lveola r cells is a n impor-
li poprotei n, that prevents luminal a dhesion sho uld the tant ma rke r of a lveolar injury and repair of a lveoli.
wa ll of t he a irway collapse on itself, particula rly d u ring ex- Respiratory bronchioles are the first part of the bronchial tree Brush cells a re a lso present in the a lveo lar wa ll, but th ey
piration. In addition, Clara cells prod uce a 16-kDa p rotei n that allows gas exchange FIGURE 18.14 are few in nu mber. T hey may serve as receptors t hat
Photomicrograph showing an alveolar sac with adjacent alveoli.
known as Clara cell pmtein (CC16), wh ich is a n abundant mo nito r a ix q ual ity in the lu ng.
This photomicrograph shows the terminal components of the respi-
componen t of t he airway secretion. CC 16 is used as a R esp irat ory bronchioles constitute a tra nsitional zone in
ratory system, namely, the alveolar sac (AS) and the surrounding alve-
meas urable pu lm o nar y m arker in bronc hoalveola r lavage the r espirator y system; they are invo lved in both a ir con- Surfactant decreases the a lveolar surface tension and actively
oli (A). The alveoli are surrounded and separated fro m one another
fluid and serum. Secretion of CC1 6 into the bronch ial tree d uc tio n and gas exchange. T hey have a narrow diameter by a thin connective tissue layer, the interalveolar septa, containing participates in the clearance of foreign materials
decreases in lung inj ury (beca use of da mage of C lara cells), a nd a re lined by cuboida l epi t he liu m . The epitheJjum of blood capillaries. On the right is the lung surface, which is covered by
while se rum levels o f CC16 may increase beca use of leak- t he init ia l segments of the respirato ry bronchioles conta ins visceral pleura containing simple squamous epithelium a nd a n un- The s urfact ant layer produced by type II a lveolar cells
age across the a ix- blood ba rrier. both c iliated cells and C lara cells (see Fig. 18.11 ). D istall y, derlying layer of connective tissue. x360. reduces the s urface ten sion at the a ir-epithelium in terface.
584 CHAPTER 18 Respiratory System CHAPTER 18 Respiratory System 'i 8 5
,
') ~ .
alveolus
type I
alveolar cell
alveolus
FIGURE 18.15
Electron micrograph of lung alveoli. This electron micrograph shows higher magnification in Figure 18.19. x 5,800. inset. Photomicrograph FIGURE 18.16
two alveolar spaces separated by an alveolar septum containing cap- of an alveolus for comparison with the alveolar wall as seen in an Electron micrograph of a type 11 alveolar cell. The type II alveolar cell alveolar cells that are joined to the ty pe II cell by occluding j unctions.
illaries, some of which contain red blood cells. Note the areas of thin electron micrograph. Arrows indicate alveolar capillaries containing has a dome-shaped apical surface w ith a number of short microvilli Both cell types rest on the basal lamina (BL). The secretory vesicles (G)
and thick portions of the alveolar septum. These are shown at a red blood cells. x 480. at its periphery and a relatively smooth-contoured apical center. The in tills specimen are largely dissolved, but their lamellar character Is
latera l cell margins are overlain to a variable degree by the type I shown to advantage in Figure 18.17b. X24,000.
The most critical agent for ai_r space sta bility is a spe- Surfactant proteins help organize the surfactant layer and
cific phosp ho lipid ca lled dipalmitoylphosphatidylcholi11e modulate alveolar immune responses Surfactant protein C (SP-C), which represents only 1% lar and ca pillary compa rtm ents. T he t hinnest a ir- blood
(DPPC), which accounts for almost all surface tension- of th e tota l mass of surfactant protein. Along w ith SP-B, barrier co nsists of a thin layer of surfactant, a type I ep -
In add ition to phospholipids, hyd rop hobic proteins are
reducing properties of surfacta nt. Smfactant synthesis in the SP-C a ids in orientation of DPPC within the surfactant it helial cell a nd its basa l lam ina, and a capi lla ry en-
necessary for the structure and function of surfacta nt.
fetus occu rs after t he 35th week of gestation an d is modu- and ma intenance of the t hin film layer w ith in t he alveoli. dothelial cell and its basa l lam ina. Often, these two basa l
These proteins ar e
lated by a va riety of hormones, including cortisol, insulin , Sur{actautprotei11 D (SP-D), a primary protei n involved laminae are fused (Fig. 18 .18 ). Connective tissue cells
prolactin, and t hyroxine. Without adequa te secr etion of Stufactant protei11 A (SP-A), the most abundant ~urfac in host d efense. It binds to vari ous microorganisms (e.g., and fibers that may be present between the two basa l
surfacta nt, the a lveoli would collapse on each successive ex- ta nt protein. SP-A is responsible fo r su rfacta n t ho me- Gram- negative bacteria) and to lymphocytes. SP-D par- lam inae widen the air-blood barrier. These two arra nge-
hala tion. Such collapse occurs in premature infants w hose ostasis (regul ating synthesis a nd secretion of surfactant ticipates in a local inflammatory response as t he result of men ts produce a thi11 portiou and a thick portiou o f the
lungs have not developed sufficiently to produce sur factant, by type II a lveolar cells). It a lso modu lates immune r e- acute lung injury and with SP-A mo dulates a n allergic barrier (Fig. 18. 19). It is though t tha t most gas excha nge
ca usi ng neona ta l respi ratory distress syndrome (RDS). Pro- sponses to viruses, bacteri a, and fungi. response to various i nha led antigens. occur s acr oss the thin po rti on of the ba rrier. T he th ick
p hylactic administratio n of exogenous surfactan t a t birth to Sur{actautpmtei11 B (SP-B), an important protein for t he po rtion is th ough t to be a site in w hich tiss ue fluid ca n
extremely prem ature infants and admi nistration to sympto- transformatio n o f t he lamella r bod y into the th in su rface The alveolar septum is the site of the air-blood barrier accu mu late a nd eve n cr oss into the alveolus. Lymphatic
matic newbo rns reduces the risk of RDS. In add ition, ad- film of surfacta nt. SP-B is a critical surfactant-organizing vessels in the connecti ve tissue of the ter minal bronchi-
ministrati on of cortisol to mothers wi th t hreatened prema- protein responsible for adsorptio n and spreading of sur- T he air-blood barrie1' refers to the cells and cell prod- oles drain fluid that accumula tes in t he thick portion of
ture de li very decreases neonatal mortality. factant onto the surface of the alveolar epithelium. ucts across w hi ch gases m ust d iffuse between the alveo- t he septum.
586 CHAPTER 18 Respirnlory Sys lem CHAPTER 18 l<.espirnlory Syslem 58 7
capillary lumen
surfactant discharged
into lumen of alveolus
a
FIGURE 18.17
Diagram of a type II alveolar cell and electron micrograph of lamel- protein, surfactant is distributed, on the surface of epithelial cells lin
lar bodies. a. surfactant is an oily mixture of proteins, phospholipids, ing the alveolus, as a thin film that reduces the surface tension.
and neutral lipids that are synthesized in the rER from precursors in b. Higher-magnification electron micrograph showing the typical
the blood. These precursors are glucose, fatty acids, choline, and lamellar pattern of the secretory vesicles of type II alveolar cells. Tl1ese
amino acids. The protein constituents of surfa ctant are produced in vesicles contain the pulmonary surfa ctant precursor proteins.
the rER and stored in the cytoplasm within lamellar bodies, which are x38,000. (Courtesy of Dr. A. Mercuri.)
discharged into the lumen of the alveolus. With the aid of surfactant
basal
lamina
type I
alveolar cell
$
FIGURE 18.18
Diagram of the interatveolar septum. This diagram shows the thick
and thin portions of the interalveolar septum. The thin portion forms
the air-blood barrier and is responsible for most of the gas exchange
that occurs in the lung. Arrows indicate the direction of C02 and 0 2 ex FIGURE 18.19
change between the alveolar air space and the blood. Tl1e thick por Electron micrograph of the alveolar septum. This high-magnification alar cell (arrows) rests on a basal lamina, and on the opposite side is
tion of the interalveolar septum plays an important role in fluid dis- micrograph shows the thin portion of the air-blood barrier where it connective tissue in which collagen fibrils and elastic fibers are evi
tribution and its dynamics. It contains connective tissue cells. Note the consists of type I alveolar cells, capillary endothelium, and the fused dent. x 33,000.
endothelial _ _ _ macrophage in the thick portion that extends its processes into the lu- basal lamina shared by both cells. In the thick portion, the type 1 alve-
cells men of the alveolus.
"""""
Alveolar macrophages remove inhaled particulate matter from like particl es of silica . Alveolar macrophages also phago-
the air spaces and red blood cells from the septum cytose infectious organisms such as Mycobacterium tu-
berculosis, which can be recognized in the cells in ap-
Alveolar macrophages are unusual in that they func- propriately sta ined specimens. T hese bacilli are not
Emphysema is a condition of the lung characterized by permanent dust, textile fibers, and construction dust. The most common cause,
tion both in the connective tissue of the septum and in digested by macrophages, however, and other infections
enlargement of the air spaces distal to the terminal bronchiole. This however, is cigarette smoking.
en largement is caused by chronic obstruction of airflow, most of
the air space of the a lveolus (Fig. 18.21 ). In a ir spaces, or conditions that damage alveola r macrophages can
The destruction of the alveolar wall may be associated with ex
ten because of narrowing of the bronchioles, and is accompanied cess lysis of elastin and other structural proteins in the alveolar they scavenge the surface to remove inhaled particulate lead to release of the bacteria and recurrent tuberculosis.
by destruction of the alveolar wall (Fig. 18.20). Thus, significant septa. Elastase and other proteases are derived from lung neu matter, e.g., dust and pollen, thus giving them one of
area for gas exchange is lost in this disease. Emphysema is rela trophils, macrophages, and monocytes. A specific genetic disease, their alternate names, dust cells. Alveolar macrophages Collateral air circulation through alveolar pores allows air to
tively common; it is seen in about half of all autopsies and is eas CY1 antitrypsin deficiency, causes a particularly severe form of em are derived from blood monocytes a nd belong to the pass between alveoli
ily recognized. Pathologists identify several types of emphysema. physema in both heterozygous and homozygous individuals. It is mononuclear phagocytotic system (page 144). They
The severity of the disease is clinically more important, however, usually fatal in homozygotes if untreated, but its severity can be re phagocytize red blood cells that may enter the a lveoli Scanning electron miCroscopic studies of alveolar
than recognition of the specific type. Emphysema is often caused duced by supplying the enzyme inhibitor exogenously. in heart failure (see Fig. 18.21). Some engorged macro- structure show openings in the interalveolar septa that
by chronic inhalations of foreign particulate material such as coa l phages pass up the bronchial tree in the mucus and are allow circulation of air from one alveo lus to another.
disposed of by swallowing or expectoration when they These alveolar pores (of Kohn) ca n be of great signifi-
reach the pharynx. Other macrophages return to or re- cance in som e pathologic conditions in which obstructive
main in the septa l connective tissue, where, filled with lung disease blocks the norma l pathway of a ir to the
accumulated phagocytized material , they may remain for alveoli. The alveoli distal to the blockage may continue
much of an individual's life. Thus, a t a utopsy, the lungs to be aerated, via the pores, from an a dj acent lobu le or
of urban dwellers as well as smokers will usually show acmus.
ma ny alveolar and septal macrophages fil led with carbon A basic summar y of information related to the respira-
particles, anthracotic p igment, and birefringent needle- tory system is included in Table 18.1.
TABLE 18.1. Divisions of the Bronchial Tree and Summary of Its Histologic Features
FIGURE 18.20
Photomicrographs of emphysema and pneumonia. a. This pho w ith red blood cells. Pathologists recognize this stage as the red
tomicrograph from the lung of an individual with emphysema hepatization stage of the pneumonia. At this stage, the affected
shows the partial destruction of interalveolar septa, resulting in portion of the lung on gross examination appears red (because of
permanent enlargement of the air spaces. Note that the changes enlarged capillaries), firm (because of the lack of air spaces), and
in the lung parenchyma are accompanied by thickening of the heavy (because of the presence of exudate within the alveoli); the
wall of the pulmonary vessels (arrows) and the presence of nu term hepatization stems from the tissue's resemblance to the liver.
merous cells within the air spaces. Th ese cells are the alveolar x 240. inset. Part of an alveolus at a higher magnification. Note
macrophages and are shown at higher magnification in Figure the enlarged, congested capillary within the alveolar septum. The
18.21. X 240. b. This photomicrograph from the lung of an individ air space is filled with neutrophils and red blood cells. The lower
ual in the early stages of acute pneumonia (inflammation of the right corner shows early organization of the intra-alveolar exu-
lung). Note that the air spaces are filled with exudate containing date; observe that the developing fibrin network contains en
white blood cells (mainly neutrophils), red blood cells, and fibrin. trapped neutrophils and several red blood cells. x 420.
The capillaries in the alveolar septum are enlarged and congested
590 CHAPTER 1 8 Rcspimlory Syslem
'!LYMPHATIC V_E~S_ELS
A dual lymphatic drainage of the lungs parallels the dual
blood supply. One set of lymp hatic vessels drains the
parenchyma of the lung and follows the ai r passages to the
hilum. Lymph nodes are found along the route of the larger
FIGURE 18.21
lymphatic vessels. A second set of lymphatic vessels drains
Photomicrograph of alveolar macrophages. This high-magnification
the surface of the lung and travels in the connective tissue
photomicrograph shows the structure of the alveolar septum and the
of the visceral pleura, a serous membrane consisting of a
lumen of an alveolus containing alveolar macrophages and red blood
cells. The cytoplasm of the alveolar macrophages, when they are surface mesothelium and the underlying connective tissue.
present in significant numbers, often contains the brown pigment he-
mosiderin from phagocytosed red blood cells. These hemosiderin-
lad en macrophages (often called "heart failure cells") are typically 9 NERVES
found in heart disease, mostly left ventricular failures that cause pu l-
monary congestion and edema. This results in enlargement of the Most of the nerves that serve the lung are not visible at the
alveolar capillaries and small hemorrhages into the alveoli. x560. level of the light microscope. They are components of the
sympathetic and parasympathetic divisions of the auto-
nomic nervous system and mediate reflexes that modify the
dimensions of the air passages (and blood vessels) by con-
\I BLOOD SUPPLY traction of the smooth muscle in their walls.
B
Figure 1, olfactory mucosa, human, Azan x 75. ever, it is typically thicker. Note the resp iratory epithe liu m
T his low-magnificati on orientation micrograph shows (REp) included in the lower right of the micrograph. T he
part of the wall of the nasal cavity. The olfacto ry mucosa feature that is most useful in identifyi ng olfactory mucosa
(OM ) and adjacent e thmoid bone (EB) are indicated. The is the presence o f numero us large, unmyel inated nerves (N)
olfactory mucosa is directly attached to the bone tissue; no a nd exte nsive olfactory (Bowman's) glands ( BG) in the
submucosa is present. In thi s specime n, however, the mu- connect ive tissue of the mucosa. Note that the adj acent res-
cosa is separated f rom the bo ne ti ssue because of shrinkage, piratory mucosa lacks the nerves and exhibits a relative
a frequently encountered artifact. The olfac to ry epithe lium paucity of glands.
(OEp) is pseudostratified, li ke respiratory e pithelium ; how-
B
may someti mes be observed extendi ng basally. The basal
At this hi gher magnificati on, it is possible to distingui sh
cells (BC), the least numerous of the principal cell types,
in a general way the three principal cell types of the olfac-
are characterized by the ir small round nuclei and scant cy-
tory epi thelium o n the basis of nuclear location and ap-
toplasm. They are irregul arly spaced and lie in proximity to
pearance, as well as by certain cytoplasmi c characteristics.
the basement membrane.
For example, the nuclei of the s upporting cells (SC) are re l-
T he lamina propria contains numerous blood vessels
atively dense and are located closest to the epithe lial sur-
(capillaries [C), veins [V}), ly mphatics, olfactory nerves
face. They are arranged in an almost discrete single layer.
(N), and olfactory (Bowman's) glands (BG). T he Bow man's
T he supporting cell has a cylind rical shape and extends
gla nds are branched tubuloalveolar structures. They exhi bi t
from the basement membrane th rough the full thickness of
a very small lumen (arrows). T he d uct ele ments extend
the e pi thelium. Immediately beneath this layer are the cell
fro m the secretory portion of the g land begi nning in close
bodi es of the olfactory receptor cells (OC). T hey lie at dif-
proxim ity to the overlying e pithelium (arrowhead) and pass
ferent levels w ithin the thic kness of the epithelium. C areful
directly through the e pi the lium to deliver their secretions at
exa minatio n of the nuclei of these bipolar neuro nal cells re-
the surface. T he ducts a re very short, making it difficult to
veals that they contain more euchro matin th an the nuclei o f
ide ntify them. T he very thin axonal processes (AP) of the
the supporting cells and ofte n ex hibit severa l nucleo li. Tn
olfac tory cells are someti mes ev ident wit hin the lami na
thi s preparati o n, the nucleoli appear as small round red
propri a prior to being ensheathed by Schwann cells to form
bodi es. In some cases, particul arl y when there is shrinkage,
the prom ine nt olfactory nerves. T he nuclei present withi n
the thin tapering dendritic process that exte nds to the olfac-
the o lfacto ry nerves represent Schwan n cell nuclei (SeC).
tory surface may be observed. S imilarly, an axonal process
KEY
A (Fig. 1), artery ES, ethmoid s inus SC, support ing cell nuclei
AP, axonal process N, olfactory nerves SeC, Schwar111 cell nuclei
nc, basal cells OC, olractory cells V (Fig. 2), vei n
BG, Bowman's glands OE p, olfactory epitheliu m arrows, lumina of Bowman's glands
C, capillary OM, olfac tory mucosa arrowhead, duct or a Bowman's gland en-
EB, ethmoid bone RE p, respi ratory epithel ium teri ng epithe lium
592
C HAPTER 18 Respiratory Syslew 59 5
Figure 1, larynx, monkey, H&E x 15. fold (VnF) or, sometimes, the false vocal fold. Be low and
The vocal folds are ridge-like structures that are oriented lateral to the vocal folds are the vocalis muscles (VM).
ITO in an anteroposterior (ventral-dorsal) direction. In frontal
secti ons, the vocal folds (VF) are cross-sectioned, g iving
Within the vocal fo ld is a considerable amount of e lastic
material, although it is usually not evident in routine H&E
the appearance seen here. The two vocal folds and the space preparations. This elastic material is part of the vocal liga-
between them constitute the glottis. Just above each vocal ment. It lies in an anteroposterior direction within the sub-
fold is an elongated recess called the ventricle (V), and stance of the vocal fold and plays an important role in
above the ventricle is another ridge called the ventricular phonation.
Figure 2, larynx, monkey, H&E x 160. Here, the contact between surfaces is considerable. Late r-
The surfaces of a vocal fold and the facing ventricular ally, the surfaces consist of stratified columnar epithelium
ITO fold within rectangle 1 in Figure 1 are turned 90 clockwise
and shown at highe r magnification in this figure. Medially,
(SCE). The contact between these surfaces is less wearing.
Small glands (GI) are in the lamina propria o f the laryngeal
both are lined by stratified squamous epithelium (SSE). mucosa.
Figure 3, larynx, monkey, H&E x 160. the stratified columnar epithelium (SCE), with its columnar
Rectangle 2 iJl Figure 1 is shown at higher magnification surface cells. The lamina propria consists of loose connec-
ITO in this figure. It shows the junction between the stratified
sq uamous epithelium (SSE), with its fl at surface cells, and
tive tissue in which glands (GI) are present.
Figure 4, larynx, monkey, H&E x 160. is needed to make the assessment. The additional informa-
Just below the portion of the larynx shown in Figure 1, tion is the presence of cilia on the pseudostratified colum-
the epithelium changes agai n, giving way, below, to the cil- nar epi thelium; this epithelium is typically ciliated. Al-
iated pseudostratified columnar epi the lium ( PSE) shown though not evident in the photomicrographs, note that
here. Note the cylinders of cytoplasm that clearly indicate stratified columnar epithelium has a very limited distribu-
the columnar nature of the surface cells. In the upper part of tion, usually occurring between stratified squamous epi the-
the figure, the epithe lium is stratified columnar; in the lower liUin and some othe r epithelial types (e.g., pseudostrati fied
part of the fig ure, it is pseudostratified columnar. This dis- columnar he re or simple columnar at the anorectal junction,
tinc tion is difficult to make from the examination of a sin- Plate 60).The lami na propria is a loose cellular connective
gle sample such as that shown here, and other information tissue, and it also shows some glands (Gl).
KEY
Gl, glands SSE, stratified squamous epithelium VM, vocal is muscles
.PSE, pseudostratified columnar epi thelium V, ven tricles VnF, ventricu lar folds
SCE, stratified columnar epithelium VF, vocal folds
594
CHAPTER 18 Respirntory Syste111 59 7
Figure 1, trachea, human, H&E x90. clear ovoid spaces in the respiratory epithe lium. A thin lam-
Figure 2, trachea, human H&E x 65. (Gl) are ev ident beneath the submucosa. The ends of the
Figure 3, trachea, human, H&E x 250; inset x 500. of the basement membrane (Bm) are more easily seen here
KEY
Ad, adi pose tissue GC, goblet cells N, nuclei of goblet cells
BB, brush border G I, g lands SM, submucosa
Hm, basement membrane IC, inflammatory cells TC, tracheal cartilage
C, cilia LN, lymphatic nodule TM, trachealis muscle '3 ... .
EP, epitheli um LP, lamina propria V, vei n
596
C H APTE R 18 Respirnlory System 59 9
Figure 1, bronchiole, H&E x75. magnification, not conspicuous. Neverthe less, it is present
A typical bronchiole is shown here. C haracteristically, and separates the muscle into bundles (i.e., the muscle layer
blood vessels (B V) are adjacent to the bronchiole. The mai n is not a single continuous layer). The connective tissue con-
features of the bronc hio la r wall that are evide nt in the fig- tai ns collagenous and some elastic fibe rs. Glands are not
ure are bundles of smooth muscle (SM) and the lining ep- present in the wall of the bronchiole. Surroundi ng the bron-
itheli um (shown at hi gher magnification in Plate 69). chi ole, comprising most of the lung substance, are the air
Higher magnification would reveal that the epithelium is spaces or alveoli of the lung.
ciliated. The connective tissue is mi nimal and, at this low
Figure 2, bronchiole and respiratory bronchioles, ( BV) and a nodule of lymphocytes (L) a re adjacent to the
H&E x 75. bronchiole.
In trus fi gure, a short length of a bronc hiole (B) is shown T he respiratory bronchi ole has a wall composed of two
longitudinally sectioned as it branc hes into two respiratory components: O ne consists of recesses that have a wa ll sim-
bronchioles (RB). The last portion of a bronchiole that leads ilar to that of the alveoli and are thus capable of gas ex-
i nto respiratory bronchioles is called a termi nal bronc hiole. cha nge; the other has a wall formed by small cuboidal cells
It is not e ngaged in exchange of air with the blood; the res- that appem to rest on a small bundle of eosinophilic mate-
piratory bro nchiole does e ngage in air exchange. Arrows rial. This is smooth muscle surrounded by a thin investment
mark the place where the terminal bronchiole ends. Not un- of connective ti ssue. Both of these components are shown
commonly, as shown here, carti lage (C) is fo und in the at hi ghe r magnification in Plate 69.
bronchiolar wall where branching occurs. Blood vessels
Figure 3, alveoli, H&E x75. The outer surface of lung ti ssue is the serosa (S); it con-
ducts (A D).
KEY
AD, alveolar ducts C, cartilage S, serosa
AS, alveolar sacs L, nodule of lymphocytes SM, smooth muscle
B, bronchi ole RB, respiratory bronchio le arrows, end of terminal bronchiole
BV, blood vessels
598
CHAPTER 18 Rrspimtory Syslr111 60 I
Respiratory bronchioles continue to divide to form alveolar ducts, passages lined solely with rows o f a lveoli that have ri ngs
of smooth muscle in knob-like intera lveolar septa. The a lveolar ducts terminate in alveolar sacs, e nlarged spaces surrounded
by c lusters of alveoli that o pen into the spaces. The al veoli are lined with type I alveolar cells, extremely thin squamous cells
that cover abo ut 95% of the al veolar sutface, and with type II alveola r cells, c uboidal cells that secrete swfactant, a surface-
active agent that reduces surface tension at the air-epithe lium surface. T he tissue between adjacent alveol i is called the alve-
olar septum. Tills consists of the a lveolar epitheUal cell s and their basal lamina, the basal lamina of the underlying capillary
endothe lium and the endothe lial cells, themselves, and any other co nnective tissue eleme nts that may lie between the two basal
laminae. The alveolar septum is the site of the air- blood barrier:
Figure 1, terminal bronchiole, H&E x550. ole, the e pithelium may include cuboidal or low columnar
Figure 2, respiratory bronchiole, H&E x550. bro nchiole except that cuboidal Clara cells instead of
A c
Figure 4, alveolus, H&E xSOO. tion of the a lveolar-capill ary complex. Elsewhere, connec-
\ .,.___ sc
EB The alveo lar wall is shown in Fig ure 4. The central com-
po nent of the wall is the capilla ry (C) a nd , in certain loca-
tions, assoc iated connective tissue. On each side, where it
faces the alveolus (A ), a flat sq ua mous cell is interposed be-
tive tissue is interposed between the pneumocyte type 1 cell
and the e ndothelial cell of the capillary; each of these ep-
ithelia l cells retains its own basal la mina.
A second cell type, the pne umocyte type II cell or septa l
tween the capillary and the air s paces. This is a pne umocyte cell (SC), also lines the a lveolar air s pace. This cell typ i- A
ty pe J cell. In some places, the type 1 cell is separated fro m call y di splays a rounded (rather than fl attened) shape, and
the capi llary endothe lia l cell by a single basa l la mina the nuc leus is surrounded by a no ticeable amo un t of cyto-
shared by the two cells. This is the thin porti o n of the alve- plasm, some of which may appear c lear. The septal cell pro-
o lar-capillary complex, readily seen in the upper part of the duces a surface-acti ve agent different fro m that of the Clara
fi gure (a rrows). Gas exchange occurs throug h the th in por- cell, which a lso acts in permitting the lung to expand.
KEY
A, alveolus PsEp, pseudostratified squamous epithelium arrows (Fig. 4 ), thin portion of
C, capillary SC, septal cell alveolar-capillary complex
CC, Clara cells SM, s mooth muscle diamond, j unction between pseud ostrati fied
colu mnar epi theli um and C lara cells
600
19
BOX 19.4. Functional Considerations: Structure and Function of Aquaporin
Water Channels 619
BOX 19.5 . Functional Considerations: Hormonal Regulation of Collecting Duct
Function 622
9 GENERAL STRUCTURE mately 90 to 95% of the blood passing th.r ough the kidney
is in the cortex; 5 to 10% is in the medulla.
capsule
OF THE KIDNEY
The cortex is characterized by renal corpuscles and their
The kidneys are large, reddish, bean-shaped organs located
associated tubules
on either side of the spinal column in the retroperitoneal
space of the posterior abdominal cavity. They extend from
The cortex consists of renal corpuscles along with the
the 12th thoracic to the 3rd lumbar vertebrae with the
right kidney positioned slightly higher. Each kid,ney meas-
convoluted and straight tubules of the nephron, the col-
cortex
lecting tubules, collecting ducts, and an extensive vascular
ures approximately 10 em long X 6.5 em wide (from con-
supply. The nephron is the basic functional unit of the kid-
cave to convex border) X 3 em thick. On the upper pole of
ney and is described below. The rena l corpuscles are spher-
each kidney, embedded within the renal fascia and a thick
ical structures, barely visible with the naked eye. They con-
protective layer of perirenal adipose tissue, lies an adrenal
stitute the beginning segment of the nephron and contain
gland. The medial border of the kidney is concave and
a unique capillary network called a glomerulus.
contains a deep vertica l fissure, called the hilum, through
Examination of a section cut through the cortex at an
which the rena l vessels and nerves pass and through which outer stripe
angle perpendicular to the surface of the kidney reveals a
the expanded, funnel-shaped origin of the ureter, called the
renal pelvis, exits. A section through the kidney shows the
relationship of these structures as they lie just within
series of vertical striations that appear to emanate from the
medulla (see Fig 19.1). These striations are the medullary outer
--- --- ---
rays (of Ferrein). Their name reflects their appearance, as medulla inner stripe
the hilum of the kidney in a space called the renal sinus
the striations seem to radiate from the medulla. Approxi-
(Fig. 19.1 ). Although not shown in the illustration, the
space between and around these structures is filled largely
with loose connective tissue and adipose tissue.
mately 400 to 500 medullary rays project into the cortex
rom the medulla.
--- --
FIGURE 19.2
Photomicrograph of human kidney capsule. This photomicrograph Each medullary ray is an aggregation of straight tubules and
Capsule of a Mallory-Azan-stained section shows the capsule (cap) and part collecting ducts
of the underlying cortex. The outer layer of the capsu le (OLC) is com-
The kidney surface is covered by a connective tissue cap- inner
posed of dense connective tissue. The fibroblasts in this part of the
Each medullary ray contains straight tubules of the medulla
sule. The capsule consists of two distinct layers: an outer capsule are relatively few in number; their nuclei appear as narrow,
nephrons and collecting ducts. The regions between
layer of fibroblasts and collagen fibers, and an inner layer elongate, red-staining profiles against a blue background represent-
medullary rays contain the renal corpuscles, the convoluted
ing the stained collagen fibers. The inner layer of the capsule (ILC)
consists of large numbers of myofibroblasts whose nuclei appear as
tubules of the nephrons, and the collecting tubules. These
round or elongate, red-stain ing profiles, depending on their orienta- areas are referred to as cortical labyrinths. Each nephron
tion within the section. Note that the collagen fibers in this layer are and its collecting tubule (which connects to a collecting papil la
renal column
relatively sparse and that the myofibroblast nuclei are more abundant duct in the medullary ray) form the uriniferous tubule. FIGURE 19.3
than those of t11e fibroblasts in the outer layer of the capsule. x 180. Diagram of two types of nephrons in the kidney and their associated
The medulla is characterized by straight tubules, collecting collecting duct systems. A long-looped nephron is shown on the left,
ducts, and a special capillary network, the vasa recta and a short-looped nephron is shown on the right. The relative posi-
tion of the cortex, medulla, papilla, and capsule are indicated. Tile in-
with a cell ular component of myo.fibrobl asts (Fig. 19.2). The straight tubules of the nephrons and the collecting verted cone-sllaped area in the cortex represents a medullary ray.
ducts continue from the cortex into the medulla. They are The parts of the nephron are indicated by number: 7, renal corpuscle
The contractility of the rnyofibroblasts may aid in resisting
accompanied by a capillary network, the vasa recta, that including the glomeru lus and Bowman's capsule; 2, proximal convo-
renal volume and pressure variations that can accompany varia-
minor runs in para llel with the various tubules. These vessels rep- luted tubule; 3, proximal straight tubule; 4, descending thin limb;
artery tions in kidney function. Its specific role, howeve1; is not
calyx 5, ascending thin limb; 6, thick ascending limb (distal straight tubule);
known. The capsule passes inward at the hilum, where it resent the vascular part of the countercurrent exchange
renal 7, macula densa located in the final portion of the thick ascending
forms the connective tissue covering of the sinus and be- system that regulates the concentration of the urine.
limb; 8, distal convoluted tubule; 9, connecting tubule; 9', collecting
comes continuous with the connective tissue forming the The tubules in the medulla, because of their arrange- tubule that forms an arch (arched collecting tubule); 70, cortical col-
medulla
wal.ls of the calyces and renal pelvis (see Fig. 19.1 ). ment and differences in length, collectively form a number lecting duct; 11, outer medullary collecting duct; and 72, inner
of conical structures called pyramids. Usually 8 to 12 but medullary collecting duct. (Modified from Kriz W, Bankir L. Kidney Jnt
as many as 1 8 pyramids may be present in the human kid- 1988;33:1-7.)
Cortex and Medulla ney. The bases of the pyramids face the cortex, and the
Examination with the naked eye of the cut face of a fresh, apices face the renal sinus. Each pyramid is divided into an
hemisected kidney reveals that its substance ca n be divided outer medulla (adjacent to the cortex) and an inne1' The renal columns represent cortical tissue contained within
into two distinct regions: medulla. The outer medulla is further subdi vided into an the medulla
minor calyx
inner stripe and an outer stripe. The zonation and stripes
major calyx
Cortex, the outer reddish brown part are readily recognized in a sagittal section through the The caps of cortical tissue that lie over the pyramids are
Medulla, the much lighter-colored inner part pyramid of a fresh specimen. They reflect the Jocation of sufficiently extensive that they extend peripherally around
FIGURE 19.1
Diagram of kidney structure. The diagram represents a hemisection T he color seen in the cut surface of the unfixed kidney re- distinct parts of the nephron at specific levels within the the lateral portion of the pyramid, forming the renal
of a kidney, revealing its structural organization. flects the distribution of blood in the organ. Approxi- pyramid (Fig. 19.3) . columns (of Bertin). Although renal columns contain the
606 CHAPTER 19 Uriunry System CHAP TER 19 Uriunry System 607
same comp onents as the rest of th e cortical tissue, they are iza tio n of the k idney is conspicuo us in the developing fe tal General Organization of the Nephron
regarded as p art of the medulla. In effect, the amount of kidney (Fig . 19 .5). Each lobe is reflected as a convexity on
cortical tissue is so extensive that it "spills" over the side the outer surface of the organ, but they usuall y disappear The nephron consists of the renal corpuscle and a tubule
of the pyramid much as a large scoop of ice cream extends after birth. The surface convexities typical of the fe tal kid- system
beyond and overlaps the sides of a n ice cream con e. ney may persist, however, until the teenage years a nd, in
The apical portion of each pyramid, which is known as some cases, into adulthood. Each human kidney contains As stated a bove, the renal corpuscle represents the be-
the papilla, projects into a mino1' calyx, a cup-shaped 8 to 1 8 lobes. Kidneys of some animals p ossess o nly one ginning of the nephron. It consists of the glomerulus, a tuft
structure that represents an extension of the renal pel vis. pyramid; these kidneys are classified as unilobar, m con- o f capillaries composed of 10 to 2 0 capillary loops, sur-
The tip of the papilla, a lso known as the area cribrosa, is trast to the multilobar kidn ey of the human. rounded by a double-layered epithelial c up, the renal or
p erforated by the openings of the collecting ducts (Fig. Bowman's capsule. Bowman's capsule is the initial portion
19.4). The minor calyces are branches of the two or t hree A lobule consists of a collecting duct and all the nephrons that of the nephron where bloo d flow ing through the glomeru-
major calyces that in turn are major divisions of the renal it drains lar capillaries undergoes filtration to p roduce the glomeru-
pelvis (see Fig. 19.1 ). lar ultrafiltrate. The glomerular capillaries are supplied by
The lobes of the kidney are fmther subdivided into lob- a n afferent arteriole and are drained by an efferent arteri-
Kidney Lobes and Lobules ules consisting of a central med ullary ray and surrounding ole tha t then branc hes, forming a new capillary network to
cortical m a terial (Fig. 19.6). Although the center or axis su pply the kidney tubules . The site where the afferent and
The number of lobes in a kidney equals the number of of a lobule is readily identified, the bou ndaries between efferent arterioles penetrate and exit from the parietal layer
medullary pyramids adjacent lobules are not obviously demarcated from one of Bowman 's capsule is called the vascular pole. Opposite
another by connective tiss ue septa. The con cept of the lob- this site is the urinary pole of the renal corp uscle, where the
Each medullary pyramid and the associated cortical tis- ule has an important physiologic basis; the medullary ray proximal convoluted tubule begins (see Fig. 19 .6).
su e a t its base and sides (one h alf of each adjacent renal containing the collecting du ct for a g roup of nephrons Continuing from Bowman's capsule, the remaining parts
column) constitutes a lobe of the kidney. The loba r organ- that drain into that duct constitutes the renal secretory of the nephron (the tubular parts) are
Proximal thick segment, consisting of the proximal con-
voluted tubule (pars convoluta) and th e proximal
straight tubule (pars recta)
Thin segment, which constitutes the thin part of the
loop of Henle
FIGURE 19.5
Distal thick segment, con sisting of the distal straight
Photomicrograph of fetal kidney. This photomicrograph of a H&E-
tubule (pars recta) a nd the distal convoluted tubule
stained human fetal kidney shows the cortex, the medulla, and two
associated pyramids. Note each surface convexity corresponds to a (pars convoluta)
kidney lobe. During postnatal life the lobar convexities disappear and The distal convoluted tubule connects to t he collecting
the kidney then exhibits a smooth surface. X 30. tubule, often through a connecting tubule, thus forming
the uriniferous tubule, i.e., the nephron plus collecting
tubule (see Fig. 19.3).
unit. It is the equivalent of a glandular secretory unjt or
lobule.
lUbes of the Nephron
The Nephron The tubular segments of the nephron are named according to
the course that they take (convoluted or straight), location
The nephron is the structural and functional unit
(proximal or distal), and wall thickness (thick or thin)
of the kidney
Beginn ing from Bowma n 's capsule, the sequen tial parts
The nephron is the fundamental structural a nd func- of the nephron co nsist o f the following tubules:
tional un it of the kidney (see Fig. 19.3). Each human kid-
ney contains approximately 2 million nephrons. Nephrons Proximal convoluted tubule originates fro m the urinary
are responsible for the production of urine and correspond p o le of Bowman's capsule. It follows a very tortuou s o r
to the secretor y part of other g lands. The collecting ducts convoluted course and then enters the medullary ray to
a re responsible for the final con centration of the urine and continue as th e proximal straigh t tubul.e.
FIGURE 19.4 are analogous to the d ucts of exocrine glands that modify Proximal straight tubule, commonly referred to as the
Renal papilla and calyx. a. This scanning electron mi crograph shows openings is designated the area crib rosa. (Courtesy of c. C;-aig Tisher.) the concentration of the secretory produc t. Unlike the typ- thick descending limb of the loop of H enle, descends
tile conical structure that represents tile renal papilla, projecting into b. Photomicrograph of a HaE-sta ined specimen of tile papilla, show- ical exocrine gland in which the secretory and duct por- into th e medulla.
tile renal calyx. Tile apex of tile papilla contains openings (arrows) of ing the distal portion of tile collecting ducts opening into the minor tions a rise from a single epithelial outgrowth, nephrons Thin descending limb is the continu a tio n of the proxi-
tile collecting ducts (of Bellini). These ducts deliver urine from the pyr calyx. x 120. and their collecting tu bules a rise from separate primor dia mal straight tubule w ithin the medulla. It makes a hair-
amids to the minor calyx. Tile surface of tile papilla containing the a nd only later become conn ected. pin turn and returns towa rd the cortex.
608 CHAPTER 19 I Urillnl)' Sy stem CHAPTER 19 UriHtny System 609
distal convoluted tubule the epithelial cells of the tubule adjacent to the afferent collecting ducts. These ducts travel to the apex of the pyra-
arteriole of the glomerulus are modified to form the mid, where they merge into larger collecting ducts (up to
macula densa. The distal tubule then leaves the region 200 f!.m), the papillary ducts (ducts of Bellini) that open
section enlarged of the corpuscle and becomes the distal convoluted into the minor calyx (see Fig. 19.4). The area on the
medullary at right
pyramid tubule. papilla that contains the openings of these collecting ducts
Distal convoluted tubule is less tortuous than the prox- is called the area cribrosa.
imal convoluted tubule; thus, in a section showing the In summary, the gross appearance of the kidney
cortical labyrinth, there are fewer distal tubule profiles parenchyma reflects the structure of the nephron. The re-
macula densa
cortex than proximal tubule profiles. At its termination, the nal corpuscle and the proximal and the distal convoluted
distal convoluted tubule empties into a collecting duct tubules are all located in and make up the substance of
that lies in the medullary ray via either an arched col- the cortical labyrinths. The portions of the straight prox-
lecting tubule or a shorter tubule simply called the con- imal and straight distal tubu les and the descending th in
C:::t:=~- medullary necting tubule. and ascending thin limbs of the loop of Henle in the cor-
rays medullary ray
(contains only tex are located in and make up the major portion of the
straight tubules) The loop of Henle forms the entire U-shaped portion of a medullary rays . The thin descending and thin ascending
collecting tubule nephron limbs of the loop of Henle are always located in the
medulla. Thus, the arrangement of the nephrons (a nd the
The proximal straight tubule, the thin descending limb c9llecting tubules and ducts) accounts for the character-
with its ha irpin turn, the thin ascending limb, and the dis- istic appearance of the cut surface of the kidney, as can
tal straight tubule are collectively called the loop of Henle. be seen in Figure 19.2.
ascending In some nephrons, the thin descending and ascending seg-
and
descending
ments are extremely short; therefore the hairpin turn may
limbs of loops be made by the distal straight tubule. Filtration Apparatus of the Kidney
of Henle
The renal corpuscle contains the filtration apparatus of the
Types of Nephrons kidney
Several types of nephrons are identified, based on the loca-
tion of their renal corpuscles in the cortex (see Fig. 19.3 ): The renal corpuscle is spherical and has an average di-
ameter of 200 p,m. It consists of the glomerular capillary
Subcapsular or cortical nephrons have their renal cor- tuft and the surrounding visceral and parietal epithelial
puscles located in the outer part of the cortex. They have layers of Bowman's capsule (Figs. 19.7 and 19.8) . The fil-
short loops of Henle, extending only into the outer tration apparatus, enclosed by the parietal layer of Bow-
meduJJa. They are typical of the nephrons described man's capsule, consists of three components:
above, wherein the hairpin turn occurs in the distal
straight tubule. Endothelium of the glomerular capillaries, which pos-
]uxtamedullary nephrons make up about one-eighth sesses numerous fenestrations (Fig. 19.9). These fenes-
of the total nephron count. Their renal corpuscles oc- trations are larger (70 to 90 nm in diameter), more nu-
cur in proximity to the base of a medullary pyramid. merous, and more irregular in outline than fenestrations
T hey have long loops of Henle and long ascending thin in other capillaries. Moreover, the diaphragm that spans
segments that extend well into the inner region of the the fenestrations in other capillaries is absent in the
FIGURE 19.6 pyramid. These structural features are essentia l to the glomerular capillaries . Endothelial cells of glomerular
Diagrams and photomicrograph of an adult human kidney. Tile dia- long loop of Henle that extends deep into the medulla. Both urine-concentrating mechanism, which is described capillaries possess a large number of aquaporin-1
gram in the upper left is a hemisection of the adult human kidney in- nephrons drain into the collecting tubules in the medullary ray. The below. (AQP-1) water channels that allow the fast movement of
cluded for orientation. Tile diagram on the right represents an en- photomicrograph shows a section of the cortex. It is organized into a Intermediate or midcortical nephrons have their rena l water through the epitheliurn.
larged portion emphasizing the relationship of two nephrons and series of medullary rays containing straight tubules and collecting corpuscles in the midregion of the cortex. Their loops of Glomerular basement membrane (GBM), a thick (300
their collecting tubules and ducts (yellow) to the cortex and medulla. tubu les and between them the cortical labyrinths containing the re- Henle are of intermediate length. to 350 nm) basal lamina that is the joint product of the
The upper nephron, a midcortical nephron, extends only a short dis- nal corpuscles and their associated proximal and distal convo luted
endothelium and the podocytes, the cells of the visceral
tance into the medulla and possesses a short thin segment in the tubules. A kidney lobule consists of a medullary ray at its center and
loop of Henle. The lower nephron, a j uxtamedullary nephron, has a half of t11e adjacent cortical labyrinth on either side. x60. Collecting Thbules and Ducts layer of Bowman's capsule. Because of its thickness, it is
prominent in histologic sections stained with the peri-
The collecting tu buies begin in the cortical labyrinth, as ei- odic acid-Schiff (PAS) procedure (see Fig. 1.2, page 7) .
Thin ascending limb is the continuation of the thin de- tubu le ascends through the medull a and enters the cor- ther connecting tubules or arched collecting tubules, and The GBM is the principal component of the fi ltration
scending limb after its hairpin turn. tex in the medullary ray to reach the vicinity of its renal proceed to the medullary ray where they join tl1e collecting barrier.
Distal straight tubule, which is also referred to as tbe corpuscle of origin . The distal straight tubule then ducts. The collecting ducts within the cortex are referred Viscera/layer of Bowman's capsule, which contains spe-
thick ascending limb of the loop of Henle, is the con- leaves the medullary ray and makes contact w ith the to as cortical collecting ducts. When cortical collecting cialized cells called podocytes or visceral epithelial cells.
tin uation of the thin ascending limb. The distal straight vascular pole of its parent renal corpuscle. At this point, ducts reach the medulla they are referred to as medullary These cells extend processes around the glomeru lar cap-
6( 0 CHAPTER 1 9 Llriua ry Sysiem
efferent
arteriole
foot processes
(pedicels) ot ~-As~~~
podocytes
glomerular
capi llaries
urinary space
illaries (Fig. 19.1 0). The podocytes arise during embry- microscope (SEM) (Figs. 19.11, a and b) . The elongated
onic development from one of the blind ends of the de- spaces between the interdigitating foot processes, called
veloping nephron through invagination of the end of the filtration slits, are about 25 nm wide and allow the ul-
tubu le to form a double-layered epithelial cup. The inner trafiltrate from the blood to enter Bowman's space. T he
cell layer, i.e., the viscera l cell layer, lies in apposition to foot processes contain numerous actin filaments that are
a capillary network, the glomeru lus, which forms at this thought to help regulate the size and patency of the fi l-
site. T he outer layer of these cells, the parietal layer, tration slits. An additional fac tor that may influence the
forms the sq uamous cells of Bowman's capsule. The cup passage of substances through the filtration slits is the
eventual ly closes to form th e spherical structure con- presence of a thin membran e simil ar to the diaphragm of
taining the glomerulus. As they differentiate, the capillary fenestrations. This membrane, the (iltrati01~
podocytes extend processes around the capillaries and slit membrane, spans the slits (Fig. 19 .12, inset). The fi l- FIGURE 19.9
develop numerous secondary processes called pedicels tration apparatus may thus be described as a semiper- Scanning electron micrograph of the interior surface of a glomeru-
or foot processes. The foot processes interdigitate with meable barrie1' having two discontin uous cellular layers lar capillary. The wall of the capillary s11ows horizontal ridges formed
foot processes of neighboring podocytes, a feature that applied to either side of a continuous extracellular layer, by the cytoplasm of the endothelial cell. Elsewhere, fenestrations are
can be clearly demonstrated with the scanni ng electron the basal lamina. seen as numerous dark oval and circular profiles. X5,600. (Courtesy
of C. Craig Tisl1er.)
6 11
61'2 CHAPTER 1 9 Uriua1y Syste111 C HAPTER 19 Uriuary Syste111 6I3
endothelia l cell
FIGURE 19.10
Schematic diagram showing the relationship between the intra- in the same compartment as the endothelium and that they can be
glomerular mesangial cells and the glomerular capillaries. The intimately associated with the basal lamina as well as with the en-
mesanglal cell and its surrounding matrix are enclosed by the basal dothelial cells. (Modified from Sakai T, Krlz W. Anat Embryo/ 1987;
lamina of the glomeru lar capillaries. Note that the mesanglal cells are 176:373-386.)
The glomerular basement membrane acts as a physical barrier work that acts as a ph ysical filter. T he laminin and other
and an ion-selective filter proteins present in th e lamina rara interna and externa
are involved in the attachment of the endothelial cells
The G BM conta ins type IV collagen, sialoglycoproteins, and podocytes to the GBM.
and other nonco llagenous glycoproteins (e.g., laminin , 6-
The GBM restricts the movement of particles, usually pro-
bronectin, entactin), as well as proteoglycans and gly-
teins, larger than approximately 70,000 da ltons or 3.6 nm
cosaminoglycans, particula rly heparan sulfate (Fig. 19.13).
radius, e.g., albu min or hemoglobin. Although albumin is
These components a re localized in particular portions of
not a usual constituent, it may sometimes be found in urine,
the GBM:
indicating that the size of albumin is close to the effective
The Lamina rara externa, adjacent to the podocyte pore size of the filtration barrier. T he polyanionic gly-
processes. It is particularly rich in polyanio ns, such as cosaminoglycans of the laminae rarae restrict the movement FIGURE 19.11
heparan sulfate, that specificall y impede the passage of of anio nic particles and mo lecules across the GBM, even Scanning electron micrograph of a glomerulus. a. Low-magnification space between the interdigitating pedicels creates the slit pores.
negati vely charged mo lecules. those smaller than 70,000 da ltons. Despite the ability of the image reveal ing the tortuous course of the podocytecovered x 14,000. Inset. This higher magnification of the area in the rectangle
T he Lamina rara interna, adjacent to the capillary en- glomerular capillaries. x 700. b. A higher magnification of the area In reveals the slit pores and clearly shows that alternating pedicels be-
fi ltration barrier to restr ict protein , several grams of protein
the rectangle in a. Note the podocyte and Its processes embracing the long to the secondary process of one cell; the intervening ped icels be-
do thelium. Its molecular featu res are similar to those of do pass through the barrier each day. This protein is reab-
capillary wall. The primary processes (1) of the podocyte give rise to long to the adjacent cell. X6,000.
the lami na rara externa. sorbed by endocytosis in the proximal convoluted tubule.
secondary processes (2), which in turn give rise to the pedicels. The
The Lamina densa, the overlapping portion of the two The presence of significant amounts of a lbumin or hemoglo-
basa l laminae, sandwiched between the laminae rarae. It bin in the urine (albuminuria or hematuria) indicates phys-
conta ins type IV collagen, w hich is organized in to a net- ical or functional damage to the GBM. In such cases (e.g., di-
614 C HAPTE R 19 Uriunry Sysle111 CHAPTER 1 9 Uri11 nry Sysi<'HI 6I5
corpuscle along the vascular pole, where they are also des-
ignated as lacis cells and form part of w hat is ca lled the
juxtaglomerular apparatus (see Fig. 19.7).
Although all of the functions of mesangial cells are not
yet fully understood, the fo llowing functions have been
demonstrated :
is the major driving force fo r reabsorption of water in the BOX 19 .4 and with fewer and less complex lateral and basal-lateral
proxim al convoluted tubule. As in the intesti nal and gall- processes. The mitochondria are smaller than those of the
bladder epithelia, this process is dri ven by active trans- cells of the con voluted segment and are randomly distrib-
port of Na+ into the later a l intercell ular space. Active uted in the cytoplasm. There are fewer apical invaginations
transport of Na 1 is followed by passive diffusion of Cl- AQPs are a recently recognized family of small, hydrophobic,
and endocytotic vesicles, as well as fewer lysosomes.
to maintain electrochemica l neutra lity. T he accumula- transmembrane proteins that mediate water transport in the
tion of NaCI in th e latera l intercellular spaces creates an kidney and other organs. To date, 10 proteins have been char- Thin Segment of Loop of Henle
osmotic gradient th at draws water from the lumen into acterized and cloned. The molecular size of AQPs ranges from
the intercellular compartment. This compartment dis- 26 to 34 kDa. Each protein consists of six transmembrane do- As noted above, the length of the th.in segment varies with
tends as the amount of .fluid in it increases; the lateral mains arranged to form a distinct pore. Tile sites where AQPs the location of the nephron in the cortex. JuxtameduU ary
folds separate to al low this distension. are expressed implicate their role In water transport, such as nephrons have the lo ngest limbs; cortica l nephrons have
AQP-1, a sma ll (-30 kDa) transmembrane protein that renal tubules (water reabsorption), brain and spinal cord (cere- the shortest. Furthermore, various cell types are present in
functions as a molecul ar wa ter channel in the cell mem- brospinal fluid reabsorption), lacrimal apparatus (secretion and the thin segment. In the lig ht microscope it is possible to
resorption of tears), and eye (aqueous humor secretion and re-
brane of proxima l convoluted tubules . Movement of detect at least two kinds of'thin segment tubules, one wi th
absorption). Most AQPs are selective for the passage of water
water through these membra ne cha nnels does not re- a more squamous epithelium than the other. Electron mi-
(AQP-1, AQP-2, AQP-4, AQP-5, AQP-6, and AQP-8), whereas
quire the high energy of Na +JK+-ATPase pumps. Im- others, such as AQP-3, AQP-7, and AQP-9, called aquaglycero- croscopic examination of th e thin segments of various
munocytochemical methods can be used to demonstrate porins, also transport glycerol and other larger molecules in nephrons reveals further differences, namely, the existence
the presence of these proteins. addition to water. Prominent members of the AQP family in- of fou.r types of epithelial cells (Fig. 19.17):
clude
The hydrostatic pressure th at builds up in the distended Type I epithelium is found in the thin descending and as-
AQP-7, expressed in kidney (proximal convoluted tubules) cending limbs of the loop of Henle of short-looped
intercellular compartment, presumably aided by contrac-
and other cell types such as hepatocytes and red blood nephrons. It consists of a th in, simple epitheli um. The
tile activity of the actin fila ments in the base of the tubule
cells. cells have almost no interdigi tations with neighboring
cells, drives an essentially isosmotic fluid across the tubule AQP- 2, present in the terminal portion of the distal con- cells and few orga nelles.
basement membrane into th e renal connective tissue. Here, voluted tubules and in the epith elium of collecting tubules
the fluid is reabsorbed in to the vessels of the peritubular Type II epithelium, found in the thin descending limb of
and ducts. AQP-2 is under the regulation of antidiuretic
capillary networl~.
long-looped nephrons in the cortical labyrinth, consists
hormone (ADH) and is thus known as an ADH-regulated
of taller epithelium . Th ese cells possess abundant or -
water channel. Mutation of the AQP-2 gene has been
The proximal convoluted tubule also reabsorbs amino acids, linked to congenital nephrogenic diabetes insipidus. ganelles and have many small, blunt microvilli. The ex-
sugars, and polypeptides AQP-3 and AQP-4 have also been detected in the baso- tent of la teral interdigitation with neighboring cells
lateral cell surface of the light cells of kidney collecting va ries by species.
As in the intestine, the microvilli of proximal convoluted ducts as well in the gastrointestinal epithelium (AQP-3) Type III epitheUum, fo un d in the thin descending lim b in
and the brain and spinal cord (AQP-4). the inner medulla, consists of a thinner epithelium. The
tubule cells are co vered with a well-developed glyco calyx
that conta ins several ATPases, peptidases, and high con- Current research into the function and structure of the AQP
cells have a simp ler structure and fewer m icrovilli than
centrations of disaccha ridases. In a ddition to am ino acids proteins may lead to tile development of water channel type II epithelia l cells. Latera l interd igitations are absent.
and monosaccharides, the ultra filt.rate also conta ins small blockers that could be used to treat hypertension, congestive Type N epithelium, fo und at the bend of lo ng-looped
peptides and disaccharides. T he latter adsorb on the gly- heart failure, and brain swelling and to regulate intracranial or nephro ns an d thro ugh the entire thin ascending limb,
FIGURE 19.16
cocalyx for further digestion before inte rnalization of the Intraocular pressure. consists of a low, fl attened epithelium witho ut mi-
Electron micrograph of a proximal convoluted tubule cell. This sec-
tion is almost tangential and slightly oblique to the base of a proxi- res ulting amino acids and monosaccharides (including glu- crovilli . The cells possess few organelles.
mal convoluted tubule cell and the subjacent basal lamina and capil- cose). Also, as in the gut, amino acid and glucose resorp - The specific functional roles of the four cell types in the
lary. In the left part of the micrograph is the capillary endothelium tion depend on active Na transport. thin segment are no t yet clear, although this segment is pa rt
(En). Characteristically, the endothelium possesses numerous fenes-
of the counter current exchange system that functions in
trations (EnF), and in this plane of section, the fenestrations are seen Proteins and large peptides are endocytosed in the proximal via the intercellular compartment and th e interstitia l con- concentrating urine. M orphologic differences, such as mi-
en face, displaying circular profiles. The plane of section also makes
convoluted tubule nective tiss ue. crovilli, mi tochondria, and degree of cellular interdig ita-
the basal lamina (BL) appear as a broad band of homogenous mate-
Also, the pH of the ul trafi ltrate is modified in the prox- tion, pro bably reAect specific active or passive roles in this
rial. To the right of the basal lamina are the interdigitating basal
processes of the proximal tubule cells. The long, straight processes Deep tubular invaginations are present between the ll) i- ima l convolu ted tubule by the rea bsorption of bicarbonate process .
contain longitudinally oriented actin filaments (arrows). In this plane crovilli of the pr oxima l convoluted tu bule cells. Proteins in and by the specific secretion into the lumen of exogeno us
of section, the basal extracellular space appears as a maze between the ultrafiltrate, on reachi ng the tubule lumen, bind to the o rga nic acids and orga nic bases derived fro m the peritu- The thin descending and ascending limbs of the loop of Henle
the cellular processes. X 32,000. glycocalyx that covers the plasma mem brane of the invagi- bular capillary circulation. differ in structural and functional properties
nations. Then endocytotic vesicles containing the bound
protein bud from the in vagina tions a nd fuse in the apicaJ Studies of ultrafi ltrate entering the thin descend ing
jor proteins a re responsible for fluid reabsorption m the Proximal Straight Tubule
cytoplasm to form large protei n-conta ining early endo- Umb and leaving the thin ascend ing limb of the loop of
proximal convoluted tubules:
somes (see Fig. 19.1 5). These early endosomes are destined T he cells of the proximal straight tubule (i.e., the th ick de- H enle revea l d rama tic changes in its osmolality. The ul-
Na+fK+ -ATPase pumps, transmembrane proteins that to become lysosomes, and the endocytosed proteins are de- scending limb of the loop ofHenJe) ar e not as specia li zed for trafiltrate that enters the thin descending limb is isos-
a re locali zed in the lateral folds of the plasma membrane. graded by acid h ydro lases. T he a mino acids produced in abso rption as a re those of the proxima l convoluted tubule. motic whereas the ultrafi ltrate leaving the thin asce nding
T hey are res ponsible for the reabsorfJtion of Na 1 , which the lysosom al degradatio n a re recycled into the circulation T hey are shorte1; with a less we ll developed brush border limp is hypoosmotic to plasma. This change is achieved
.....
6JO CHAPTER 19 I llriH nry Sys iCIII CHA PTER 19 UriJW)' Sysl f lll 611
long-looped fluid in the medulla is hyperosmotic, water diffuses out and the lateral margins of the cells are indistinct. The nu- Distal Convoluted li.lbule
nephron of, and salt diffuses into, the nephron at this site. The cleus is located in the apical portion of the cell and some-
cells of this limb do not actively transport significant times, especially in the straight segment, causes the cell to The distal convoluted tubule exchanges Na+ for K+ under al-
cortex
II-
' amount of ions; thus changes in osmolarity are the result
of passive movement of water into the peritubular con-
nective tissue and of salt and urea into tbe tlun descend-
ing limb.
bulge into the lumen. As noted above, these cells have ex-
tensive basal-lateral plications, and there are 11.umerous mi-
tochondria associated with these basal folds (Fig. 19.18).
They also have considera bly fewe r and less well developed
dosterone regulation
In the medulla, the p rin cipal interstitial cells resemble stance has been neither isolated nor characterized. In addi- of the med ulla from the corticom eduilary junction to the
myo.fibroblasts. They are oriented to the lo ng axes of the tion, prostaglandins and prostacyclin m ay a lso be synthe- papilla.
tubular structures and may have a rol e in compressing sized in the interstitium.
these structures. The cells contain prominent bundles of Vasa recta containing descending arterioles and ascending
actin filaments, abundant rough endoplasmic reticulum venules' act as countercurrent exchangers
(rER ), a well-developed Golgi complex, an d lysosom es. 9 HISTOPHYSIOLOGY
Prominent lipid droplets in the cytoplasm appear to in- OF THE KIDNEY For a n understanding of the countercurrent excha nge
crease and decrease in relation to the diuretic state. Some mechan ism, it is necessary to resume the description of the
The countercurrent multiplier system creates hyperosmotic
evidence suggests that t hese cells ma y secrete a hormone- renal ci rc ula tion at the point a t which the efferent a rterio le
urine
like material t hat reduces blood pressure, but this sub- leaves the renal corpuscle.
The efferent arterioles of the renal corpuscles of most of
The term countercurrent indica tes a flow of fluid in ad-
the cortex branch to form the ca pillary n etwork that sur-
jacent structures in opposite directions. The ability to ex-
rounds the tubula r portions of the n ephron in the cortex, the
crete hyperosmotic urine d epe nds on the countercurrent
peritubular capillary network. The efferent arterioles of the
multipliet system that involves three struct ures: juxtamedullary ren al corpuscles form several unbra nched ar-
Loop of Henle, w hich acts as a countercurrent multi- terioles tha t descend into the medullary pyramid. These ar-
FIGURE 19.19 plier. The ultrafiltrate m oves within th e descen ding limb tetiolae rectae make a hairpin turn deep in the medullary
Scanning electron micrograph of a collecting tubule. This micro
of the thi n segment of the loop toward the ren a l papilla pyramid and ascend as the venulae rectae. Together, the de-
graph shows dark cells (asterisks), with numerous short lamellipodla Water permeability of the epithelium of the collecting ducts and moves back towaTd the corticomedullary junction scending a rterioles and the ascending venules a re ca lled the
or microridges on their surface, and light cells, each witl1 a single cil- Is regulated by antidiuretic hormone (ADH or vasopressin), a
ium on its free surface along with small microvilli. The terms "light" withi n the ascending limb of the thin segment. The os- vasa recta. The arteriolae rect ae form capillary plex uses
hormone produced in the hypothalamus and released from motic gradients of the medu lla a re esta blished alo ng th e lined by fen estrated endothelium tha t supply the t ubula r
and "dark" refer to the staining character of sectioned cells and not to the posterior lobe of the pituitary gland. ADH increases the
the density differences reflecting charge characteristics of the coated axis of the loop of Henle. structures a t the various levels of the med ullary pyramid.
permeability of the collecting duct to water, thereby produc-
surface of the specimen. (Courtesy of C. Craig Tisher.) Vasa recta, form loops parallel to the loop of H enle.
Ing more concentrated urine. At the molecular level, ADH
acts on ADHregulated water channels, AQP2, located in the They act as countercurrent exchangers of water and Interaction between collecting ducts, loops of Henle, and vasa
epithelium of the terminal portion of the distal convoluted solutes between the descending part (arterio lae rectae) rectae is required for concentrating urine by the countercur-
tubule and in the epithelium of the collecting tubules and a nd ascending part (venulae rectae) of th e vasa recta. rent exchange mechanism
crovilli with the transmtsston electron microscope ducts. However, tile action of ADH is more significant in the The vasa recta help to maintain the osmotic gradient of
(TEM) (see Fig. 19.19). They do not show basal in fold- collecting tubules and collecting ducts. ADH binds to recep- the medulla . Beca use the thin ascending limb o f the loop of H enle has
ings but have basally located interdigitations w ith neigh- tors on the cells of these tubules and triggers the following Collecting duct in the m edulla acts as an osmotic equil- a high level of tran sport activ ity a nd because it is im per-
boring cells. N umerous vesicles are p resent in the apical actions: ibrating device. Modified ultrafiltrate in the collecting mea ble to water, the modified ultrafiltrate that ultimately
cytoplasm. Translocation of the AQP-2-containlng Intracytoplasmic ducts ca n be further eq uilibra ted with the hyperosmotic reaches th e d ista l convoluted tubule is h)'poosmotic. When
The cells of th e collecting ducts grad ually become taller vesicles into the apical cell surface-a short-term effect. medullary interstitium. T he level of equilibra tio n de- ADH is present, the distal convoluted tubules, the collect-
as the ducts pass fro m th e outer to the inner medull a a nd This results In an Increased number of available AQP2 pends on activation of ADH-dependent water channels ing tubules, and the collecting ducts are h ighly permeable
become columnar in the region of the renal papilla. The channels at the cell surface, thus Increasing water perme- (AQP-2). to water. Therefore, within the cortex, in which th e inter-
number of d a rk cells gradually decreases until non e a re ability of the epithelium. sti tium is isosm o tic with blood, the modified ultrafiltrate
Synthesis of AQP-2s and their insertion into the apical cell A standing gradient of ion concentration produces w ithin t he di stal convoluted tubule equilibrates and also
present in t he du cts as they approach the papilla.
membrane- a long-term effect. hyperosmotic urine by a countercurrent multiplier effect becomes isos mo tic, partly by loss of water to the intersti-
An increase in plasma osmolality or a decrease in blood tium a nd p artl y by addition o f ions other than Na + a nd Cl-
9 INTERSTITIAL CELLS volume stimulates release of ADH, as does nicotine. The loop of H enle creates and m aintains a gradient of to the ultrafi ltrate. In the medulla, increasing amounts of
In the absence of ADH, copious, dilute urine is produced. ion con centration in the medullary interstitium t hat in- water leave the ultrafiltra te as the collecting d ucts pass
The connective tissue of the kidney pa rench yma, called in- This condition is called central diabetes insipidus (CDI). Recent creases from the corticomedu lla ry junct ion t o the renal through the increasing ly h yperosmotic interstitium o n
terstitial tissue, surro unds the nephrons, ducts, and bloo d studies indicate that mutation of two genes encoding AQP2 papilla . As noted above, the thin descending limb of the their course to the p api llae.
and ADH receptors is responsible for a form of CDI called loop of H en le is freely permeable to Na+, Cl-, and wa- As noted a bove, the vasa recta also form loops in the
and lymphatic vessels. This tissue increases conside rabl y in
nephrogenic diabetes Insipidus. In this disease, the kidney ter, w he reas the ascending limb of the loop of H enle is medulla tha t parallel the loop of Henle. This arrangement
a moun t from the cortex (wh ere it constitutes approxi-
does not respond to ADH because of defective AQP2 and
ma tely 7% of t he volume) to the inner region of t he impermeable to water. Further, the thin ascending lim b ensu res t ha t the vessels p rovide circu lation to t he medulla
ADH receptor proteins synthesized by the collecting tubule
medulla and papilla (where it may constitute more than cells add Na + and C J- to the interstitium. w ithout disturbing the osmotic gradient established by
and duct epithelial cells. Excess water consumption can also
20 % of the volume). inhibit ADH release, thereby promoting the production of a Because water cannot leave the thi n ascending li mb, transp ort of C J- in the epithelium of the ascend ing limb of
In the cortex, two types of interstitial cells are recog- large volume of hypoosmotic urine. the interstitium becomes hype rosmotic r elati ve to the lu- 't he loop of H e nle.
nized: cells tha t resemble fibroblasts, fou nd between th e Increased secretion of ADH can produce an extremely hy- mina l conten ts. Alth o ug h some of the CI- anci Na + o f the The vasa r ecta form a countercurrent excha11ge system in
basement memb rane of the tubu les and the adjacen t per- perosmotic urine, thereby conserving water in the body. lnad interstitium diffuses back into the nephron at th e thin the fo llowing mann er: Both the arterial and venous sides of
itubular capillaries, and occasional macrophages. In their equate consumption of water or loss of water due to sweating, d escending limb, the ions are tra nsported out again in the loop are thin-walled vessels that form plex uses of fenes-
intimate relationship with the base o f th e tubular epi thelial vomiting, or diarrhea stimulates release of ADH. This leads to the t hin ascending limb and di stal stra ight tubule (thick trated capillaries a t a ll levels in the medulla. As the a rterial
an increase in the permeability of the epithelium of the distal ascending limb). This p roduces the countercurrent mul- vessels descend through the medulla, the blood loses water to
cells, the .fibroblasts resemble th e subepithelial .fibroblasts
and collecting tubules and promotes the production of a small tiplier effect. Thus, the concentration of NaCI in th e in- the interstitium and ga ins salt from the interstitium so that a t
of the intestine. T hese cells synthesize a nd secrete the col-
volume of hyperosmotic urine. terstitium g radually increases d own the length of th e the tip of the loop, deep in the medulla, the blood is essen-
lagen and glycosaminoglycans of the extracellular matri x
of the intersti tium. loop of H enle and, consequently, through the t hi ckn ess tially in equilibrium with the hyperosmotic interstitial fluid.
614 CHAPTER 19 Uriunry Syste111 CHAPTER 19 llriunry Syste111 6 '2 5
Active transport
.. Active exchange
then turn to follow an arched course along the base of the Q LYMPHATIC VESSELS
pyramid between the medulla and the cortex. Thus, these
Active cotransport interlobar arteries are designated arcuate arteries. The kidneys contain two major networks of lymphatic
Interlobular arteries branch from the arcuate arteries vessels. These networks are not usually visible in routine
~ Passive diffusion urea loop of Henle and ascend through the cortex toward the capsule. Al- histologic sections but can be demonstrated by experi-
ADH dependent though the boundaries between lobules are not distinct, 'mental methods. One network is located in t he o uter re-
H20 movement
the interlobu lar arteries, when included in a section cut gions of the cortex and drains into larger lymphatic ves-
~ Aquaporin dependent collecting duct
..... H20 movement perpendicular to the vessel, are located midway between sels in the capsule. The other network is located more
[gJ @I (AQP) adjacent medullary rays, traveling in the cortical labyrinth. deeply in the substance of the kidney a nd drains into
As they traverse the cortex toward the capsule, the inter- large lymphatic vessels in the renal sinus. There are
FIGURE 19.20 lobular arteries give off branches, the a fferent arterioles, numerous anastomoses between the two lymphatic
Diagram showing movement of substances into and out of the nephron and collecting system. The symbols one to each glomerulus. A single afferent arteriole may networks.
indicate the mode of transport as noted in the key. spring directly from the interlobular artery, or a common
626 CHAPTER 19 J Urinary Syslcm
CHAPTER 19 Uriu ary Syslem 62 7
Q NERVE SUPPlY
The fibers that form the rena l plexus are derived mostly 0
from the sympathetic division of the autonomic nervous
system. They cause contraction of vascular smooth muscle
and consequent vasoconstriction.
the bladder however, is not as clearly separated into dis- rior wall of this segment, and many small prostatic ducts In the female, the urethra is short, measuring 3 to 5 em
tinctive Ia yers. also empty into this segment. in length from the bladder to the vestibule of the vagina,
Membranous urethra extends for about 1 em from the where it normally terminates just posterior to the cli-
apex of the prostate gland to the bulb of the penis. It toris. The mucosa is traditionall y described as having
Urinary Bladder
passes through the urogenital diaphragm of the pelvic longitudinal folds. As in the male urethra, the lining is
The bladder is a distensible reservoir for urine, located in floor as it enters the perineum. Skeletal muscle of the uro- initially transitional epithelium, a continuation of the
the pelvis, posterior to the pubic symphysis; its size and genital diaphragm surrounding the membranous uretrua bladder epithelium, but changes to stratified squamous
shape change as it fills. It contains three openings, two for forms the external (voluntary) sphincter of the urethra. epithelium before its termination. Some investigators
the ureters (ureteric orifices) and one for the urethra (in- Transitional epithelium ends in the membranous urethra. h ave reported the presence of stratified columnar and
ternal urethral orifice). The triangular region defined by This segment is lined with a stratified or pseudostratified pseudostratified columnar epithelium in the midportion
these three openings, the trigone, is relatively smooth and columnar epithelium that resembles the epithelium of the of the female urethra.
constant in thickness, whereas the rest of the bladder wa ll genital duct system more than it resembles the epithelium Numerous small urethral glands, particularly in the
is thick and folded when the bladder is empty and thin and of the more proximal portions of the urinary duct system. prox imal part of the urethra, open into the urethral lumen.
smooth when the bladder is distended. T hese differences Penile (spongy) urethra extends for about 15 em through Other glands, the paraurethral glattds, which are homolo-
reflect the embryologic origins of the trigone and the rest the length of the penis and opens on the body surface at gous to the prostate gland in the male, secrete into the
of the bladder wall: the trigone is derived from the embry- the glans penis. The penile urethra is surrounded by the common paraurethral ducts. These ducts open on each
OJuc mesonephric ducts, and the major portion of the wall corpus spongiosum as it passes through the length of the side of the external urethral orifice. They produce an alka-
originates from the cloaca. penis. It is lined with pseudostratified columnar epithe- line secretion. The lamina propria is a highly vascularized
The smooth muscle of the bladder wa ll forms the detru- lium except at its distal end, where it is lined with strati- layer of connective tissue that resembles the corpus spon-
sor muscle. Toward the opening of the urethra, the muscle fied squamous epithelium continuous with that of the giosmn in the male. Where the urethra penetrates the uro-
FIGURE 19.25
Diagrams of the luminal surface of transitional epithelial cells. The
fibers form the involuntary internal urethral sphincter, a skin of the penis. Ducts of the bulbourethral glands genital diaphragm (membranous part of the urethra), the
upper drawing depicts part of a surface cell in a distended bladder; the ring-like arrangement of muscle around the opening of the (Cowper's glands) and of the mucus-secreting urethral striated muscle of this structure forms the external (volun-
lower drawing depicts the same cell as it would appear in a relaxed uretrua. The srnooth muscle bundles of the detrusor mus- glands (glands of Littre) empty into the penile m ethra. tary) urethral sphincter.
bladder. The plasma membrane is thickened in regions to form cle are less regularly arranged than that of the tubular por-
plaques. The interplaque regions consist of membrane that Is not tions of the excretory passages, and thus, the muscle and
thickened. In tile relaxed bladder, the plaques are invaginated into collagen bundles are random ly nuxed. Contraction of the
the cell, and although they retain their continuity with tile surface, the detrusor muscle o f the bladder compresses the entire organ
invaginated plaques typically appear as isolated fusiform vesicles in and forces the urine into the urethra.
electron micrographs. Filaments attached to tile undersurface of the The bladder is innervated by bod1 sympathetic and para-
plaques may prevent undue st retching In the distended bladder.
sympathetic divisions of the autonomic nervous system:
(Modified from Staehelin LA, Chlapowski FJ, Bonneville MA. J Cell Bioi
1972;53:73-91.) Sympathetic fibers form a p lexus in the adventitia of the
bladder wall. These fibers probably innervate blood ves-
sels in the wal l.
the wall of the ureter. The remainder of the wall is com-
Parasympathetic fibers originate from 51 to 54 segments
posed of smooth muscle and connective tissue. The smooth
of the spina l cord and travel with pelvic splanchnic
muscle is arranged in three layers: an inner longitudina l
nerves into the bladder. They end in terminal ganglia in
laye1; a middle circular layer, and an outer longitudinal
the muscle bundles and the adventitia and are the effer-
layer. However, the outer longitudinal layer is present only
ent fibers of the micturitiott 1'eflex.
at the distal end of the ureter. Usua lly, the ureter is embed-
Sensory fibers from the bladder to the sacra l portion of
ded in the retroperitoneal adipose tissue. The adipose tis-
the spina l cord are the afferent fibers of the micturition
sue, vessels, and nerves form the adventitia of the uxeter.
refl ex.
As the bladder distends with urine, the openings of the
meters are compressed, reducing the possibility of reflu x of
urine into the ureters. Contraction of the smooth muscle of Urethra
the bladder wall a lso compresses the openings of the The urethra is the fibromuscular tube that conveys urine
ureters into the bladder. This action helps prevent the from the urinary bladder to the exterior through the exter-
spread of i11fection from the bladder and urethra, frequent nal urethral orifice. The size, structure, and functions of
sites of chronic infection (particularly in females), to the the urethra differ in males and females.
kidney. In the male, the urethra serves as the terminal duct for
In the termina l portion of the ureters, a thick outer both the urinary a nd genital systems. Tt is about 20 em
layer of longitudinal muscle is present in add ition to the long and has three distinct segments:
two listed above, particularly in the portion of the meter
that passes tluough the bladder wall. Most descriptions Prostatic urethra extends for 3 to 4 em from the neck of
of the bladder musculature indicate that this longitudi- the bladder through the prostate gland (see page 707). lt
nal la yer continues into the wall of the bladder to form is lined with tra nsitional epithelium (urothelium). The
a principal component of its wa ll. The smooth muscle of ejaculatory ducts of the genital system enter the paste-
l
CHAPTER 19 Uriuary System 63 I
left, has not been included in the plane of the section. The
B
Figure 1, kidney, human, fresh specimen x 3.
A section through the hilum is shown here. The hilar re- papillae are free tips of the pyramids that project into the
gion of the kidney is below, and the convex lateral border is first of a series of large collecting vessels, the minor calyces
above. The outer part of the kidney (except at the hilum) (MC); the inner surface of the calyx is white. Minor calyces
has a reddish-brown appearance; this is the cortex. It is eas- drain into major calyces, and in turn, these open into there-
ily distinguished from the inner portion, the medulla, which nal pelvis, which funnels into the ureter.
is further divided into an outer portion (OM), identified here An interesting feature in this specimen is that the blood
by the presence of straight blood vessels, the vasa recta has been retained in many of the vessels, thereby allowing
(VR), and an inner portion (IM), which has a light appear- for visualization of several renal vessels in their geographic
ance. The medulla consists of pyramidal structures, the pyr- location. Among the vessels that can be identified in the cut
amids, which have their base facing the cortex and their face of the kidney shown here are the interlobular vessels
apex in the form of a papilla ( P) facing the hilar region of (IV) within the cortex; the arcuate veins (AV) at the base of
the kidney. The pyramids are separated, sometimes only the pyramids; and, in the medulla, the vessels going to and
partially in this figure, by cortical material that is desig- from the capillary network of the pyramid. The latter ves-
nated the renal columns (RC). Note, also, that the two pyr- sels, both arterioles and venules, are relatively straight and
amids depicted in the illustration share the same papilla. are designated collectively as the vasa recta (VR).
Most of the pyramid belonging to the other papilla, on the
Figure 2, kidney, human, H&E x20. seen in the cortex are groups of tubules that are more or less
KEY
AA, arcuate arteries OM, outer medulla VR, vasa recta
AV, arcuate veins P, papilla arrows, medullary rays
IM, inner medulla RC: Fig. I , renal column; Fig. 2, renal cor- dashed line (Fig. 2), boundary between cor-
IV, interlobular vessels puscles tex and medulla
MC, minor calyx
630
CHAPTE R 19 llri11ary System 6 35
Figure 1, kidney, human, H&E x240. is often star shaped ; this is not the case with distal tubules.
Figure 2, kidney, human, H&E x 240. ray, as is shown by the label ing of each tubule in this figure.
Figures 3 and 4, kidney, human, H&E x 360. A distal (DC) and two proximal (PC) convoluted tubules
KEY
A, arteriole MD, macula dcnsa Pod, podocyte (v isceral layer of Bowman's
BC, Bowman's capsule (parietal layer) P, proximal thick segment (straight portion) capsule)
CT, collecting tubule PC, prox imal convoluted tubule asterisks, urinary space
D, distal thick segment (straight portion) double-headed arrow (Fig. 4), blood vessel
DC, distal convoluted tubule at vascul ar pole of renal corpuscle
CHA PTER 1 9 llriunry Syslt llf 6 37
B
Figure 1, kidney, human, H&E x 240. cells. Count the m ! Finally, boundaries between the cells
A section through the outer portion of the medulla is that constitute the collecting tubules are usually evident
shown in this figure. This region contains proximal and dis- (asterisks); this serves as one of the most dependable fea-
tal thick segments, thin segments, and collecting tubules. tures for the identification of collecting tubules.
All of the tubules are parallel, and all are cut in cross sec- The thin segments (T) have the thinnest walls of all re-
tion; thus, they present circ ular profiles. The proximal ( P) nal tubules seen in the medulla. They are formed by a low
thick segments display typical star-shaped lumina a nd a cuboidal or simple squamous epithelium, as seen here, and
brush border (or the fragmented apical cell surface from the lumina are relatively large. Occasio nally, a section in-
which the brush border has been par tially broken). These cludes the region of transition from a thick to a thin seg-
tubules have outside diameters that are generally larger than ment and can be recognized even in a cross section throug h
those of the distal tubules (D). As mentioned previously and the tubule. One s uc h junction is evident in this figure (the
as shown here, the distal tubules display a larger number of tubule with two arrows in the lumen). On one side, the
nuclei tha n do comparable segments of proximal tubule tubule cell (left-pointing arrow) is characteristic of
cells. Note, also, that the lumen of the di stal tubule is more the proximal segment; it possesses a distinctive brush bor-
rounded and the apical surface of the cells is sharper. The der. The other side of the tubule (right-pointing arrow) is
collecting tubules (CT) have oute r diameters that are about composed of low cuboidal cells that resemble the cells
the same as those of the proxima l tubules and larger than fom1ing the thin segments. In additi o n to the renal and col-
those of di stal tubules. The cells forming the collecting lecting tubules, there are many other small tubular struc-
tubules are cuboidal and smaller than those of proximal tures in thi s fi gure . Thin-walled and lined by endothelium,
tubules ; thus, they also display a re latively larger number of they are sma ll blood vessels.
nucle i tha n do comparable segme nts of proximal tubule
Figure 2, kidney, human, H&E x 20. The apical portion of the pyramid (a rrowhead), known
KEY
AV, arcuate vessels T, thin segment diamonds, boundary between a transitional
CT, collecting tubules TEp, transitional epi thelium and a columnar epithe lium
D, distal thick segment arrowhead, location of apex of pyramid left-pointing arrow (Fig. 1), proximal
P, proxi mal thick segment asterisks, boundaries between cells of a col- tubule celJ
RC, renal corpuscle lecting tubule right-pointing arrow (Fig. 1), thin segment
SCEp, simple columnar epithelium cell
636
T
CHA PTER 1 9 l/riuary Sysltm 6 39
B
Figure 1, ureter, monkey, H&E x 160. tive tissue constitute the mucosa (Muc). A distinct submu-
The wall of the ureter from the rectangular area in the cosa is not present, although the term is someti mes applied
orientation micrograph is examined at higher magnification to the connective tissue that is closest to the muscle.
in this figure. One can immediately recogni ze the thick ep- The m uscul aris (Mus) is arranged as an inner longitudi-
ithelial lining, which appears distinct and sharply delineated nal layer (SM ( l)), a midd le circular layer (SM(c)), and an
from the remainder of the wall. This is the transitional ep- outer longitudinal layer (SM(l )). However, the oute r longi-
ithelium (Ep). The remai nder of the wall is made up of con- tud inal layer is present only at the lower end of the ureter.
nective tissue (CT) and smooth muscle. The latter can be rec- In a cross section through the ureter, the inner and outer
ognized as the darker-staining layer. The section also shows smooth muscle layers are c ut in cross section, whereas the
some adipose tissue (AT), a component of the adventitia. middle circul ar layer of the muscle cells is c ut longitudi-
The transitio nal epithelium and its supporting connec- nally. This is as they appear in this figure.
B
Figure 2, ureter, monkey, H&E x 400. acteristically the largest, and some are binucleate (an vw).
This figure shows the inne r longitudinal smooth muscle The basal cells are the smallest, and typicall y, the nuclei ap-
layer (SM (l)) at higher magnification. Note that the nuclei pear crowded because o f the minimal cytoplasm of each
appear as round profiles, indicating that the muscle cells cell. The intermediate cells appear to consist of several lay-
have been cross-sectioned. This figure also shows the tran- ers and are composed of cells larger in size than the basal
sitional epithelium to advantage. The surface cells are char- cells but smaller than the surface cells.
KEY
Adv, adventitia Ep, transi tional epithelium SM(c), circular layer of smooth muscle
AT, adipose tissue M uc, mucosa SM(I), longitudi nal layer of smooth muscle
BV, blood vessels Mus, muscularis arrow (Fig. 2), binucleate surface cell
CT, connective tissue Ser, serosa
638
C H APTER 19 Uriuary Syslw1 64 I
Figure 1, urinary bladder, human, H&E x60. what denser than the smooth muscle of the underlying mus-
Figure 2, urinary bladder, human, H&E x250. sectioned smooth muscle (SM(L)) that belong to the ureter.
Figure 3, urinary bladder, human, H&E x 250. trac ted bladder, it appears that there are as many as ten cell
KEY
A, artery Lym, lymphatic vessel U, ureter
BV, blood vessel M, muscularis V, vein
CT, connective tissue SM(L), longitudinally cut smooth muscle arrows, binucleate cells
Ep, transitional epithelium
640
hormones, which are carried to their destination via con- Hormones interact with specific hormone receptors to alter
steroid ho rmone
carri er ~ physiologic
protein ~ - effects \ hyp~thalamus
~ new proteins
~NA~d
optic chiasma
physiologic effects
a b pars nervosa
FIGURE 20.1
General mechanisms of hormone action. a. This schematic diagram of steroid hormones, which use intracellular receptors. Binding of t he
shows the basis for protein hormone action involving cell surface re- hormone to this receptor causes allosteric transformation of the pars distalis
ceptors. Hormone molecules bind to the receptor and initiate synthe- receptor into a form that binds to DNA. This binding leads to follicles
sis of second-messenger molecules. These molecules, in turn, activate mRNA transcription and production of new proteins that produce b
a cascade of reactions that produce hormone-specific responses in hormone-specific responses in the stimulated cell.
the stimulated cell. b. This diagram shows the mechanism of action posterior anterior lobe
lobe
FIGURE 20.2
Pituitary gland. a. Photomicrograph of a human pituitary gland. The of the pituitary gland consists of the pars distalis, pars tuberalis, and
function, cells of the GEP system exercise paracrine Posterior lobe (neurohypophysis), the neural secretory pituitary gland lobes can be identified on the basis of their appear pars intermedia; the posterior lobe of the pituitary gland consists of
control of the activity of adjacent epithelial cells by diffu- tissue ance, location, and relation to each other. x7. b. Drawing of a human the infundibulum and pars nervosa.
sion of peptide secretions through the extracellular spaces. pituitary and related regions of the hypothalamus. The anterior lobe
These two portions are of di ffere nt embryo logic or igin .
The anterior lobe of the pituitary gland is derived from an neuroectoderm
\1 PITUITARY GLAND (HYPOPHYSIS) evagination of the ectoderm of the oropharynx toward
neu roectoderm
the brain (Rathke's pouch). The posterior lobe of the pi-
T he pituitary gland and the hypothalamus, the portion of tuitary gland is derived from a downgrowth (the future
the brain to which the pituitary gland is attached, are in fundi bu I um) of neuroectoderm of the floor of the third
morphologically and functionall y linked in the endocrine ventricle (the diencepha.lon) of the developing brain (Fig.
and neuroendocrine control of other endocrine glands. Be- 20.3) .
cause they play central roles in a number of regulatory The anterior lobe of the pituitary gland consists of three
feedback systems, they are often called the "master or- deriva tives of Rathke's pouch:
gans" of the endocrine system .
Pars distalis, w hich comprises the bulk of the anterior
lobe of the p ituitary gla nd and arises from the thickened
Gross Structure and Development anterior wall of the pouch
Pars intermedia, a thin remnant of the posterior wall of
The pituitary gland is composed of glandular epithelial tissue
the pouch that abuts the pars distalis
c
and neural (secretory) tissue Rathke's
Pars tuberalis, which develops from the thickened lat- pouch
eral walls of the pouch and forms a collar or sheath
The pituitary gland is a pea-sized, compound endocrine FIGURE 20.3
around the infundibulum
gland that weighs 0.5 g in males and 1.5 g in multiparous Development of the pituitary gland. This diagram shows sequential stages (a to c) in the development of the pituitary gland.
females. It is centrally located at the base of the brain,
The embryonic infundibulum gives rise to the posterior
where it lies in a saddle-shaped depression of the sphenoid
bone called the sella turcica. A short stalk, the infundibu-
lobe of the pituitary gland. The posterior lo be of the pitu- Blood Supply These vessels arise from the internal carotid arteries
itary gland consists of and posterior communicating artery of the circle of
lum, and a vascular network connect the pituitary gland to Knowledge of the unusual blood supply of the pituitary
W illis.
the hypotha lamus. Pars nervosa, which contains neurosecretory axons and gland is important to understanding its functions. The pi-
The pituitary gland has two functional components (Fig.
Inferior hypophyseal arteries prin1arily supply the pars
their endings tuitary blood supply is derived from two sets of vessels
nervosa. These vessels arise solely from the internal
20.2): (Fig. 20.4) :
Infundibulum, w hich is continuous with the median carotid arteries. An important functional observation is
Anterior lobe (adenohypophysis), the glandu lar epithe- eminence and contains the neurosecretory axons fann- Superior hypophyseal arteries supply the pars tu- that most of the anterior lobe of the pituitary gland has
lial tissue ing the hypothalamohypophyseal tracts. bera lis, median eminence, and infundibular stem. no direct arterial supply.
64 6 C HAPTE R 20 I Ewlocriur O r!)nu s CHAPTER 20 fu dorriue Or!)nus 647
Structure and Function of the Pituitary Lobes T he two rem aining h ormones of the a n terior lobe, growth other empirically derived combinations of stains (e.g.,
horm o ne (GH) a nd p rolactin (PRL), are not considered aldehyde-fuchsin), enables investigators to ch aracterize the
ANTERIOR LOBE OF T HE PITUITARY GLAND
tropic because they act d irectly o n target organs that a re cells further. Acidophils a nd basophils have been subdi-
(ADEN OHYPOPHYSIS)
not endocrin e in n ature. The general character a nd effects vided into smaller groups that more closely correlate stain-
o f the p itu itary hormo nes of the anterior lobe a re summa- ing properties with function, as summa rized in Table 20.2.
The anterior lobe of the pituitary gland regulates other
endocrine glands and some nonendocrine tissues
ri zed in Ta b le 20.1. Histophysiologic studies. T he cells in Table 20.2 are
capillaries c haracterized as acidoph ils a nd basophils on the basis of
of the media n -::::..--:::.-----.
e mine nce a nd M ost of the a nt er ior lobe o f the pituit ary gland has t he
Pars Distalis their stai ning ch aracteristics. The role of the cells, how-
infundibulum Th e cells within the pars distalis vary in size, shape, and ever, was identified by combin ing info rmation on stain -
t ypical organizat ion of e ndocr in e tissue. The cells ar e or-
sta ini ng propert ies. T he cells a re a rra nged i11 cords and ing p roper t ies wit h changes in the n umber, size, and
ganized in cl ump s a nd cords separa ted by fenestrated
nests w ith in terweav ing capilla r ies. Early descrip t ions of stain ing inten sity o f t he cells as the t arget organs of the
sin usoidal capillaries of relatively large diameter. These
t he cells with in the par s d istalis were based solely o n the pitu ita ry hormo nes were p hysiologically manipulated.
cells resp o nd to signals fr om the h yp ot halamus and syn-
staining p roperties o f secretory vesicles with in th e cells. Pa thologic cond itions were also correla ted with the ab-
thesize and secrete a num ber of pi tuitar y ho rmones. Fo ur
Using m ix t ures of acidic and basic dyes (Fig. 20.6), histol- sence o r overgrowth of specific h ypophysea l cells. T hese
horm ones of th e anterior lobe- adrenocorticotropic
ogists identified three types of cells accord ing to their stain- physiologic and pat hologic observations have led to the
infe rior hor mone (ACTH ), t h yr o id-st imulating (t hyrotropic ) hor-
hypophyseal- ---u ing reaction, na mely, basophils (10%), acidophils (40%), recognition that many of the cells originally identified as
m o ne (TSH , thyrotropin), fo llicle-stimu lating hormo ne
a rte ry capillaries of the hypophyseal a nd chromophobes (50%). H owever, this classification chromophobes are actually transiently degranulated
(FSH ), a nd luteinizing hormon e (LH)-are called tropic
porta l system in the pa rs distalis contains n o info rma tion regarding the hormonal secretory fo rms of secretory cells.
hormones beca use th ey regulate t he acti vity of cells in
FIGURE20.4 o ther endocrine glands t hro ugho ut the body (Fig. 20.5).
activity or fu nctional role of t hese cells. Electron microscopy and immunocytochemistry. Ultra-
Diagram of the blood supply to the pituitary gland. The hypophyseal st ruct ura lly, the cells of the a nterio r lobe of the pituitary
portal veins begin in the capillary beds of tile median eminence and Histochemical, physiologic, a nd immunocytochemical methods gland show relatively distinctive characteristics based on
infundibulum and end in the capillaries of the pa rs dista lls. better define the functions of the cell types in t he pars distalis comparison o f celJ s ize and sh ape, degree of develop-
higher brain centers ment of cytop lasmic organelles, a nd secretory vesicle
The thr ee methods used to define the fu n ct ions of t he size, d en sity, and distrib ution (Table 20.3).
The hypothalamohypophysea/ porta/system provides the differe nt cell types of th e pa rs distalis are
crucial link between the hypothalamus and the pituitary gland Five functional cell types are identified in the pars dist alis on
Histochemist1y. T he use of histochemical stains for sp e- the basis of immunocytoche mical reactions
T he arteri es tha t supply the p a rs tuberalis, med ia n e mi- cific ch emical groups, such as the period ic acid- Schiff
nence, a nd infundibular stem give r ise to fe nestrated ca pil- (PAS) reaction for carb ohydrates of glycoproteins, Alllmown ho rmones of t he anterior lobe of the pitu itary
la ries (the primary capillary plexus). T hese ca piJla ri es t richrome stains (Mallor y's, C leveland-Wo lfe, etc.), and gla nd are small protein s o r glycoproteins. This important
dra in into porta l veins, called th e hypophyseal portal
veins, wh ich ru n al ong th e p ars tubera lis and give rise to a
second fenestrated sinusoidal capillary network (the sec-
ondary capillary plexus). Th is system of vessels carries the TABLE 20.1. Hormones of the Anterior Lobe of the Pituitary Gland
ne u roendocrine sec retio ns of h ypotha lam ic ne rves fro m Hormone Composition MW (kDa) Major Functions
a nterior lobe
t he ir sites o f release in the media n e mine nce a nd in- of pituitary
fun d ibular stem directly to the cells of the p a rs dista lis. gland Growth hormone (soma- Straight-chain protein (191 aa) 21,700 Stimulates liver and other organs to synthesize and
totropin, GH) secrete insulin-like growth factor I (IGF-1), which in turn
M o st of t he blood fro m the pituitary gland dr ains into
stimulates division of progenitor cells located in growth
the ca vernous sin us a t t he base o f the diencep ha lo n and plates and in skeletal muscles, resulting in body growth
th en into the systemic circula tion. Some evidence suggests, thyroid g la nd
Prolactin (PRL) Straight-chain protein (198 aa) 22,500 Promotes mammary gland development;
howeve r, th a t blood can flow via sho rt po rta l ve ins fro m initiates milk formation; stimulates and maintains
the par s dista lis to the pars nervosa a nd tha t blood fro m secretion of casein, lactalbumin, lipids, and
the pa rs nervosa ma y flo w towa rd th e h ypotha la mus. carbohydrates into the milk
These short pa thways provide a route by w hic h t he ho r- Adrenocorticotropic hor- Small polypeptide (39 aa) 4,000 Maintains structure and stimulates secretion of
m ones of t he an terior lo be of the pituita ry g la nd co uld pro- mone (ACTH) glucocorticoids and gonadocorticoids by the zona
fasciculata a nd zona reticularis of the adrenal cortex
vide feed back d irectly to th e bra in w itho ut m a k ing the f ull
circ ui t of the syst emic circul ation. Follicle-stimulating hor- 2-chaln glycoprotein' (a, 92 28,000 Stimulates follicular development in the ovary and
thyroid hormones mone (FSH) aa; (3, 111 aa) spermatogenesis In the testis
FIGURE20.5 luteinizing hormone (LH) 2-chain glycoproteinA(a, 92 28,300 Regulates final maturation of ovarian follicle, ovulation,
Nerve Supply Interaction of the hypothalamus, anterior lobe of the pituitary aa; (3, 116 aa) and corpus luteum formation; stimulates steroid
secretion by follicle and corpus luteum; in males,
T he n erves t ha t enter the infund ibular stem a nd p a rs ner - gland, and thyroid gland. Production of thyroid hormones is regu-
essential for maintenance of and androgen secretion by
lated through a negative feedback system. The thyroid hormone can the Leydig (interstitial) cells of the testis
vosa from the hypotha la mic nuclei are co mponents of the
feed back on the system and inhibit further release of thyroid hor-
posterior lo be of th e p itui tary g lan d (see below). T he Thyrotropic hormone 2-chain glycoproteinA(a, 92 28,000 Stimu lates growth of thyroid epithelial cells; stimulates
mones. Such inhibition occurs at the level of the anterior lobe and the
nerves th at enter the an te rior lobe of t he p ituita ry gla nd (TSH) aa; (3, 112 aa) production and release of thyroglobulin and thyroid
llypotha lmus. The system is activated in response to low thyroid hor- hormones
are postgang lionic fibers of the a uto n omic nervous system mone levels or in response to metabolic needs. TRH, thyrotropin-re-
and ha ve vasomoto r functio n. leasing hormone; and TSH, thyroid-stimulating hormone. The n chains of FSH, LH, and TSH are Identical and encoded by a single gene; the 13 chains are specific for each hormone.
64 8 CHAPTER 2 0 I 11docri11e Orga 11 s
TABLE 20.4. Hormones of the Posterior Lobe of the Pituitary Gland TABLE 20.5. Hypothalamic Regulating Hormones
Hormone Composition Source Major Functions Hormone Composition Source Major Functions
oxytocin Polypeptide contain- Cell bodies of neurons located in Stimulates activity of the contractile cells around the Growth hormone- Two forms in human: Cell bodies of neurons los:ated in the Stimulates secretion and gene expression
ing 9 amino acids the supraoptic and paraventricu- ducts of the ma mmary glands to eject milk from the releasing hormone polypeptides containing arcuate nucleus of hypothalamus of GH by somatotropes
lar nuclei of the hypothalamusA glands; stimulates contraction of smooth muscle cells (GHRH) 40 and 44 amino acids
in the pregnant uterus Somatostatin Polypeptide containing Cell bodies of neurons located in the Inhibits secretion of GH by somatotropes
Antidiuretic hor- Polypeptide contain- Cell bodies of neurons located in Decreases urine volume by increasing reabsorption of 14 amino acids periventricular, paraventricular, and ar-
mone (ADH; va- ing 9 a mino acids; the supraoptic and paraventricu- water by collecting ducts of the kidney; decreases the cuate nuclei of hypothalamus
sopressin) two forms: arginine- lar nuclei of the hypothalamusA rate of perspiration In response to dehydration; Dopamine Catecholamine (amino Cell bodies of neurons located in the
ADH (most common increases blood pressure by stimulating contractions of acid derivative) arcuate nucleus of hypothalamus Inhibits secretion of PRL by lactotropes
in humans) and smooth muscle cells in the wall of arterioles Corticotropin- Polypeptide containing Cell bodies of neurons located in the Stimulates secretion of ACfH by corti
lysine-ADH releasing hormone 41 amino acids arcuate, periventricular, and medial cotropes; stimulates gene expression for
(CRH) pa raventricular nuclei of hypothala POMC in corticotropes
' Immunocytochemical studies Indicate that oxytocin and ADH are produced by separate sets of neurons within the supraoptic and paraventrlcuiar nuclei of the
hypothalamus. Biochemical studies have demonstrated that the supraoptic nucleus contains equal am ounts of both horm ones, whereas the paraventricular nu- mus
cleus contains m ore oxytocin than ADH, but less than the amount found in the supraoptic nucleus. Gonadotropin- Polypeptide containing Cell bodies of neurons located in the Stimulates secretion of LH and FSH by go
releasing hormone 10 amino acids arcuate, ventromedial, dorsal, and par- nadotropes
(GnRH) aventricula r nuclei of hypothalamus
Thyrotropin Polypeptide containing 3 Cell bodies of neurons located by the Stimulates secretion and gene expression
and collecting ducts by acting on ADH-regulated water The pituicyte is the only cell specific to the posterior lobe of the releasing hormone amino acids ventromedial, dorsal, and paraventric- of TSH by thyrotropes; stimulates synthe-
ch a nnels (AQP-2) (see page 619), ca using rapid resorption pituitary gland (TRH) ular nuclei of hypothalamus' sis and secretion of PRL
of water acr oss the tubu le epitheliwn . In the a bsen ce or re-
' Immunocytochemical studies indicate that oxytocin and ADH are produced by separate sets of neurons within the supraoptic and paraventrlcular nuclei of the
duced produc tio n of ADH, most commonly due to lesions In addition to the numerous axons a nd terminals of t he hypothalamus. Biochemical studies have demonstrated that the supraoptic nucleus contains equal amounts of both hormones, whereas the paraventricular nu
of the hypoth alamus or posterior lobe of the pituitary hypothalamic nemosecretory neurons, the posterior lobe cleus contains more oxytocin than ADH, but less than the amount found in the supraoptic nucleus.
gla nd, large volumes of dilute wine are produced. Individ- of the pituitary gland contains fibroblasts, mast cells, and
u a ls w ith this condition, called diabetes insipidus, prod uce specia lized glia l cells called pituicytes, associated with the
up to 20 L of urine p er d ay and have extreme thirst. fenestrated capillaries. These cells are irregular in shape, the h ypothalamus to regula te the secretion of hypotha la- The pineal gland contains two types of parenchymal cells:
Plasma osmolality a nd blood volume ar e monitored by with many branches, and resemble astroglial cells. Their mic releas ing hormones (see Fig. 20.5) . The two levels of pinealocytes and interstitial (glial) cells
specia lized receptors of th e cardiovascular system (e.g., nuclei are round or oval, and pigment vesicles are presen t feedback allow exquisite sensitivity in the control of secre-
carotid bodies a nd juxtaglom eru la r apparatus). An increase in the cytoplasm. Like astroglia, they possess specific in- tory function. Th e ho rmone itself normally regulates the Pinealocytes are the chief cel ls of the pineal gla nd. They
in osmolality or a decrease in b.lood volume stimulates termediate filaments called glial fibrillary acidic protein secretory activity of the cells in the hypotha lamus a nd pi- are arranged in clum ps or cords within lo bules formed by
ADH release. Additionally, the cell bodies of the hypotha l- (GFAP). Pituicytes often have processes that terminate in tuitary gla nd that regula te its secretion. connective tissue septa t hat extend into the gland from the
amic secretory ne urons may also serve as osmoreceptors, the perivascula r space. Beca use of their many processes In additi on, info rma ti o n from most physiologic a nd pia ma ter that covers its surface. These cells have a large,
in itiating ADH release. Pain, trauma, emotion al stress, and a nd relationships t o the blood, the p ituicyte serves a sup- p sychologic stimuli that reach the brain a lso reaches the deeply infolded nucleu s w ith one or more p romin ent nucle-
drugs, such as nicotine, also stimulate release of ADH. porting role similar to that of astrocytes in the rest of the hypotha lamus. The hypoth ala mic-hypophyseal feedback oli a nd conta in lipid d roplets within their cytoplasm. When
CNS (see page 299). loop provides a regulatory path w hereby general infor- examined w ith the transmission electron microscope
Oxytocin promotes contraction of smooth muscle of the uterus mation from t he CNS contributes to the regulation of t he (TEM), pinealocytes sh ow typical cytoplasmic organelles
and myoepithelial cells of the breast The hypothalamus regulates hypophyseal function anterior lobe of th e pituitary gla nd and, con sequently, to along with numerous, dense-co red, membrane-bounded
the regula tion of the en tire end ocrine system . The secre: vesicles in their elaborate, elongated cytoplasmic processes.
O xytocin is a more potent promoter of smooth muscle T he hypothalamus produces numerous neurosecretory tion of h ypotha lam ic regula tory peptides is the primary The processes also contain numero us parallel bundles of
contraction tha n is ADH. Tts primary effect includes pro- products. ln addition to oxytocin and ADH , hypothala- mechanism by which c ha nges in e motional state are microtubules. T h e expanded, club-like endings of the
mo tion of contraction of mic neurons secrete polypeptides t h at promote and in- tran slated into changes in the physio logic ho meosta tic processes are associated w ith th e blood capilla ries. This fea-
hibit the secretion and release of h orm o n es from the a n - state. ture strong ly suggests neuroendocrine activity.
Ute rine smooth muscle du.ring orgasm, menstruation,
terior lobe of the pi tuitary gland (Table 20 .5). These The interstitial (glial) cells constitute a bout 5% of the
and parturition
hypotha la mic polypeptides also accumulate in nerve end - cells in the gland. They have sta ining and ultrastructural
M yoepith elial cells of the secretory alveol i and a lveolar
ducts of the mamma ry gland
ings n ear the median eminence a nd infundibula r stalk Q PINEAL GLAND features that closely resemble those of astrocytes a nd are
and are released into the capillary bed of the h yp othala- reminiscent of the pituicytes of the p osterior lobe of t he pi-
Oxytocin secreti on is triggered by ne ura l stimuli that mohypophyseal portal system for tra nsport to the pan T he pineal gland (p ineal body, epiphysis cerebri) is a u en - tuitary gland.
reach the hypothalamus. These stimuli initiate a n eurohu- distalis. docrine or neuroendocrine gland that regulates daily body ln addition to the two cell types, the human pineal gland
m o ra l reflex that resembles a s imple sensorimotor reflex. rh ythm. It develops from ne uroectoderm of the posterior is ch aracterized by the presence of calcified conc ret io ns,
Tn the uterus, the ne urohum oral reflex is initiated by dis- A feedback system regulates endocrine function at two levels: portion of the roof of the die ncephalon a nd remains at- called corpora arenacea or brain sand (Fig. 20.11). These
tension of the vagina a nd cervix. ln the breast, the reflex is hormone production in the pituitary gland and hypothalamic tach ed to the brain by a short stalk. In humans, it is lo- concretions appear to be derived from precipitati on of cal-
initiated by nursing (suckling). Con traction of the myoep- releasing hormone production in the hypothalamus cated at the p osterior wall of the third ventricle near the cium phosphates an d carbonates OL1 carrier proteins that
ithelial cells that surro und the base of the a lveolar secre- center of the brain. T he pinea l gland is a flattened, pine are released in to the cytoplasm w hen the pineal secretions
tory cells and cells of the larger ducts causes milk to be r e- The circu lating level of a specific secretory product of a cone-shaped structure, hence its name (Fig. 20.10). It a re exocytosed . The concretions are recogniza ble in c hild-
leased and pass through the du cts that open onto the target organ, a hormone o r its m eta bolite, may act directly meas ures 5 to 8 mm high and 3 to 5 mm in diameter a n d hood a n d increase in number w ith age. Because they a re
nipple, i.e., milk ejection (see page 762). on the cells of the anterior lobe of the pituitary gland or w eighs between 100 and 200 mg. opaqu e to x-rays a nd located in the midline of the brain,
6 54 CHAPTER 2 0 I 11docri11e O rga11s CHAPTER 20 E11docri11e O rga11s 6 55
and LH from the anterior lobe of the pituitary gland. In two lobes. During this downward migration, the thy-
addition to melatonin, extracts of pineal glands from many roglossal duct undergoes atrophy, leaving an embryologic
animals contain numerous neurotransmitters such as sero- remnant, the pyramidal lobe of the thyroid, which is pres-
tonin, norepinephrine, dopamine, histamine, and h ypo- ent in about 40% of the population. About the ninth week
thalamic regulating hormones such as somatostatin, and of gestation, endodermal cells differentiate into plates of
TRH. Clinically, tumors that destroy the pineal g land are follicular cells that become arranged into follicles. By
associated with precocious (early-onset) puberty. week 14, well-developed follicles lined by the follicular
Animal studies demonstrate that information relating to cells contain colloid in their lumen. During week 7, ep-
the length of daylight reaches the pineal gland from pho- ithelial cells lining t he invagination of the fourth branchial
toreceptors in t he retina. The pinea l gland thus influences pouches (sometimes called the fifth branchial pouches)
seasonal sexual activity. Recent studies in humans suggest known as the ultimobranchial bodies start their migration
that the pineal gland has a role in adjusting to sudden toward the developing thyroid gland and become incorpo-
changes in day length, such as those experienced by travel- rated into the lateral lobes. After fusing with the thyroid,
ers w ho suffer from jet lag. In addition, the pineal gland ultimobranchial body cells disperse among t he follicles,
may play a role in altering emotional responses to reduced giving rise to parafollicular cells that become incorporated
day length during winter in temperate and subarctic zones into the fo llicular epithelium.
(seasonal affective disorder, or SAD).
The thyroid follicle is the structural unit of the thyroid gland
COLLOID @)
MIToe T3.!1 T48
synthesis
OtT- resorption
cells. Both hormones regulate cell and tissue basal me- and is catalyzed by membrane-bound thyroid perox- hormones. Th yroid hormone deficiency during fetal devel-
tabo lism and heat productio n and influence body idase. After oxidation the iodine is then released into opment results in irreversible damage to the CNS, incl ud-
growth and development. Secretion of these hormones is the colloid. ing r ed uced nu mbers of neurons, defective m yelination,
regulated by T SH released from the anterior lobe of the 3. Iodination of thyroglobulin. One or two io dine and mental retardation. If maternal th yro id deficiency is
pitu itary gland. atoms are then added to the specific tyrosine residues Synthesis of T, and T4 is regulated by a simple feedback sys-
present p1:ior to the development of the fetal thyro id gland,
Calcitonin (thyrocalcitonin) is synthesized by the of thyroglobulin. This process occurs in the colloid at tem. The secretion of thyroid hormones is controlled by the re- the mental retardation is severe. Recent studies reveal th at
parafollicul ar cells (C cells) and is a physiologic antago- the microvillar surface of the follicular cells and is lease of TSH from the anterior lobe of the pituitary gland into thyroid hormones also stimulate gene expression fo r GH
nist to parathyroid hormone (PTH ). Calcitonin lowers a lso catalyzed by thyroid peroxidase. Addition of one t he bloodstrea m. Under the influence of TSH, thyroid follicular in the somatotropes. Therefore, in add ition to neural ab-
blood calcium levels by suppressing the resorptive action iodine atom to a single tyrosine residue forms epithelial cells increase in size and activity. The cells become normalities, a generalized stunted body growth is typical.
of osteoclasts and promotes calcium deposition in bones monoiodotyrosine (MIT). Addition of a second io- more columnar, and the iodide transporters and extracellular The combination of these two a bn ormalities is called con-
dine atom to the MIT residue forms a diiodotymsine iod ination of thyroglobulin are stimulated. In addition, thy- genital hypothyroidism (cretinism).
by increasing the r ate of osteoid calcification . Secretion
(DIT) residue. roglobulin synthesis, endocytosis, and lysosoma l breakdown
of calcitonin is regulated directly by blood ca lciu m lev-
4. Formation of T 3 and T 4 by oxidative coupling reac- increase, resulting in the release of large amounts of thyroid
els. High levels of calcium stimulate secretion; low levels
inhibit it. Secretion of calcitonin is unaffected by the hy- tions. The thyroid hormones are formed by oxidative hormones. Low levels of free T, and T4 initiate the release of
TRH from the hypothalamus. In turn, TRH stimulates thy-
9 PARATHYROID GLANDS
poth alamus and pituitary gla nd. Although calcitonin is coupling reactions of two iodinated tyrosi ne residues
rotropes in the anterior lobe of the pituitary gland to secrete
used to treat patients with hypercalcemia, no clinical in close proximity. For example, when neighboring TS H. High serum levels of free T, and T4 inhibit the synthesis The parathyroid glands are small endocrine glands closely
disease has been associated with its deficiency or even its DIT and MIT residues undergo a coupling reaction, and release of TSH. associated w ith the thyroid. They are ovoid, a few mil-
absence after tota l thyroidectomy. T 3 is formed; when two DIT residues react with each linleters in diameter, an d arranged in two pairs, constitu t-
other, T 4 is for med. After iodi nation, T 4 and T3 as ing the supe1ior and infe1ior parathyroid glands. T hey are
The principal component of colloid is thyroglobulin, an inactive well as the DIT and MIT resid ues that are still linked usually located in the connective tissue on the posterior
to a thyroglobu lin molecule a re stored as the collo id Thyroid hormones play an essential role in normal fetal surface of the lateral lobes of the thyroid gland. H owever,
storage form of thyroid hormones
within the lumen of the follicle. development the nu mber and location may vary. In 2 to 10% of indi-
The principal component of colloid is a large (660 kDa) 5. Resorption of colloid. In response to TSH, follicular vidua ls, addi tiona l glands are associated w ith the thymus.
cells take up thyroglobuli n from the collo id by a ln humans, th yroi d hormones are essentia l to normal Structurally, each parathyroid gla nd is surround ed by a
iodinated glycoprotein called thyroglobulin conta ining
process of receptor-mediated endocytosis. Large end o- g rowth and developrnent. In norma l pregnancy both T 3 thin connective tissue capsul e that separates it fro m the
about 120 tyrosine residues. Colloid also contains several
cytotic vesicles called colloidal resorption droplets are and T 4 cross the placenta l barrier and are critical in the thyroid. Septa extend fro m theca psule into the gland to eli-
enzymes and other glycoproteins. It stains with both basic
present at this stage in the apical region of th e follicu- early stages of brain development. In addition, the feta l vide it into poorly defined lobules and to separ ate the
and acid ic dyes and is strongly PAS positive. Thyroglobu-
lar cells. They gradually migrate to the basal surface thyroid gland begins to function during th e fo urteenth densely packed cords o f cells. The con nective tissue is more
lin is not a hormone. It is an inactive storage form of the
of the cells, where they fuse with lysosomes. Thy- week of gestation and also contributes additional thyroid evident in the adu lt, w.ith th e deve lopment of fat cells that
thyroi d hormones. Active thyroid hormones are liberated
from thyroglobulin and released into the fenestrated blood roglobulin is then degraded by lysosomal proteases increase with age and ultimately constitute as m uch as 60
capillaries that surrmmd the follicles only a fter further cel- into constituent amino acids and carbohydrates, leav- to 70 % of the gla ndu lar mass.
lular processing. The thyroid is unique among endocrine ing free T 4 , T 3, DIT, and M IT mo lecules. If the levels The glands receive their blood supply from the inferio r
glands because it stores large amounts of irs secretory of TSH remai n high, the amou nt of colloid in the fo l- thyroid arteries or from anastomoses between the superior
product extracellula rly. licle is reduced because it is synthesized, secreted, iod- and inferio r thyroid arteries. Typical of endocrine glands,
inated, and r esorbed too rapidly to accumulate. rich networks of fenestrated blood capillaries and lymphatic
synthesis of thyroid hormone involves several steps 6. Release of T 4 and T 3 into the circulation and recy- The most common symptom of thyroid disease is a goiter, the capiJlaries surround the parenchyma of the parathyroids.
cling pmcesses. T 4 and T 3 are liberated from thy- enlargement of the thyroid gland. It may Indicate either hy
roglobulin by lysosoma l action in a T 4 -to-T 3 ratio of pothyroidism or hyperthyroidism. . Parathyroid glands develop from the endodermal cells derived
The synthesis of the two major thyroid hormones, th y-
20:1. They cross the basa l membrane and enter the Hypothyroidism can be caused by insufficient dietary iodine from the third and fourth branchial pouches
rox ine (T4 ) and T .1 takes place in the thyroid follicle in a se-
blood and lymphatic capillaries. Most of the released (Iodine-deficiency goiter, endemic goiter) or by one of several
ri es of discrete steps (see Fig. 20 .13): Inherited autoimmune diseases, such as Hashimoto's thyroidi-
hormones are immed iately bound to either a specific Embryologically, the inferio r parath yro id glands (a nd the
tis. The tow levels of circulating thyroid hormone stimulate re
1. Synthesis of thyroglobulin. T he precursor of thy- plasma protein (54 kDa), thymxin-binding protein thym us) are derived from the th ird branchial po uch; the su-
lease of excessive amounts of TSH, which cause hypertrophy
roglobulin is synthesized in th e rER of the fo llicular (70%), or a nonspecific p rea lbumin fraction of serum perior glands, from the fourth branchia l pouch. Normally,
of the thyroid through synthesis of more tl1yroglobulin. Adult
epithelial cells; it is glycosylated there and in the protein (25%), leaving only small amounts (-5%) of the inferior parathyro ids sepa rate from the thymus and
hypothyroidism is ca lled myxedema and is characterized by
Golgi apparatus before it is packaged into vesicles free circulating hormones that are metabolicall y ac- mental and physical sluggishness and edema of the connec come to lie below the superior parathyroids. Failure of these
and secreted by exocytosis into the lumen of the fol - tive. Only the follicula r cells are capable of prod ucing tive tissue. structures to separate results in the atypical association of
licle. T 4 , w hereas most T." wh ich is five times more active In hyperthyroidism {toxic goiter, Graves' disease), thyroid the parath yroids wi th the th ymus in the adult. The principa l
2. Resorption, diffusion, and oxidation of iodide. Fol- than T 4 , is produced through conversion fro m T 4 by cells are stimulated and increase in number and size. However, (chief) cells differentiate during embryonic development and
licular epithelial cells actively transport iodide from organs such as the kid ney, liver, and heart. The free there is little colloid. Thyroid l1ormones secreted at abnormally are functiona lly active in regulating feta l calcium meta bo-
circulating hormones a lso function in the feedback high rates cause an increase in metabolism. Often, toxic lism. T he oxyphil cells differentiate later at pu berty.
the blood into their cytoplasm using ATP-dependent
system that regu lates the secretory activity of the thy- amounts of hormones are produced (thyrotoxicosis). Levels of
iodide transporters. These cells can esta blish an in- TSH are usually normal in hypert hyroidism. In some cases, an
tracellular concentration of iodide that is 30 to 40 roid. Once unco upled fro m thyroglobulin, DIT and Principal cells and oxyphil cells constitute the epithelial cells of
abnormal immunoglobulin called long-acting thyroid stimula the parathyroid gland
times greater than that of the serum. Iod ide ions then MIT molec ules are fu rther deiodi nated within the cy-
tor (LATS) appears to bind to tile TS H receptors on the follicu
diffuse rapid ly toward the apica l cell membrane toplasm of the fo llicular cells to release the amino tar cells, which leads to continuous stimulation of the cells.
w here they are oxidized to iodine, the act ive fo rm of acid tyrosine and iodide, which are then ava ilable for Principal (chief) cells, th e more numerous of the
iodide. This process occurs in the a pical cytoplasm recycling. parenchyma l cells of the para thyroid (Fig. 20.15) , are re-
660 C H AP TER 2 0 ftrdo criue O rg~us C H APTER 20 Eudocriur Orgaus 66 1
sponsible for the secre tio n o f PTH. They are sm a ll, a nd phospha te ar e both released from calcified bone ma-
polygonal cells, with a diameter of 7 to 1 0 J.Lm and a trix into the extracellular fluid.
centrally located n ucleus. The pale-sta ining, sligh tly aci- Kid1tey excretion of calcium is decr eased by PTH stimu -
dophi lic cytoplasm conta ins lipofuscin-containing ves i- lation of tu bula r r eabsor p tio n , t hus conserving calci um.
cles, large acc umulations of glycogen , a nd lipid droplets. U1inary phosphate excretion is increased by PTH secre-
Sm a ll, dense, m embrane- limited vesicles seen with the tion, thus lowering p hospha te concentra t ion in the
TEM or after using specia l stains w ith the ligh t m ic ro- blood a nd extracellular fluids.
scope a re t hought to be the storage form of PTH. Kidney conversion of 25-0H vitamin D 3 to h ormo n a lly
Oxyphil cells constitute a mi n or portion of the active 1,25-(0H) 2 vitamin D 3 is regul ated primaril y by
parenchyma l cells and are not known to have a secretory PTH, w hich stimulates activity of 1-a-h ydroxylase and
role. They ar e found singly o r in clusters; the cells ar e increases the production of a ctive ho rmone.
more rounded , co nsid erably larger than the principal Intestinal absorption of calcium is increased under the
cells, and have a distinctl y ac idoph ilic cytoplasm (see influence of PTH. Vitamin D3 , however, has a grea ter ef-
Fig. 20.15) . Mitoch ondria, often with bizarre shapes fect t han PTH on intestina l absorptio n of c alcium .
and sizes, almost fi ll the cytoplasm and a re responsi ble
fo r the strong acid ophi lia of t hese cells. No secretory PTH and calcitonin have reciprocal effects in the regulation of
vesicles a nd little if a ny rER are present. Cytoplasmic blood calcium levels
incl usion bodies consist of occasional lysosomes, lipid
droplets, a nd glycogen distributed a mong the mito- Although PTH increases blood ca lcium levels, the peak
chondr ia. increase following its release is not reached for severa l
hours. PTH app ears to have a rathe r slow, long-term
PTH regulates calcium and phosphate levels in the blood
ho meostatic a ction. Calcitonin, ho wevet; rap id ly lowers
blood calciLUn levels and has its pea k effect in a bout 1
T he parathyr o ids f unctio n in the regula tion of calcium hour; therefore, it has a rapid, acute homeostatic action.
a nd phosphate levels. PTH, o r parathormoneJ is essentia l
for life. Therefore, ca re must be taken during thyro idec-
tomy to lea ve some funct ioning parathyro id t issue. If the
gla nds a re totally remove d, dea t h wi ll ensue beca use mus-
\1 ADRENAL GLANDS
cles, including the la ryn gea l and othe r res pirato ry muscles, The adrenal (suprarenal) glands secrete both ste ro id hor- FIGURE 20.16
go into teta nic contractio n as the blood calcium level fa lls. mones and ca techo la mines. T h ey have a flatte ned tria ngu - Photomicrograph of the adrenal gland. This low-power micrograph
PTH is a n 84-am_in o acid .linea r peptide (Table 20.8). It
lar shape an d ar e em bedded in t he perirena l fa t a t t he su- of a H&E-sta ined specimen shows the full thickness of the adrenal
b inds to a specific PTH rece ptor o n ta rget cells t hat inte r- perio r poles of the kidneys. gland with tile cortex seen on both surfaces and a central region con-
FIGURE 20.15
act s w ith G protein to activate a second-messenger system. The a d rena l glan ds are covered wi th a thic k conn ective taining the med ulla. Within the medulla are profiles of the central
Photomicrograph of human parathyroid gland. This HaE-stained
specimen shows the gland with part of its connective tissue capsule PTH release ca uses th e level o f ca lcium in the blood to in- ti ss ue caps ule fro m w hich trabecul ae extend into t he vein. Note that the deeper portion of the cortex stains darker than the
(Cap). The blood vessels (BV) are located in the connective tissue sep- crease. Simulta neously, it reduces t he concentra tion of parenchym a, carrying blood vessels a n d nerves. The secre- outer portion, a reflection of the washed-out lipid in the zona
tum between lobes of the gland. The principal cells are arranged in serum phosphate. Secretion of PTH is regulated by t he glomerulosa and outer region of the zona fasciculata. This section
t or y parenchymal tissue is organ ized into c011:ical a nd
two masses (top and bottom) and are separated by a large cluster of serum calcium level th rough a simple feedback system . also includes a cross section of the adrenal vein, which is character-
medullary regions (Fig 20.1 6):
oxyphil cells (center). The oxyphil cells are the larger cell type with Low levels of serum ca lc ium st imulate secretion o f PTH; ized by the longitudinally arranged bundles of smooth muscle in its
promi nent eosinophilic cytoplasm. They may occur in small groups or hi gh levels o f serum calcium inh ibit its secret ion. wall. x20.
in larger masses, as seen llere. The principal cells are more numerous. PTH functio ns a t severa l sites: The cortex is the st eroid-secret ing portion . It lies be-
Tiley are smaller, having less cytoplasm, and consequently exhibit nea t h the capsule and con stitutes nea rly 90% of th e
closer proximity of tlleir nuclei. Adipose cells (AC) are present in vari- Bone resorption is stim ulated by PTH. T he hormone ac- gla nd by weig ht. Blood Supply
able, though limited, numbers. x 175. tiva tes os teo lys is by osteoclas ts during w hich calcium T he medulla is the catech ola min e-sec reting portion. It
T he ad renal gla nds a re supp lied with b lood by th e supe-
lies deep to the cortex and fo rms the center of t he gla nd.
riot; middl e, a nd in ferior supra ren a l arter ies. These vessels
branch before ente ring the caps ule, to prod uce many sma ll
Parenchymal cells of the cortex and medulla are of different
TABLE 20.8. Parathyroid Hormone a rteries th at p enet ra te th e ca psule. In t he capsule, t he ar -
embryologic origin
.teries bra nch to g ive rise to three principa l patterns of
Hormone Composition Source Major Functions
blood d istribut io n (Figs. 20. 1 8 an d 2 0.1 9) . T he vessels
Embryologically, the corti cal cells origina te from meso -
Parathyroid hormone Polypeptide con- Principal (cllief Increases blood calcium level In three ways: (1) promotes calcium form a system that consists of
d ermal mesenc hym e, w hereas t he med ulla originates fro m
(parathormone, PTH) taining 84 amino cells) release from bone (increases relative number of osteoclasts), (2) acts
on kidney to stimulate calcium reabsorption by distal tubule while neural crest cells that m igra te into the develo ping gland Capsular capillaries that suppl y the capsul e
acids
inhibiting phosphate reabsorption in tile proximal tubule, (3) increases (Fig. 20.1 7). Altho ugh em bryologicall y distinct, the two Fenestrated cortical sinusoidal capillaries tha t supply
for mation of hormonally active 1,25-dihydroxycholecalciferol (1 ,25- portio ns o f th e adrena l gla nd a re functiona lly rela ted (see the cortex a nd the n d ra in into the fenestrated medullar y
(0H}, vitamin D,) in the kidney, which promotes tubular reabsorption below). T he parenchyma l cells of the a dren a l cortex a re capi llary sinusoids
of calcium controlled , in part, by the a nteri or lo be of t he pitu itary Medullary a11:erioles that traverse th e cortex, traveling
'Some evidence suggests that oxyphil cells, which first appear in the parathyroid gland at about 4 to 7 years of age and Increase In number after puberty, may g la nd a nd function in reg ulatin g metabo lism a nd ma tn - with in the trabecul ae, a nd bri ng a rteri a l blood to the
also produce PTH. ta ini ng norma l electrolyte bala nce (Table 20 .9). medullary capillmy sinusoids
66'1 C H AP TE R 20 Eudocriut Orgnus CH APTER 20 fudorriur Orgnus 66 3
FIGURE 20.22
Electron micrograph of cells in
the zona fasdculata. The bound-
ary between adjacent cells of the
cord is indicated by the arrow-
heads. Lipid droplets (L) are nu-
merous (the lipid has been par-
tially extracted). XlS,OOO. Inset. A
higher magnification of an area in
the cell at the top of the micro-
graph reveals the extensive sER
that is characteristic of steroid-
secreting cells. Portions of the
Golgi apparatus are also evident.
X40,000.
FIGURE 20.21
Photomicrographs of the cortex and medulla of the human adrenal gorged with red blood cells. x 120. b. The deep parts of the zona fas-
gland. a. This photom icrograph shows a H&E-stained specimen of ciculata, zona reticularis, and medulla are s11own here. Note that the
the outer cortex. It includes the connective tissue capsule, the zona linear arrays of the cords in the zona fasciculata give way to irregular ing interleukin-1 (IL-l) and IL-2 production by lympho- ZONA RETICULARIS
glomerulosa, and t11e zona fasciculata. Continuous with the zona groups of cells of the zona reticularis. The medulla, in contrast, con- cytes and macrophages. Glucocorticoids also stimulate de-
glomerulosa are the straight cords of cells that characterize tile zona sists of ovoid groups of cells and short interconnecting cords of cells.
struction of lymphocytes in lymph nodes and inhibit mito- The zona reticularis produces glucocorticoids and androgens
fasciculata. Between the cords are the capillaries and the less numer- A central adrenomedullary vein is also seen here. Note t11e thick lon-
sis by transformed lymphoblasts. Cells of the zona
ous arterioles. The red linear stripes represent capillaries that are en- gitudinally sectioned smooth muscle in part of its wall. Xl20.
fasciculata also secrete small amounts of gonadocorticoids, The cells of the zona reticularis are noticeably smaller
principally androgens. than those of the zona fa sciculata, and their nuclei are more
deeply stained. They are arranged in anastomosing cords
also have a well-developed Golgi a ppara tus and numerous glucose and fatty acids, both of which are immediate ACTH regulates secretion of the zona fasciculata separated by fenestrated capillaries. The cells have relatively
profiles of rER that may give a slight basophilia to some sources of energy. Within this broa d function, glucocorti-
few lipid droplets. Both light and dark cells are seen. Dark
parts of the cytoplasm (Fig. 20.22). In general, however, coids may have different, even opposite effects in differ- The secretion and production of glucocorticoids and sex cells have abundant large lipofuscin pigment granules, and
the cytoplasm is acidophi lic and contains munerous lipid ent tissues: steroids by the zona fasciculata is under feedback control deeply staining nuclei are evident. The cells in this zone are
droplets, although it usually appears vacuolated in routine
In the liver, glucocorticoids stimulate conversion of of the CRH-ACTH system. ACTH is necessary for cel l sma ll because they have less cytoplasm than the cells in the
histologic sections because of the extraction of lipid during
amino acids to glucose, stimulate the polymerization of growth and maintenance and also stimulates steroid syn- zona fasciculata; thus the nuclei appear more closely
dehydration. The lipid droplets contain neutral fats, fatty
glucose to glycogen, and promote the uptake of amino thesis and increases blood flow tluough the adrenal gland . packed. They exhibit features of steroid-secreting cells,
acids, cholesterol, and phospholipids that are precursors
acids and fatty acids . . Exogenous ACTH maintains the structure and function of namely, a well-developed sER and numerous elongated mi-
for the steroid hormones secreted by these cells.
In adipose tissue, glucocorticoids stimulate -the break- the zona fasciculata after hypophysectomy. In animals, ad- tochondria with tubular cristae, but they have little rER.
down of lipids to glycerol and free fatty acids. ministration of ACTH causes hypertrophy of the zona fas-
The principal secretion of the zona fasciculata is
In other tissues, they reduce the rate of glucose use and ciculata. The principal secretions of the zona reticularis are weak
glucocorticoids that regulate glucose and fatty acid metabolism
promote the oxidation of fatty acids. Circulating glucocorticoids may act directly on the pitu- androgens
In cells such as fibroblasts, they inhibit protein synthesis itary gland, but they most commonly exert their feedback
The zona fasciculata secretes glucocorticoids, so called and even promote protein catabolism to provide amino control on neurons in the arcuate nucleus of th e hypothal- The principal secretion of the cells in the zona reticularis
because of their role in regulating gluconeogenesis (glu- acids for conversion to glucose in the liver. amus, causing the release of CRH into the hypothalamo- consists of weak androgens, mostly dehydroepiandros-
cose synthesis) and glycogenesis (glycogen polyme1'iza- hyophyseal portal circulation. Evidence also suggests that terone (DHEA). The cells also secrete some glucocorti-
tion). One of the glucocorticoids secreted by the zona fas- Glucocorticoids depress the immune and inflammatory circulating glucocorticoids and the physiologic effects that coids, in much smaller amounts than those of the zona fas-
cicu lata, cortisol (hyd1'ocortisone), acts on many different responses and, as a result of the latter, inhibit wound heal- they produce stimulate higher brain centers that, in turn, ciculata. Here, too, the principal glucocorticoid secreted is
cells and tissues to increase the metabolic availability of ing. They depress the inflammatory response by suppress- cause the hypothalamic neurons to release CRH. corti sol.
668 CHAPTER 20
I -.~
PLATE 76. PITUITARY I I
PT I /
I~ ,~
The pituitary gland is located in a bony fossa in the floor of the cranial cavity. It is connected by a stalk to the base of the
brain. Although joined to the brain, only part of the gland, the neurohypophysis, develops from the neural ectoderm. The larger j fJ
I
part of the pituitary, the adenohypophysis, develops from oral ectoderm as a diverticulum of the buccal epithelium, called
Rathke's pouch.
The adenohypophysis regulates other e ndocrine glands. It is composed of clumps and cords of e pithelioid cells, separated
by large-diameter fenestrated capillaries. The neurohypophysis is a nerve tract whose terminals store and release secretory
...
products synthesized by their cell bodies in the supraoptic and para ventricular nuclei. The secretions contain either oxytocin
or vasopressin (antidiuretic hormone [ADH]). Other neurons from the hypothalamus release secretions into the fenestrated
capillaries of the infundibulum, the first capillary bed of the hypophyseal portal system that carries blood to the fenestrated
capillaries of the adenohypophysis. These hypothalami c secretions regulate the activity of the adenohypophysis.
Figure 1, pituitary, human, H&E x50. pars distali s, the anterior lobe of the gland, is its largest
is the expanded portion of the neurohypophysis that is con- Each of the components of the adenohypophysis; i.e. , .'
I
tinuous with the infundibulum. The pars tuberalis (PT) is the pars distalis, pars tuberalis, and pars intermedia, when
located around the infundibular stem but may c over the pars examined at higher magnification, exhibit features at the
nervosa to a variabl e extent. The pars intermedia (PI) is a cellular level that aid in their identification. These features
nruTow band of tissue that lies between the pars distalis are described in the following figures as well as those on
(PD) and the pars nervosa. It borders a small cleft (Cl) that Plate 77.
constitutes the remains of the lumen of Rathke's pouch. The
~Caps
1
]
Figure 2, pituitary, human, H&E x375. Chromophobes (C) are also very numerous in thi s field. The
This photomicrograph shows a region of the pars clistalis
that is rich jn acidophils (A). Basophils (B) are present in
cytoplasm stains poorly in contrast to that of the aciclophils
and basophils. The cells are arranged in cords and clumps,
.
thjs area in lesser numbers. The acidophi ls are readily iden- between which are capillaries (Cap), so me of which can be
tified by the acidophilic staining of their cytoplasm, in con- recognized, but most are in a collapsed state and difficult to
trast to the basophils whose cytoplasm is clearly basophilic. vis ualize at thi s magnifi cation.
Figure 3, pituitary, human, H&E x375. though, typicall y, one cell type outnumbers the other in a
Figure 4, pituitary, human, PAS/aniline blue-black red appearance. The pars intermedia contains a number of
] xao.
This photomicrograph shows a small portion of the pars
cljstalis ( PD ); the remainder reveals the pars inte rmedia
small cysts (Cy). The cells that make up the pars interme-
dia, which is relatively small in humans, consist of small
basophi ls and c hromophobes. The basophils have taken up
( PI). The pars distalis shown here contains numerous capil- the blue stain, thus making them prominent. To the extreme
laries filled w ith reel blood cells, thus producing the bright right is a less cellular area, the pars nervosa ( PN).
KEY
A, aciclophils Caps, capsule PI, pars in termed i a
B, basoph ils Cl, c left PN, pars nervosa
C, chromophobes Cy, cysts PT, pars !Liberal is
Cap, capillaries PD, pars clistalis
670
C H APTER 20 EHdocriH e Orgnus 673
Figure 2, pituitary, human, H&E x325. oxytocin a nd antidiuretic hormone (ADH) (also called va-
KEY
A , acidophil s C, chromophobes HH, Herring bodies
B, basophils Cap, capillaries
672
C HAP TER 20
Figure 1, pineal gland, human, H&E x 180. small arteries (A) and veins (V), course through the con-
Figure 2, pineal gland, human, H&E x 360; inset cells of the pi neal gland). Pinealocytes are modifi ed neu-
x 700. ron s. Their nuclei are spherical and are relatively lightly
This micrograph shows at higher magnification the stained because of the amount of euchromati n that they
parenchyma of the pineal gland as well as a component contain. The second cell type is the interstitial cell or glial
called brain sand (BS) or corpora arenacea. When viewed at cell that constitutes a relatively small percentage of the
even higher magnifications, the corpora arenacea are seen cells in the gland. Their nuclei are smaller and more e lon-
to have an indistinct lamellated structure. Typically, they gate than those of the pinealocytes. The inset reveals sev-
stain heavily with hematoxylin. The presence of these eral glial cells (G) that can be identified by thei r more
structures is an identifyin g feature of the pineal gland. A densely staining nuclei. The majority of the nuclei of the
careful examination of the cells within the gland at the light other cells seen here belong to pinealocytes. Also seen in
microscopic level reveals two specific cell types. One cell the inset are several fibroblasts (F) that are present within a
type represents the parenchymal cells. These are by fa r the trabecula.
most numerous and are referred to as pi nealocytes (or chief
KEY
A, artery Cap, capsule G , glial cell
BS, brain sand CT, connective tissue L, lobule
C, capillary F, fibrobl ast V, vein
674
CHAPTER 20 Eudocriur Organs 677
Figure 1, parathyroid gland, human, H&E x 320. smaller and more intensely staining nucleus. Their cyto-
Figure 2, thyroid gland, human, H&E x 200. nucle i of the cells serve as an indication of their location
KEY
A, adipose cells CT, connective ti ssue a rrows, tangential section of fo llicle wall
BV, blood vessels F, fo ll icles asterisks, shri nkage arti fact
CC, chief cell s OC, oxy phil cell s
676
CHAPTER 20 Emlocrinr Orga11s 679
Figure 1, adrenal gland, human, H&E x45. From the inner portion, the medulla, note the lighter appear-
This low-magnification micrograph of a section through ance of the medullary tissue. A small amount of adipose tis-
the partial thickness of an adrenal gland shows the outer cap- sue (AT) in wh ich the gland is partially embedded is seen at
sule (Cap), the cortex (Co rt) from o ne surface of the gla nd, the upper center of d1e micrograph. The corticomedullary
the underlying medulla (Med), and a very small p01tion of boundary (dashed lines) has a wave-like contour, a reflection
the cortex from the other smface of the gland (Cort, bottom. of the inegu lar shape of the g land. Within the medulla are a
center). The cortex has a distinctly different appearance in number of relatively large blood vessels (BV). These are the
both structural organization and staining characteristics. medullary veins that drain both d1e COitex and the medulla.
Figure 2, adrenal gland, human, H&E x 180. The zona fasciculata (ZF) consists of radially oriented
This is a higher magnification of a portion of the capsule cords and sheets of cell s, usuall y two cells in width, that ex-
and the f ull thickness of the cortex from an area in Figure tend toward the medulla. The cells of the outer part of the
I . T he capsule consists of dense connecti ve tissue in which zona fascicu lata are generally larger tha n those of the inner
the larger arteries (A) travel to give ri se to smaller vessels portion of this zone and typically stain poorly because of
that will supply the cortex a nd medulla. The zona glomeru- the large number of lipid drople ts that they conta in. The
losa (ZG) is located at the outer part of the cortex, immedi- cells of the zona reticul aris (ZR) are relatively small and
ately under the capsule. T he parenchyma of thi s zone con- conta in little or no lipid droplets and, consequently, stain
sists of small cells that appear as arching cords or as oval prominently with eosin. Because of thei r small size, the nu-
groups of cells. clei are in close proximity to one another, much like the
cells of the zona glomerulosa.
Figure 3, adrenal gland, human, H&E x 245. with lipid droplets, thus, the very poor staining characteristic
This is a higher magnification of the area inscribed by the of their cytoplasm. Delicate connective tissue trabeculae (ar-
left rectangle in Figure 2. It shows the zona glomerulosa (ZG) mws) extend fro m d1e capsule to surround the glomerular
and the outer portion of the zona fasciculata (ZF). Note the groups of cells and extend between the cords of cells in the
smaller size of the cells in the zona glomerulosa than those in zona fasciculata. Capillaries and arterioles are located within
the zona fasciculata. In addition , cells of the zona glo merulosa the connective tissue trabecul ae. Usually, the capillaries are
contain fewer lipid droplets than those of the zona h1sciculata. collapsed and, without the presence of red blood cells in their
Typically, the cells in this part of the zona fasciculata are fi lled lumina, are thus difficult to identify.
Figure 4, adrenal gland, human, H&E x245. in lesser amounts. The cells of the zona reticularis (ZR) are
T hi s is a higher magnificatio n of the area inscribed by auanged in irregular a nastomosing cords and contain at
the right rectangle in Figure 2. This deep portion of the best only a small a mount of li pid and, consequently, the ir
zona fascic ulata (ZF) reveals smaller cells, altho ugh they cytoplasm stains with eos in.
are still arranged in cords and contain lipid droplets, though
KEY
A, arteries Cort, cortex ZR, zona reticularis
AT, adipose tissue Med, medulla arrows, connective tissue trabeculae
BV, blood vessels ZF, zona fascicu lata dashed line, corticomedullary boundary
Cap, capsule ZG, zona glomerulosa
678
CHAPTER 2 0 f,docri~tt Orgnus 68 I
Figure 1, adrenal gland, human, H&E x 175; inset greater intensity of eosin staining. In this photomicrograph ,
@ X250.
This moderately low p ower photomicrograph shows the
cells of the adre nal medulla. The medullary cells are organ-
a portion of the wall , namely, the tunica media (TM) of a
medullary vei n, can be seen. The nature of the medull ary
veins is described in Figure 2. The inset shows the ovoid
ized in ovoid groups and short inte rconnecting cords. The groups of medullary cells at a higher magnification. Be-
cytoplasm of the medullary cells may stain with d ifferent tween these groups of cells are capillaries (Cap) that, as in
intensity. The cytoplasm of some cells is very poorl y the cortex, can be identified w hen they contain red blood
stai ned, appearing almost clear, whereas others show cells as shown here.
Figure 2, adrenal gland, human, H&E x 125. Thus, the muscle seen he re is c ut in cross section, as is the
Figure 3, adrenal gland, human, H&E x 350. titia in the smaller medull ary veins. fnstead, its connective
KEY
Cap, capillary MC, medullary cells TI, tunica intima
GC, ganglion cells MV, medul lary vei n TM, tunica media
L, lumen of medull ary vein SM, smooth muscle
680
\1 OVERVIEW OF THE MALE pended by the spermatic cords and tethered to the scrotum
Male Reproductive
cles, prostate, and bulbourethra l glands. The two primary The testes develop on the posterior wall of the abdomen and
functions of the testis are the production of sperm, male later descend into the scrotum
ga metes (spermatogenesis) and synthesis of androgens, or
BOXES
bulbourethral gland
BOX 21 .1. Functional Considerations: Hormonal Regulation of
Spermatogenesis 690
BOX 21.2. Clinical Correlations: Factors Affecting Spermatogenesis 694 ductus deferens
BOX 21.3. Clinical Correlations: Sperm-Specific Antigens and the Immune
Response 700
BOX 21.4. Clinical Correlations: Benign Prostatic Hypertrophy and Prostatic tunica vaginalis testis epididymis
Cancer 709
FIGURE 21.1
BOX 21.5. Clinical Correlations: Mechanism of Erection and Erectile Schematic diagram demonstrating the components of the male re- bilateral structures including the testis, epididymis, ductus deferens,
Dysfunction 712
productive system. Midline structures are depicted in sagittal section; and seminal vesicle are shown intact.
682 683
684 CHAPTER 2 1 Mnle Rcproduclivr Syslem CHAPTER 21 Mnle Re~roduclive Syslem 685
mesonephric duct
duct of
epididymis
testis with the developing scrotum. The testes descend into XV
the scrotum by passing thro ugh the inguinal canal, the
mesorchium
narrow passage between the abdominal cavity and the
degenerating scrotum. Descent of the testis is sometimes obstructed, re- ~ ch romoso mes
para mesonephric sulting in cryptorchidism, or undescended testes. This con- determining
duct genetic
d ition is common (30 %) in premature newborns and
about 1 % of full-term newborns. Cryptorchidism can lead sex
efferent ductule
to irreversible histologic changes in the testis and increases
rete testis the risk of testicular cancer. Therefore, an undescended SRY gene
testis requ ires surgical correction. Orchiopexy (placement T DF(+) region
paramesonephric
duct in the scro tal sac) should be performed, preferably before
histo logic changes become irreversible at approximately 2
~
1
seminiferous tunica .,..__ region
cords albuginea
b septum c years of age. determining
gonadal
FIGURE 21.2
Spermatogenesis requires that t he t estes be maintained below sex
Schematic diagram of the stages of testicular development. a. This entiation of the primary sex cords into seminiferous cords. At the
diagram shows the 5-week embryo in the stage of indifferent gonads. same time, the developing gonad produces MOIIerian-inhibiting fac normal body temperature
gonad in
The gonadal ridges visible on the posterior abdomina l wall are being tor (MIF), which causes regression of the paramesonephric duct and
indifferent
infiltrated by primordial germ cells (green) that migrate from the yolk those structures derived from it. Note that the mesonephric tubules As the testes descend from the abdominal cavity into the stage
sac. Most of the developing gonad is formed by mesenchyme derived come in close contact with the developing rete testis. c. Final stages scrotum, they carry with them blood vessels, lympha tic
from the coelomic epithelium. The primordial germ cells become in- of testicular development. The tunica albuginea surrounding the vessels, autonomic nerves, and an extension of the abdom-
corporated in the primary sex cords. b. At a later stage, under hor- testis contributes to development of the testicular septa. TI1e rete ina l peritoneum called the tunica vaginalis, which covers
monal influence of testis-determining factor (TDF). the developing go- testis connects with the seminiferous cords and with the excurrent their a nterolatera l surface. Within the scrotum the temper-
nad initiates production of testosterone. This is followed by differ- duct system that develops from the mesonephric duct and tubules.
ature of the testes is 2 to 3C below body tem perature . .
T his lower temperature is essential for spermatogenesis,
but is not required for hormo ne production (steroidogene- secret ion
determining
sis), which ca n occur at norma l body temperature. If the r.:::::;:l hormonal
P1'im01'dial germ cells that migra te from the yolk sac velop into either a ma le or female. Earl y in male develop- testes are ma intained at higher temperatures (e.g., because -~ ~sex
into developing gonads, wher e they di vide and d ifferen-
tiate in to spermatogonia
ment, mesenchyme separati ng the seminifer ous cords gives
rise to Leydig (interstitial) cells that produce testosterone
,_____
~ ---' t
to stimu late development of d1e indiffe rent pr imord ium paramesonephric mesonephric ,.--
u-ro_g_e_n-it_a_l _
s i_n_u_s_ J
Migration of the primordial germ cells into the geni- into a testis. Testosterone is also responsible for the growth duct duct and indifferent genitali~
ta l ridges ind uces mesodermal cel ls of the urogenital and differentiation of rhe mesonephric (Wolffian) d ucts mesonephric
FIGURE 21.3 tubules
l
ridges and cells of the coelomic mesothelium to prolif- that develop into the male genita l excurrent ducts. Also in
Schematic diagram of m ale sex development and hormonal influ-
erate and form the primary sex cords. Later, these cords this early stage, the Sertoli (sustentacular) cells that de-
ence on developing reproductive organs. TI1is diagram illustrates
differentiate into th e seminiferous cords, w hich give rise velop within the seminiferous cords produce another im-
three levels on which the sex of the developing embryo is deter-
to the seminife1'0us tubules, straight tubules, and rete porta nt hormo nal substa nce, called Miillerian-inhibiti11g mined. The genetic sex is determined at the time of fertilization; go- efferent ductules penis
testis (Fig. 2 1.2). factor (MIF). MIF's molecula r structure is simila r to that nadal sex is determined by activation of the SRY gene located on the epididymis scrotum
ln the firs t stage of development, th e testes develop on of tra nsfo rming growth factor f3 (TGF-[3 ). It is a large gly- short arm of chromosome Y; and hormonal sex is determined by a ductus deferens prostate gland
the posterior abdo minal wa ll fr om indiffe rent pri mo rd ia of
urogenital ridges that ar e identica l in both sexes. Duting
this indifferent stage a n em bryo has th e potential to de-
co pro tein tha t inhi bits cell d ivision of the paramesonephric
(Mi.illerian) ducts, wh ich in turn in hibits development of
fem ale repro ductive organs (Fig. 21.3).
hormone secreted by the developing gonad. The diagram shows the
Influence of MOIIerian-inhibiting factor (MIF), testosterone, and dihy-
drotestosterone (DHT) on the developing structures.
regression J seminal vesicle
ejaculatory duct
prostatic urethra
penile urethra
686 CHAPTER 21 Mn/ e Re/Jrotluctive Systc111 CHAPTER 21 lvln/e Re!notluctiiJe Syste111 687
of feve r) or if they fail to descend into the scrotum, sperm Structure of the Testis Each lobule consists of several highly convoluted seminiferous seminiferous epithelium is an unusual ai1d complex strati-
are not produced . tubules fied epithelium composed of two basic cell populations:
Each testis receives blood through a testicular artery, a The testes have an unusually thick connective tissue capsule,
direct branch of the abdominal aorta. It is highly convo- the tunica albuginea Each lobule of the testis consists of 1 to 4 seminiferous Sertoli cells, also known as supporting, or sustentacu-
luted near the testis, where it is surrounded by the tubules in which sperm are produced and a connective tis- lar, cells. These cells do not replicate after puberty. Ser-
pampiniform venous plexus, which carries blood from the An unusually thick, dense connective tissue capsule, sue stroma in which Leydig, or interstitial, cells are con- toli cells are columnar cells with extensive apical and lat-
testis to the abdominal veins. This arrangement allows the tunica albuginea, covers each testis (Fig. 21.4). The tained (Fig. 21.5). Each tubule within the lobule forms a eral processes that surround the adjacent sper matogenic
heat exchange between the blood vessels and helps main- inner part of this capsule, the tunica vasculosa, is a loop and, because of its considerable length, is highly con- cells and occupy the spaces between them. However, this
tain the testes at a lower temperature. The cooler venous loose connective tissue layer that contains blood vessels. voluted, actually folding on itself within the lobule. The elaborate configuration of the Sertoli cells cannot be
blood returning from the testis cools the arterial blood be- Each testis is divided into approximately 250 lobules by ends of the loop are located near the mediastinum of the seen distinctly in routine hematoxylin and eosin (H&E)
fore it enters the testis through a countercurrent heat ex- incomplete connective tissue septa that project from the testis, where they assume a short straight course. This part preparations. Sertoli cells give structural organization to
change mechanism. In addition, the cremaster muscle, capsule. of the seminiferous t ubule is called the straight tubule the tubules as they extend through the full thickness of
whose fibers originate from the internal abdominal oblique Along the posterior surface of the testis, the tunica al- (tubuli recti). It becomes contin uous with the rete testis, an the seminiferous epitheli um.
muscle of the anterior abdominal wall, responds to buginea thickens and projects inward as the mediastinum anastomosing channel system within the mediastinum. Spermatogenic cells, which regular ly replicate and dif-
changes in ambient temperature. Its contraction moves the testis. Blood vessels, lymphatic vessels, and the genital ex- ferentiate into mature sperm . These cells are derived
testes closer to the abdominal wall, and its relaxation low- current ducts pass through the mediastinum as they enter The seminiferous tubules consist of a seminiferous epithelium from primordial germ cells originating in the yolk sac
ers the testes within the scrotum. or leave the testis. surrounded by a tunica propria that colonize the gonadal ridges during early develop-
ment of the testis. Spermatogenic cells are organized in
Each seminiferous tubu le is approximately 50 em long poorly defined layers of progressive development be-
(range, 30 to 80 em) and 150 to 250 f.J..m in diameter. The tween adjacent Sertoli cells (Fig. 21.6). The most imma-
rent ductules
ductus
deferens ...
..
. .
~
.. .. '
,. ~
~
septum
mediastinum tunica f.
testis albuginea
4<
rete testis
tunica
vaginal is
straight tubules
of the epididymis
a
FIGURE 21.4
Sagittal section of the human testis. a. This scl1ematic diagram shows Biology: A Textbook of Histology. 6th ed. Baltimore: Urban & Schwarzen- FIGURE 21.5
a midsagittal section of th e human testis. The genital duct system, berg, 1988.) b. Sagittal section of a H&E-stained section of the testis Photomicrographs of human testis. a. This low-magnification pho- present in tile section are variable in appearance. X30. b. A higher
wh ich includes the tubuli recti, rete testis, efferent ducts, duct of tl1 e and the head and body of the epididymis. Again note the surround- tomicrograpll of a H&E-stained section of a human testis shows sem- magnification of t11e previous specimen shows several seminiferous
epididymis, and ductus deferens, is also shown. Note the thick con- ing tunica albuginea and tunica vagina lis. Only a small portion of tl1e iniferous tubules and tile tunica alb!Jginea. The larger blood vessels tubu les. Note the population of Leydig (interstitial) cells tllat occur in
nective tissue covering, the tunica albuginea, and the surrounding tu- rete testis is visible in this section. Its connection with the excurrent are present in the inner aspect of the tunica albuginea. The seminif- small clusters in t11e space between adjoining tubules. x250.
nica vaginalis. (Modified from Dym M. In: Weiss L, ed. Cell and Tissue duct system is not evident in t11e plane of this section. x 3. erous tubules are highly convoluted; thus the profiles that they
688 CHAPTER 21 1\tlnle Repmtlucrive Syslem
C H APTER 2 1 Mnle ReJnoduclillc System 6 89
ture spermatogenic cells, called spermatogonia, rest on duct system. Blood vessels an d extensive lymphatic vascu-
the basal lamina. The most mature cells, called sper- lature as well as Leydig cells are present externa l to the
matids, are attached to the apical portion of the Sertoli m yoid layer.
cell, where they bo rder the lumen of the tubule. As a normal consequence of aging, the tunica propria in-
creases in thickness. This thickening is accompanied by a
The tunica (lamina) propria, also called peritubular tis- decreased rate of sperm production and an overall reduc-
sue, is a multilayered connective tissue that lacks typica l tion in the size of the seminiferous tubules. Excessive thick-
fibroblasts. In man, it consists of three to five layers of ening of the tunica propria earlier in life is associated w ith
myoid cells (peritubular contractile cells) and collagen infertility.
fibrils, external to the basal lamina of the seminifero us ep-
ithelium (see Fig. 21.6). In rodents, the tunica propria
Leydig Cells
consists of a single layer of squamous myoid cells in an ep-
ithelioid arrangement. At the ultrastructural level, myoid Leydig cells (interstitial cells) are large, polygonal ,
cells demonstrate features associated with smooth muscle eosinophilic cells that typically contain lipid droplets (Fig.
cells, including a basal lamina and large numbers of actin 21.7) . Lipofuscin pigment is also freque ntly present in
filaments. They also exhibit a significant amo unt of rough these cells as well as distinctive, rod-shaped cytoplasmic
endoplasmic reticulum (rER), a feature indicating their crystals, the crystals of Reinl<.e (Fig. 21.8). In routine his-
role in collagen synthesis in the absence of typical fibrob- tologic preparations, these crystals are refractile and meas-
lasts. Rhythmic contractions of the myoid cells create ure approximately 3 X 20 f.LITl Although their exact nature
peristaltic waves that help move spermatozoa and testicu- and function remain unknown, they probably represent a
lar fluid through the seminifero us tubules to the excurrent protein product of the cell.
FIGURE 21.7
Electron micrograph of Leydig cells. This electron mi
crograph shows portions of several Leydig cells. The
cytoplasm contains an abundance of sER, a character
istic of Leydig cells. Other features characteristic of the
Leydig cell seen in the lower-power mi crograph are the
numerous lipid droplets (L), the segmented profiles of
late spermatid the Golgi apparatus (G), and the presence of variable
numbers of lysosomes (Ly). Occasional profiles of rER
are also seen. Note also the presence of microvilli
along portions of the cell surface (arrows). M, cytoplasm ...
... ~. ":; ...
of adjacent macrophage. X10,000. Inset. sER at higher " ,'
...~~ ,\', ~: _.M
pachytene
magnificati on. The very dense particles are glycogen.
X60,000
' .'
~ ( ') I ~
-1'.
. , :: ..:....
~ .. "l ,,, :
.'
;'
primary
spermatocyte
junctional comple><
Like other steroid-secreting cells, Leydig cells have an At puberty, secretion of testosterone is responsible for the
basal lamina elaborate smooth endoplasmic reticulum (sER), a feat ure in.itiation of sperm production, accessory sex gland secre-
that accou nts for their eos in ophilia (see Fig. 21.7) . The en- tion, and development of secondary sex characteristics.
zymes necessary fo r the synthesis of testosterone from cho- In the adult, secretion of testosterone is essential fo r the
peritubular (myoid) ce lls
lesterol are associated with the sER. MitochondTia with ma intenance of sperma togenesis and of secondar y sex
tu bulovesicul ar cristae, another characteristic of steroid- characteristics, genital excurrent ducts, and accessory
type A dark type B pale
spe rmatogon ium secreting cells, a re also present in Leyd ig cells. sex gla nds.
spe rmatogonium
Leydig cells differentiate and secrete testosterone during
FIGURE 21 .6 earl y fetal life. Secretion of testosterone is req uired dur ing The Leydig cells are active in the earl y differentiation of
Schematic drawing of human seminiferous epithelium. This drawing epithelium below the junctional complex, between adjacent Sertoli
embryonic development, sexual matura tion, and reproduc- the male fetus and then undergo a period of inactivity be-
shows the relationship of the Sertoli cells to the spermatogenic cells. cells. Pachytene primary spermatocytes, early spermatids, and late ginning at about 5 months of fetal life. Inactive Leydig cells
tive fu nction:
The seminiferous epithelium rests on a basal lamina, and a layer of spermatids, with partitioning residual cytoplasm that becomes the are difficu lt to distinguish from fibroblasts . When Leydig
peritubular cells surrounds the seminiferous tubule. The sperrnatogo residu al body, are seen above the junctional complex in the ablurni In the embryo, secretion of testosterone and other an- cells are exposed to gonadotropic stimulation at puberty,
nia-type A pale, type A dark, and type B pale-and preleptotene sper nal compartment. (Redrawn from Clermont Y. Am J Anat 1963;112:35.) drogens is essentia l for the normal development of the they again become androgen-secreting cells and remain ac-
matocytes are located in the basal compartment of the seminiferous gonads in the male fetus. ti ve throughout life.
690 C HAPTER 21 Mnle Reprodccctive System CHAPTER 21 /vlnle RepmdciCtive System 69 l
Spermatogonial Phase nia that remain as stem cells or to a pair of type Ap sper-
matogonia (see below).
In the spermatogonial phase, stem cells divide to replace Type A pale (Ap) spennatog011ia ha ve ovoid nuclei with
themselves and provide a population of committed lightly staining, finely gran ular chromatin. Ap sper-
spermatogonia matogonia are committed to the differentiation process
The endocrine function of the testis resides primarily in the
Leydig cell population that synthesizes and secretes the prin-
that pr od uces the sperm. They undergo several succes-
cipal circulating androgen, testosterone. Nearly all of the Spermatogonial stem cells undergo multiple divisions sive mitotic divisions, thereby increasing their number.
testosterone is produced by the testis; less than 5% is pro- and produce spermatogonial progeny that display differ- Type B spermatogottia have genera lly spherical nuclei
duced by the adrenal glands. It is estimated in humans that the ences in nuclear appearance in routine H&E preparations. with chromatin that is condensed into large clumps
total Leydig cell population produces about 7 mg of testos- Human spermatogonia are classified into three types on along the nuclear envelope and aro und a central nucleo-
terone per day. As the testosterone leaves the Leydig cells, it the basis of the appearance of the nuclei in ro utine histo- lus (see Fig. 21.6).
passes into blood and lymphatic capillaries and across the per- logic preparations:
itubular tissue to reach the seminiferous epithelium. An unusual feature of the division of an Ad spermato-
High local levels of testosterone within the testis (estimated Type A dark (Ad) spermatogonia have ovoid nuclei with gonium into two type Ap spermatogonia is that the
to be as much as 200 times the circulating levels) are neces- da ughter cells remain connected by a thin cytoplasmic
intensely basophilic, finely granu lar chromatin. These
sary for the proliferation and differentiation of spermatogenic
spermatogonia are thought to be the stem cells of the bridge. This same phenomenon occurs through each sub-
cells. The lower peripheral level of testosterone influences
semi niferous epithelium. They divide at irregular inter- sequent mitotic and mei otic division of the progeny of the
Differentiation of the central nervous system (CNS) and vals to give rise to either a pair of type Ad spermatogo- original pair of Ap spermatogonia (Fig. 21.9). Thus, a ll of
the genital apparatus and genital excurrent duct system
Growth and maintenance of seconda1y sexual character-
istics (such as the beard, male distribution of pubic llair,
and low-pitched voice)
Growth and maintenance of the accessory sex glands
(seminal vesicles, prost ate, and bulbourethral gland s),
genital excurrent duct system, and the external genitalia
(mainly by products of testosterone conversion to DHT)
Anabolic and general metabolic processes, including
skeletal growth, skeletal muscle growth, distribution of
subcutaneous fat, and kidney function
Behavior, including libido
the progeny of an initial pair of Ap spermatogonia are plate. This random sorting is another som ce of genetic di- MEIOSIS
connected, mucb like a strand of pearls. These cytoplas- versity in the resulting sperm. MITOSIS prophase I
mic connections remain intact to the last stages of sper- The cells derived from the first meiotic division are
matid maturation and are essential for the synchronous called secondary spennatocytes. These cells immediately
development of each clone from an original pair of Ap enter the prophase of the second meiotic division without
cells. S'yn thesizing new DNA (i.e., without passing through an S
After several divisions, type A spermatogonia differenti- phase; see page 69). Each secondary sperma tocyte has 22
ate into type B spermatogonia . The appearance of type B autosomes and an X or a Y cluomosome. Each of these
spermatogonia represents the last event in the spermatogo- chromosomes consists of two sister chromatids. The sec-
nial phase. onda1y spermatocyte has the 2n (diploid) amount of DNA. prophase
Du ring metap hase of the second meiotic division, the chro-
mosomes line up at the metaphase plate, and the sister
Spermatocyte Phase (Meiosis) chromatids separate and move to opposite poles of the
spindle. As the second meiotic division is completed and
In the spermatocyte phase, primary spermatocytes undergo the nuclear membranes reform, two haploid spermatids,
meiosis to reduce both the chromosome number and the each containi ng 22 single-stranded chromosomes and the
amount of DNA metaphase
ln amount of DNA, a re formed from each secondary sper-
matocyte (Fig. 21.10).
The mitotic division of type B spermatogonia produces
primary sperm atocytes. They replicate their DNA shortly
after they form and before meiosis begins, so that each pri-
Spermatid Phase (Spermiogenesis)
mary spermatocyte contains twice the normal chromoso-
anaphase telophase I
mal number (4n) and doub le the amount of DNA.
Meiosis results in reduction of both the num ber of cl1ro- In the spermatid phase, spermatids undergo extensive cell re-
mosomes and the amo unt of DNA to the haploid condi- modeling as they differentiate into mature sperm
tion. Meiosis is described in detail in Chapter 2 (see page
69); a brief description of sperm atocyte meiosis follows .
Prophase of the fust meiotic division, during which tbe
chromatin condenses into visible chromosomes, lasts up to
22 days in human primary spermatocytes. At the end of
prophase, 44 a utosomes and an X and a Y ch romosome,
Each spermatid that results from the second meiotic di-
vision is haploid in DNA content and ch1omosome num-
ber (22 autosomes and an X or Y chrornosome) . No fur-
ther division occurs. The haploid spermatids undergo a
differentiation process that prod uces mature sperm, which
(3.
.
telophase
.:
.... ..-..
ole
=;;:
cn'5
c0
'(i)
u; (ij spermatids
0-
each having two chromatin strands (chromatids), can be are also haploid. The normal diploid condition is restored .Q) 0
daughter cells
identified. Homologous chromosomes are paired as they when a sperm fertilizes an oocyte. Eiil
::l
CT
line up on the metap hase plate. The extensive cell remodeli.n g that occurs during di ffer- ~
The paired homologous chromosomes, called tetrads be- entiation of the spermatid population into matu re sperm t t t .... . \
spermatozoa ~ ~ \
cause they consist of fou r chromatids, exchange genetic
material in a process call ed crossing-over. During this ex-
(spermiogenesis) consists of four phases. These phases oc-
cur while the spermatids are physically attached to the Ser- f \ spe rmiogenesis
cha nge, the four chro matids rearrange into a tripartite toli cell plasma membrane by specialized junctions. The FIG URE 21 .10
structure called a S)maptonemal complex. This process en- morp hologic changes in all four phases that occur during Comparison of mitosis and meiosis in a spermatogonial cell. Tile two number of chomosomes (n). ln addition, during the chromosome
sures genetic diversity. T hro ugh genetic exchange, the four spermiogenesis are described below and sumtnarized in pairs of chromosomes (2n) of maternal and paternal origin are de pairing in prophase l of meiosis, chromosome segments are ex-
picted in red and blue, respectively. Tile mitotic division produces changed, crossing-over, creating genetic diversity. In humans, the first
spermatids produced from each spermatocyte differ fro m Figure 21.11.
daughter cells that are genetically Identica l to the parental (2n) cell. polar body does not divide, but it does so in otl1er species. *Note that
each o ther and from every other spermatid. After crossing-
The meiotic division, which has two components, a reductional divi propl1ase ll, anapl1ase ll, and telophase II are not shown.
over is complete, the homologous chromosomes sepa rate Golgi phase. This phase is characterized by the presence sion and an equatorial division, produces a cell that l1as only half tile
and move to the opposite poles of the meiotic spindle. of peri odic acid-Schiff (PAS)-positive gra nu les that ac-
T hus, the tetrads, w hich have been modified by crossing- cumulate in the mu ltiple Golgi complexes of the sper-
over, sepa rate and become d yads agai n. The two chro- matid . These pmacrosomal granules, rich in glycopro- nine peripheral microtubule doublets and two central Sertoli cell and points toward the basal lamina. The de-
matids of each original chromosome (although modi.fied teins, coalesce into a membra ne-bounded vesicle, the m icrotubules that constitute the axoneme of the sperm veloping flagellum extends into the lumen of the semi-
by crossing-over ) remain together. Thi s is just the opposite acrosomal vesicle, adjacent to the nuclear envelope. The tail (see page 92). niferous tubule. The condensed nucleus of the spermatid
of what happens in mitosis, in which the paired chro- vesicle enla rges and its contents increase durin g this Cap phase. In this phase, the acr osomal vesicle spreads flattens and elonga tes, the nucleus and its overlying
matids- o ne representing " template" and the o ther, newly phase. The position of the acrosornal vesicle determines over the anterior half of the nucleus. This reshaped struc- acrosome also move to a position immediately adjacent
synthesized DNA-separate. the anterior pole of the developing sperm. Also during ture is called the acrosomal cap. The portion of the nu- to the anteri or plasma membrane, and the cytoplasm is
The movement of a particular chromosome of a homol- this phase, the centrioles migrate from the juxtanuclear clear envelope beneath the acrosomal cap loses its pores displaced posteri orly. T he cytoplasmic microtubules be-
ogous pair to either pole of the spindle is random; i.e., ma- region to the posterior pole of the spermatid, wher e the and becomes thicker. The nuclear contents also condense. come organized into a cylindrical sheath, the manchette,
ternally derived chromosomes and paternall y derived chro- mature centrio le aligns at right angles to the plasma Acrosome phase. In this ph ase, the spermatid reorients which extends from the posterior rim of the acrosome
mosomes do not sort themselves o ut at the metaphase membrane. T he centriole initiates the assembly of the itself so tha t the head becomes deep ly embedded in the toward the posterior pole of the spermatid.
694 CH APTER 21 Male Reflroduclive Sysle111 CHAPTER 21 Malr Rrprotluclivr Systr111 69 5
This short segment of the tail distal to the fibrous cell membrane
sheath is called the end piece.
Maturation phase. This last phase of spermatid rem od-
eling r educes excess cytoplasm. The Sertoli cells th en
phagocytose t h is excess cytoplasm, also termed the nucleus nucleus
residual body. The intercell ular bridges that have char-
acterized the developing gametes since t he prespermato-
cyte stages remai n with the resid ual bodies. Spermatids
are no longer attached to each o ther and are released
from the Sertoli cells.
manchette
acrosomal cap
Structure of the Mature Sperm
head1
postacrosoma l
annulus region
The events of spermiogenesis result in a structurally unique
neck-c
cell
} m;ddle p;ec,
The mature h uman sperm is about 60 tJ.m long. T he
sperm head is flattened and pointed and measures 4.5 J.UTI
long by 3 tJ.m wide by 1 fJ-111 thick (see Fig. 21.12). The
acrosoma l cap that covers t he an terior two-thirds of the
nucleus contains hyalu ronidase, neuraminidase, acid phos-
phatase, and a trypsin-like p rotease ca lled acrosi n. T hese ---~mitochond r i al
acrosoma l enzymes are essentia l for penetration of the sheath
zona pellucida of the ovum. The release of acrosomal en-
principal
FIGURE 21.11 zymes as t he sperm touches the egg is the first step in the piece
Schematic diagram of spermiogenesis in the human. The basic tail
acrosome reaction. This complex p rocess faci litates sperm outer dense fibers
changes in the structure of the key organelles of the spermatid are il- penetration a nd subsequent fertilization and prevents the
lustrated (see text for detailed explanation). (Modified from Dym M. microtubules of the
entry of add itional sperm into the ov um . axo nemal complex
In: Weiss L, ed. Cell and Tissue Biology: A Textbook of Histology. 6th ed.
Baltimore: Urban & Schwarzenberg, 1988.)
1
fibrous sheath
The centrioles, which had earlier initiated the devel- eod p;ece
opment of t he flage ll um, now move back to the poste-
rior surface o f the nucleus where the immature cent riole outer dense
Spermatogenic cells are very sensitive to noxious agents. De fibers 4, 5, 6
becomes attac hed to a shallow groove in the nucleus.
generative changes, such as premature sloughing of t he cells outer doublets of axonemal com plex
They are then modified to fo rm the connecting piece, or
neck region, of the developing sperm. Nine coarse fibers or formation of multinucleated giant cells, are readily apparent central pair of microtubules of axonemal complex
following exposure to such agents. Factors that affect sper-
d evelop from the centrioles attached to the nucleus and FIGURE 21.12
matogenesis include
extend into t he tail as the outer dense fibers periph eral Diagram of a human spermatozoon. Regions of the spermatozoon piece of the spermatozoon are illustrated on the right. (Modified from
to the micro tubules of the axoneme. These fibers unite Dietary deficiencies are indicated on the left. Key structural features of tile head (viewed Pederson PL, Fawcett OW. In: Hafez ESE, ed. Human Semen and Fertil-
the nucleus with the flagellum, hence the name connect- General or local infections in frontal and sagittal planes), tl1e middle piece, and the principal ity Regulation in the Male. St. Louis: CV Mosby, 1976.)
ing piece. Elevated testicular temperature
As the plasma membrane moves posteriorly to Steroid hormones and related medications
cover the growing flagellum, the manchette disappears, Toxic agents such as mutagens, drugs, antimetabolites, The sperm tail is su bdivided into the neck, the m id d le piece, approximately the last 5 fJ.lTI of the flagellum in the
and pesticides (particularly short-chain halogenated hy-
and the mitochondria mig rate from the rest of the cy- piece, the principa l piece, and the end piece. T he short neck mature sperm, contains only t he axonema l comp lex.
drocarbons)
toplasm to form a tight, helicall y wrapped sheath conta ins the centrioles and t he origin of the coarse fibers .
Radiation
around the coarse fibers in the neck regio n and its T he m idd le piece is app roximately 7 fJ.ITI lo ng and contains Newly released sperm are nonmotile
immediate posteri or extension (Fig. 21.12). This regio n Proliferating cells are particularly sensitive to mutagenic agents the m ito chondria, helically wra pped around the coarse fibers
is th e middle piece of the ta il of the sperm. Distal to and the absence of essential metabolites. Therefore, nondivid- and the axonema l com plex. These mitocho ndria provide t he Newly released sperm ar e carried from the sem iniferous
ing Sertoli cells, Leydig cells, and reserve stem cells, which energy for movement o f the tail and th us are responsible fo r
the middle piece, a fibrous sheath consisting of two t ub ules in a flu id secreted by the Sertoli cells. T he fluid and
demonstrate low mitotic activity, are much less vulnerable
longitudinal columns an d n umero us connecting ribs the mo ti lity of the sperm. T he principal piece .is approxi- sper m flo w t hrough t he seminiferou s tubules, facilita ted by
than actively dividing, differentiating spermatogenic cells.
surrou nds t he nine lo ng itudina l fibers of the principal mately 40 tJ.m long and contains the fibrous sheath external peristaltic contractions of the per itu bul ar contra ctile cells
piece and extends nearly to the end of the flagellum. to the coarse fibers and the axonemal comp lex. T he end o f the lamina p ropria . T hey then enter the straight tubules,
CHA PTER 21 Mnle Reproductive Sys te111 69 7
696 CHAPTER 21 lvlale ReproductiiJe Syslew
STAGE I
a short segment of the seminiferous tubule where the ep- sies of the seminiferous tubules. In this way, the time re-
ithelium consists only of Sertoli cells. At the mediastinum qu ued for the labeled cells to go through the va rious
testis the fluid and sperm enter the rete testis, an anasto- stages can be determined. Several generatio ns of devel-
mosing system of ducts lined by simple cuboidal epithe- oping cells may be present in the thickness of the semi-
lium. From the rete testis, they move into the extratesticu- niferous epithelium at any given site and at any given
lar portion of the ef(e1'ent ductules (ductuli efferentes), the time, which produces the characteristic cell associations.
first part of the excurrent duct system, and then into the Autoradiographic studies have revealed that the duration
proximal portion of the duct of the epididymis (d uctus of the cycle of the seminiferous epithelium is constant,
epididymis). As the sperm move through the 4 to 5 m of lasting about 16 days in humans. In humans it would
the highly coiled duct of the epididymis, they acquire require about 4.6 cycles (each 16 da ys long), or ap-
motility. Contractions of the smooth muscle that sur- proximately 74 days, for a spermatogonium produced by Sertoli cell
rounds the progressively distal and larger ducts continue to a stem cell to complete the process of sperm atogenesis.
move the sperm by peristaltic action until they r each the It would then require approximately 12 days for the
distal portion of the duct of the epididymis where they are spermatozoon to pass through the epididymis. Approxi-
stored before ejaculation. mately 300 million sperm cells are produced daily in the
type B pale type A dark type A pale type B pale type A dark
Sperm can live for several weeks in the male excurrent human testis. The length of the cycle and the time re- spermatogonium spermatogonium spermatogonium spermatogonium
spermatogonium
duct system, but they will survive only 2 to 3 days in the quired for spermatogenesis are constant and specific in STAGE Ill
female reproductive tract. They acquire the ability to fer- each species. Therefore, in any pharmacologic interven-
tilize the ovum only after some time in the female tract. tion (e.g., therapy for male infertility), if a drug is given
This process, which involves removal and replacement of that affects the initial phases of spermatogenesis, a p-
glycocalyx components (glycoconjugates) on the sperm proximately 86 days are required to see the effect of that
membrane, is called capacitation. compound on sperm production.
In both compartments, spermatogenic cells are sur- inifero us t ubule, where high concentrations of testosterone a nd a re essential for t he secretio n of ABP, i11 hibin , and
ro unded by complex processes o f the Sertoli cells. Because a re essential fo r normal maturation of the developing plasminogen activator (Fig. 21.18 ).
of the unusually close relationships between Sertol i cells sperm.
and diffe rentia ting spe rmatogenic cells, it has been sug- Sertoli cells also secrete several endocrine su bstances
Two basic facts are well established about the immunologic gested that Serto li cells serve as "nurse," or supporting, such as inhibin, a 32-kDa glycoprotein hormone involved \1 I~TRATESTICULAR DUCTS
importance of the blood-testis barrier: cells, i.e., they function in the exch ange of meta bolic sub- in the feedback loop that inhibits FSH release from the an -
strates and wastes between the developing spermatogenic terior pituita ry gla nd. Sertoli cells, themselves, are stimu- At the end of each seminiferous tubule there is an abrupt
Spermatozoa and spermatogenic cells possess molecules
cells and the circulatory system. lated by both FSH and testosterone. In addition, Sertoli transition to the straight tubules, or tubuli recti. T his
that are unique to these cells and are recognized as 'for-
eign (not self) by the immune system. In addition, Sertoli cells p hago cytose and br eak down cells also synthesize plasminogen activator, which con- short terminal section of the seminiferous tubu le is lined
Spermatozoa are first produced at puberty, long after the the residual bodies formed in t he last stage of spermiogen- verts p lasmin ogen to the active proteolytic hormone plas- only by Sertoli cells. Near their termination, the straight
individual has become immunocompetent, i.e., capable of esis. T hey also phagocytose a ny spermatogenic cells t hat min) a nd trattsferrin (an iron-transporti ng protein) . FSH tubules n arrow, and their lining changes to a simple
recognizing foreign molecules and producing antibodies fail to differentiate completely. receptors are believed to be present only on Sertol i cells cuboidal epi t helium.
against them.
The Sertoli cell-to-Sertoll cell junctional complex is the site of
Failure of the spermatogenic cells and spermatozoa to remain
~,-----,I ~--------~
the blood-testis barrier
isolated results in the production of sperm-specific antibodies.
Such an immune response is sometimes seen after vasectomy
and in some cases of infertility. After vasectomy, sperm-specific In addition to the p hysical compartmentalization de-
I other CNS centers
antibodies are produced as the cells of the immune system are scribed above, t he Sertoli cell- to-Serto li cell junctiona l
exposed to the spermatozoa that may leak from the severed complex also creates a permeability barrier called the
ductus deferens. Thus, sperm no longer remain isolated from blood-testis barrier. This ba rrier is essential in crea ting a hypothalamus
the immune system within the reproductive tract. In some ph ysiologic compartmen ta li zation within t he seminifer o us
cases of infertility, sperm-specific antibodies have been fou nd epithelium with resp ect to ionic, a mino acid, carbohy-
in the semen. These antibodies ca use the sperm to agglutinate, drate, and protein composition. T herefor e, the comp osi-
preventing movement and interaction with the ovum.
tion of the fl u id in the sem iniferous tu bules and excurrent
ducts d iffers considerably fro m th e composition of t he
blood p lasma and testic ular lymph.
Plasma proteins and circu la ting a n ti bod ies a re excluded
from the lumen of the sem inife rous tubules. The exocr ine
tiona! sp ecia lizations of the Sertoli cells include gap junc- secretory products of the Sertoli cells, particularly 90-kDa
ti ons between Sertoli cells, desmosom e-li ke junctio ns be- androgen-binding protein (ABP), which has a high bind-
t ween Sertoli cells and ea rl y-stage s permatoge ni c cells, ing a ffin ity fo r testosterone and DHT, a re h ighly con cen-
and he midesmoso mes at the Sertoli cell- basa l lamina in- trated in the lu men of th e sem ini fer o us tubules and main-
terface.
tain a high concentration of testosterone, wh ich provides a Iinhibin I
favorable microen vironment for the diffe rentiating sper-
The Sertoli cell-to-Sertoli cell junctional complex divides the ma togenic cells.
seminiferous epithelium into basal and luminal compartments Leydig cells
Most im portantly, t he blood-testis barrier iso lates the
genetically different and t herefore a ntigen ic hap loid germ
The Sertoli cetl-to-Sertoli cell junc tions establish two cells (secondar y sperma tocy tes, sper matids, and sperm)
e p ithe lial compartments, a basal epithelial compartment from the im m une system o f the adult ma le. Antigens p ro-
a nd a luminal compartment. Spermatogo nia and early d uced by, or speci fic to, th e sper m are p revented from
primary sp erma tocy tes are restrict ed to th e basa l com - reaching the systemic circu lation . Conver sely, ')'-globuli ns
pa rtment, i.e., between the Sertoli cell-to- Sertoli cell and specific sp erm antibodi es fou nd in some individuals
.. -
juncti o ns and the basal lamina. More mature spermato- are prevented fro m reach ing the developing spermatogenic
cytes a nd spermatids are restricted to the lumina l side of cells in t he sem ini fe ro us tu bule. Iestradiol! testosterone
t he Sertoli cell-to- Sertoli cell junctions. Ea rl y spermato- Therefore, the blood-testis ba rrier ser ves an essen ~ial I
I?
cytes produced by mitotic di vision of type B sper mato- ro le i11 isolating th e spermatogenic cells from t he immu ne
gonia must pass through th e junctional complex to mo ve system.
from the basa l compartme nt to the luminal compart-
men t. This movement occurs via the formatio n of a new Sertoli cells have both exocrine and endocrine secretory
junctio na l co mp lex between Serroli cell processes t hat ex- functions - inhibitory
FIGURE 21.18
tend beneath th e newly formed spermatocytes, followed - stimulatory
Diagram depicting the hormonal regula-
by the breakdow n of the junctio n a bove t hem. T hus, in In addition to secreti ng flu id tha t fac ilitates passage o f accessory reproductive organs
tion of male reproductive function. Blue ar-
the diffe rentia tion of th e spermatoge n ic cells, the th e maturi ng sperm along the semin iferous t ub ules to t he secondary sexual cha racte ristics
rows indicate stimulatory action on the sys-
p rocesses of meiosis and spermiogenesis occu r in the lu- metabolic effects
intra testicular d ucts, Sertoli cells secrete ABP. ABP concen- tem; red arrows indicate inhibitory feedback. behavioral effects
min al compartment. trates testosterone in the lu m ina l compartment of the sem- See text for explanation.
701 CHAPTER 21 i\4nle Re{Jrorlllt liru Syslcm CHAPTER 21 Mnlc Rc{nodr~elive Syslem 70 3
rete testis
ejaculatory duct
prostatic
utric le
seminiferous
tubule
tun ica
albuginea
FIGURE 21.19
Photomicrograph of human testis. a. This H&E-stained specimen lined by a simple cuboida l epithelium. x ?O. b. This higher magnifi ca-
shows the site that includes t11e mediastinum of the testis. On the tion from a slightly deeper section of the same specimen shows the
a b
right are seminiferous tubules, and on the left are the anastomosing rete testis (left), a cross section of a seminiferous tubule (upper right), FI GURE 21.20
channels of the rete testis. The arrow indicates termination of a Schematic diagram of development of intratesticular and excurrent ejaculatory ducts, ductus deferens, epididymis, and efferent ductules
and a terminating straight tubule (asterisk) where it is entering the rete
straight tubule that is lined only by Sertoli cells. It is at this site that duct systems. a. This diagram shows the testis In the seventh week of are all developed from the mesonephric duct and tubules. The semi
testis. Note the abrupt change In the epithelial lining at this site. As
the tubule content enters the rete testis and the channels are then development before it descends into the scrotal sac. Note that the niferous tubules, straight tubules, and rete testis develop from the in-
noted, the lining epithelium of the rete testis is simple cuboidal. X275.
mesonephric duct and its tubules give rise to the excurrent duct sys- different gonads. The prostate gland develops from the prostatic pri-
tem for the developing testis. b. Sagittal section of a fully developed mordium that originates from the pelvic urethra.
testis positioned within the scrotum. Note that the seminal vesicles,
The straight tu bules em pty into the rete testis, a com- with the developing semi n iferous cords a nd finally develop
plex series of interconnecti ng channels within t he h ighl y into the efferent ductules (Fig. 21.21). T hey connect the
vascular connect ive tissue of t he mediastinum (Fig. develop ing rete testis with the d uct of t he epididymis. The The efferen t duendes are lined with a pseudostratified Epididymis
21. 19). A si mple c uboida l or low columnar epi thelium dista l p art of the mesonephric duct acq u ires a thick, colu m nar epith eliu m that contains clumps of tall and short
lines the cha nnels of the rete testis. These cells have a smooth muscle coat an d becomes the ductus deferens. T he cells, giving the .l uminal surface a sawtooth appearance The epididymis is an organ that contains the efferent ductules
sing le ap ical cilium and relatively few short apical mi- end of the distal mesonephric d uct g ives rise to th e ejacu- (Fig. 21.21). In terspersed among the columnar ceUs are oc- and the duct of the epididymis
crovilli. latory duct and seminal vesicles. casiona l basa l cells that serve as epithelial stem cells. T he
tall columnar cells are ciliated. T he short nonciliated cells T he epididymis is a crescent-shaped structure that lies
The efferent ductules are lined with pseudostratified columnar have numero us micr ovilli and canalicular invaginations of along the superior and posterior surfaces of the testis . It
\} EXCURRENT DUCT SYSTEM epithelium th e apical surface as well as numerous p inocytot ic vesicles, measures about 7.5 em in length and consists of the ef-
membrane-bo unded dense bodies, lysosomes, and other fe1'ent ductules and the duct of the epididymis and asso-
The excurrent duct system develops from the mesonephric In rnan, approximately 20 efferent ductules co nnect t he cytoplasmic structures associated with endocytotic activity. ciated vessels, smooth muscles, and connective tissue cov-
(Wolffian) duct and mesonephric tubules c ha n nels of the rete testis at the superior end of the medi- Most of the fluid secreted in the seminiferous tubules is re- erings (Fig. 21.22) . The duct of the epididymis is a highly
astinum to the proximal portion o f the duct of the epi- absorbed in the efferent ductules. coi led tube measuring 4 to 6 m in length. The epididymis
The initial development of Leydig cells and initiatio n of didymis. As the efferent ductules exit the testis, they be- A smooth muscle layer in the excurrent ducts fil'St ap- is div ided into a head, a body, and a tail (see Fig. 21.4).
testostero ne secretion stim ula re the mesonephric (Wolf- come highly coi led a nd form 6 to 10 conical masses, the pea rs at t he beginJ1ing of the efferent duendes. The smooth The efferent duendes occupy the head, and th e duct of
fian) duct to differentiate into the excretory d uct system coni vasculosi, w hose bases form part of the head of the muscle cells for m a layer several cells thick in wh ich the the epididymis occupies the body and tail. Newly pro-
for the developing testis (Fig. 21.20). The portion of th e epididymis. The coni vascu losi, each about 10 mm in cells are arrayed as a circular sheath in the wa ll of the duc- duced sperm, which enter the epididymis from the testis,
meso neph ric duct adjacent to the d eveloping testis be- length, contain the high ly convoluted ducts that measure t u le. Inter spersed among the muscle cells are elastic fibers. mature during their passage through the duct of the epi-
comes con voluted and differentiates into the duct of the 15 to 20 em in length . At the base of th e cones, the effer - Tra nsport of the sperm in the efferent ductules is effected didymis, acquiring motility and the ability to fertilize an
epididymis. ln addition, a n um ber (about 20) of t he re- ent d uc ts open into a si ngle chan nel, the d uct of the epi- largely by both ciliary action and contraction of this fibro- oocyte. During this androgen-dependen t ma t uration
mai n ing m eso nephric tubules in t his region make conta ct did ymis (see Fig. 21.4). m uscu la r layer. process, the head of the sperm is modified by t he addition
704 CH APTER 21 lvlale Reproductive Syste111 CHAPTER 21 Ma le Reproductive Sy str111 70 5
The principal cells in the pseudostratified epithelium of the epi- Epididymal cells function in both absorption and secretion
didymis are characterized by stereocilia
Most of the fluid that is not reabsorbed by the efferent
Like most of the excurrent duct system, the duct of the ductules is reabsorbed in the proximal portion of the epi-
epididymis is also lined with a pseudostratified columnar didymis. The epithelial cells also phagocytose any residual
epithelium. It contains principal cells (tall ) and basal cells bodies not removed by the Sertoli cells as well as sperm
(short) (Fig. 21.23). The principal cells vary from about 80 that degenerate in the duct. The apical cytoplasm of the
JJ.m in height in the head of the epididymis to about 40 JJ.m principal cells contains numerous invaginations at the
in height in the tail. Numerous long, modified microvilli bases of the stereocilia, along with coated vesicles, multi-
called stereocilia extend from the luminal surface of the vesicular bodies, and lysosomes (Fig. 21.24 ).
principal cells. The stereoc ilia vary in height from 25 JJ.m The principa l cells secrete glycerophospbocholine, sialic
in the head to approximately 10 JJ.m in the tail. The sm all, acid, and glycoproteins, which, in addition to tbe glycoca-
round basal cells rest on the basal lamina. They are the lyx and steroids, aid in the maturation of the sperm. They
stem cells of the duct epithelium. In addition, intraepithe- have mtmerous cisternae of rER surro unding the basally
Jial lymphocytes called halo cells are found in the epithe- located nucleus and a rema rkably large supranuclear Golgi
lium. Under normal conditions, the epithelium of the epi- apparatus. Profiles of sER and rER are also present in the
didymis is the most proximal level of the excurrent duct apical cytoplasm .
system in which lymphocytes are present.
The smooth muscle coat of the duct of the epididymis gradually
increases in thickness to become three-layered in the tail
FIGURE 21.24
FIGURE 21.25
Electron micrograph of epididymis. a. Electron micrograph of the epi- x3,000. b. Apical surface of the epithelial cell with its numerous long section of tile ductus deferens shows tile thick muscular wall organ-
Photomicrograph of human spermatic cord. a. This low-magnifica-
didymal epithelium, showing principal cells (PC) extending to the lu- microv illi (stereocilia). The middle piece of a sperm (5) is evident in the tion photomicrograph shows a cross section of the spermatic cord ized in three distinct smooth muscle layers: an inner longitudinal
men and a basal cell (BC) limited to the basal portion of the epithe- lumen. The small, light circular profiles (arrowheads) are endocytotic conta ining several structures. These include the ductus deferens, the (SM(L)), middle circular (5M(C)), and outer longitudinal (SM(L)). x 100.
lium. Profiles of sperm (5) are seen in the lumen. The apical cytoplasm vesicles. X13,000. Inset. A higher magnification shows the pseudostratified epithel ium
accompanying testicular artery and vein, and veins of the pampini-
of the principal cells exhibits numerous long microvilli (stereocilia). lining the ductus deferens. The tall principal cells possess long mi-
form plexus. XlS . Inset. A higher magnification of a pampiniform
vein. Note the bundles of longitudinal smooth muscles (cut in cross crovilli (stereocilia) (arrows). The basal cells are in close proximity to
section) in the tunica adventitia and tunica intima. xss. b. This cross the basement membrane and possess spherical nuclei. x 215.
The ampulla has taller, branched mucosal folds that of- ens to form the ejaculat01y duct. Seminal vesicles de-
ten show gland ular diverticula. The muscle coat surround- velop as evaginatio ns of the mesonephric (Wolffian)
ing the ampulla is thinner than that of the rest of the duc- ducts in the region of future ampu llae. The wa ll of the
tus deferens, and the longitudinal layers disappear near the seminal vesicles contains a mucosa, a thin layer of though prostaglandins were first isolated from the prostate pelvis, inferior to the bladder, w here it surrounds the pro-
origin of the ejaculatory du ct. The epithelium of the am- smooth muscle, and a fibrous coat (Fig. 21.26). The mu- gland (hence the name), they are actually synthesized in static part of the urethra . It consists of 30 to 50 tu buloalve-
pulla and ejaculatory duct appears tO have a secretory cosa is thrown into numerous primary, secondary, and large amounts in the semina l vesicles. Contraction of the olar glands arranged in three concentr ic layers: an inner
function. The cells contain large numbers of yell ow pig- tertiary folds that increase the secretory surface area. All smooth muscle coat of the seminal vesicles during ejacula- mucosal layer, a n in termediate submucosal layer, and ape-
ment granu les. The wall of the ejacu latory duct does not of the irregular chambers thus formed, however, com- tion discharges their secretion into the ejaculatory ducts ripheral layer containing the main prostatic glands (Fig.
have a muscularis layer; the fibromuscular tissue of the mu nicate with the lumen. and helps to flush sperm out of the urethra. The secretory 21.27). The g lands of the mucosal layer secrete directly into
prostate substitutes for it. The pseudostratified columnar epithelium contains tall, function and morphology of the seminal vesicles are under the ureth ra; the other two layers have ducts that open in to
nonciliated colu mnar cells and short, round cells that rest the control of testosterone. the prostatic sinuses located o n either side of the urethral
on the basal lam in a. The short cells appear identical to crest on the posterior wa ll of the urethra.
9 ACCESSORY SEX GLANDS those of the rest of the excurrent duct system. They are the The ad ult prostatic parenchyma is divided into fo ur
stem cells from w hich the columnar cells are derived. The Prostate Gland anatomically and clinically distinct zones:
The paired seminal vesicles secrete a fluid rich in fructose columnar cells have the morphology of protein-secreting
cells, with a well-developed rER and large secretory vac- The prostate, the largest accessory sex gland, is divided into The peripheral zone corresponds to the main prostatic
The seminal vesicles are paired, elongate, and high ly uo les in the apical cytoplasm_ several morphologic and functional zones glands and constitutes 70% of the gland ular tissue of the
folded tubular glands located on the posterior wall of The secretion of the seminal vesicles is a whitish yellow, prostate. This zone is the most susceptible to inflamma-
the urinary bladder, parallel to the ampulla of the duc- viscous material. It contains fructose, wh ich is the princi- The prostate is the lar gest accessory sex gland of the ma le tion. It is also the site of most prostatic carcinomas. The
tus deferens. A short excretory duct from each seminal pal metabolic substrate for sperm, along with other simple reproductive system. Its size and shape are common ly com- peripheral zone is palpable during digital examination of
vesicle combines with the ampulla of the ductus defer- sugars, am ino acids, ascorbic acid, and prostaglandins. AI- pa red to those of a walnut. The gla nd is located in the the rectum.
708 CHAPTER 21 Mnlr Rrtlroclrrrtille Systrur CHAPTER 2 1 !VInJe Rrproclr~rri11r Sy stem 709
Benign prostatic hypertrophy (nodular hyperplasia, BPH) occurs al- detectiot:J was uncommon, because the abnormal growth of the tu
most exclusively in the transitional and periurethral zones, leading mor did not impinge on the urethra to produce symptoms that de-
to partial or total obstruction of the urethra. A widely accepted the- manded prompt attention. Therefore, prostatic cancer was often in-
ory of the pathogenesis of BPH is related to the action of DHT. DHT operable by the tim e it was discovered. However, beginning in the
Is synthesized in the stromal cells by conversion from circulating late 1980s, the introduction of PSA testing for prostate cancer has
testosterone in the presence of Sa-reductase. Once synthesized, dramatically increased early diagnosis of this disease. The PSA test
DHT acts as an autocrine agent on the stromal cells and as a revolutionized the early detection, management, and follow-up of
pa racrine hormone on the epithelial cells, causing them to prolif- patients with prostate cancer and Is considered one of the best bio-
erate. Clinical trials have shown that inhibitors of Sa-reductase re- medical markers currently available in the field of oncology. Its use
duce the DHT concentration and thus decrease the size of the with annual digital rectal examination in prostate cancer screening
prostate and reduce urethral obstruction. BHP is believed to occur programs has significantly increased early detection of the disease.
to some extent in all men by age 80 years. It is routinely treated by Treatment of the cancer is by surgery, radiotherapy, or both for pa
the transurethral remov al of prostatic parenchyma. Th is procedure tients with localized disease. Hormonal therapy is the treatment of
is called transurethral prostatectomy (TURP). choice for advanced cancer with metastases. Since prostatic cancer
Cancer of the prostate is one of the most common cancers in the cells depend on androgens, the goal of the therapy is to deprive the
male, affecting approximately 1 in 20. The incidence of prostatic cells of testosterone by performing orchiectomy (removal of the
cancer increases w ith age, and it is estimated that 70% of men be- testis) or by administration of estrogens or gonadotropin-releasing
tween the ages of 70 and 80 will develop this disease. Tumors usu- hormone (GnRH) agonists to suppress testosterone production. De-
ally develop in the peripheral zone of the gland. In the past, early spite treatment, patients with metastasis have a poor prognosis.
co mponents. Together w ith the glandular nodules of prostate gland , which in normal ind ivid uals releases PSA
the transitional zone, this gro wth causes increased ure- only into pro static secretion. H ow ever, in prostate cancer,
FIGURE 21.26 t hra l compr ession an d further retention o f urine in th e serum concentratio n o f PSA increases. In this case, the ad-
Photomicrograph of human seminal vesicle. a. This low-magnifica- extensive folding. It rests on a thick smooth muscle (SM) investment ditional PSA is produced an d released in to the circulation
bladder.
tion photomicrograph shows part of a H&E-stained section of a hu- that is organ ized in two layers: an inner circular layer and an outer
by t he pros ta te gla nd. T herefor e, the elevated levels of PSA
man seminal vesicle. Th is gland is a tortuous tubular structure and in longitudinal layer. x 20. b. This higher magnification shows the mu-
The prostate g lan d secretes prostatic acid p hosphatase (PAP), are di rectly related to increased activity of the prostatic
a section exhibits what appear to be a number of isolated lumina. In cosal folds surfaced by a pseudostratified epithel ium. Arrows indicate
fibrinolysin, citric add, and prostate-specific antigen (PSA) cancer cells. Increased blood levels of bot h PAP and PSA
actuality, there is only one lumen. The mucosa is characterized by the basal cells. x soo.
are used as ma rkers of t he p resence and progress ion of the
W ithin each p rostate zone the par enchymal epithelium is disease.
genera lly simple col umnar, but t here m ay be pa tches th at
bladder The central zone co nta ins a bo ut 25 % o f the g landula r a re simple cuboida l, sq uamous, or o ccasio nally pseudo-
tissue and is res ista nt to both ca rcinom a and inflamma- stra tified (Fig. 21. 28) . T he epithelium depends on testos- Bulbourethral Glands
tion. In comparison to the other zones, cells in the cen- teron e for normal m o rp hology an d function. T he alveo li o~
tral zone ha ve d istinctive morphologic fea tures (mo re t he prostatic g lands, especia ll y those in o lder men, often The b ulbourethral glands secrete preseminal f luid
central zone prominent an d slightl y basophi lic cytop lasm and larger conta in prostatic concretious (corpora amylacea) of va r-
periu rethral nuclei displaced at d ifferent levels in adjacent cells). Re- ied shape a nd size, often up to 2 mm in dia meter (see Fig. T he paired bu.lbourethral glands (Cowper's glands) are
cent findi ngs suggest that t his zone originates embry- 2 1.2 8) . T hey appear in sections as co ncentric lamellated pea-sized structures located in the urogen ita l diaphragm
ologica lly from the incl usion of mesoneph ric d uct cells bod ies and are believed to be for med by pr ecipitatio n of se- (see Fig. 21.1 ). T he duct of each gla nd passes thro ugh the
into th e d evelopi ng prostate. creto ry ma teria l aro und cell fragments. They may become inferi o r fascia of the urogenital d iaph ragm and joins the
The trmtsitional z o11e conta ins t he mucosal glands. In partially calcified. initial portion of t he penile ureth ra. The glands are com-
o lder indiv iduals, the pa renchyma l cel ls o f t his zone fr e- T he pr o static ep ithe lial cells prod uce enzy mes, par- pou nd tubuloalveolar glands that structu ra lly resemble
quen tl y undergo ex tensive divisio n (h yper plas ia) and ticular ly PAP, fibrinolysin, a nd citric acid. They a lso mucus secretory glands (Fig. 21.29 ). T he simple col umnar
fo rm nodular masses o f epithelial cells. Because this secrete serine protease, clinical ly known as PSA. T his epitheliwn, which varies considerably in height depending
zone is in close p roxim ity to th e prostatic urethra, these enzyme is secreted into the alveoli and is ul timate ly in- on the fu nctional state of the gland , is un der the control of
nod ules can compress t he prostatic ureth ra, ca usi ng d if- co rpo ra ted in to sem ina l fluid. T he alveola r secreti on is testosterone.
zone ficulty in urina tion. T his cond iti on is kn own as benign pumped into the prostatic ureth ra during ejaculat ion by T he clea r, mucus-like gla ndular secretion contains con-
prostatic hyperplasia (BPH) and is disc ussed in the clin- contracti o n of the fibromuscular tissue of the prostate. siderable amou nts of galactose and galactosamine, galac-
ical box (page 709) . The fibri no lys in in t he secretio n serves to liquefy the t uro nic acid, sialic acid , and methylpentose. Sexual stimu-
FIGURE 21.27
Schematic drawing of the zones of the human prostate gland. This The periu1'ethm l zone con ta ins mucosal and subm u- semen . lation causes re lease of the secretion, which constitutes the
drawing Illustrates the relative location, by color, of the four zones of cosal glands. In later stages of BPH t his zone may un- Norma l individuals have a low se rum concentration of ma jo r portion of t he p reseminal Aui d and probably serves
the prostate gland. dergo pathologic growth, but ma inly fro m the stromal PSA . Circul atin g PSA is produced by the liver, not by the to lub ricate the pen ile u reth ra.
7 10 CHAPTER 2 1 Male Reproductive System CHA PTER 2 1 Male Reproductive Systeou 7I I
FIGURE 21.28
Photomicrograph of human prostate gland. a. This Mallory-azan- an area where the glandular epithe lium Is pseudostratified. The round
stained specimen shows the tubuloalveola r glands (GI) and the fibro- nuclei adjacent to the connective tissue (arrowheads) belong to the
muscular tissue that fo rms the septa between glandular tissue. Within basal cells. Those nuclei that are more elongate and further removed
the lumina, various-sized prostatic concretions can be seen. The stain from the base of the epithelium belong to the secretory cells. Note the FIGURE 21.29
uti lized for this specimen readily distinguishes the smooth muscle terminal bars (arrows) that are evident at the apical region of these Photomicrograph of human bulbourethral gland. This photomicro-
component (stained red) from the dense connective tissue component cells. The red-stained sites within the dense connective tissue repre- graph shows a H&E-stained section of the compound tubuloalveolar
(stained blue) of the stroma. X 60. b. This higher magnification shows sent smooth muscle cells. x 635. bulbourethral gland. The epithelium consists of col umnar mucus-se-
creting cells. The nuclei are displaced to the base of the cells by the
accumulated secretory material that they contain. The cytoplasm has
an appearance similar to typical mucus-secreting cells. Note several
ducts (D) lined by a simple colu mnar epithel ium. The ducts will merge
to form a single excretory duct. In some sites the ducts contain
9SEMEN 9 PENIS mucus-secreting cells (arrows). X40.
Semen contains fluids and sperm fro m the testis and secre- Erection of the penis involves the filling of the vascular spaces
tory products from the epididymis, ductus deferens, of the corpora cavernosa and corpus spongiosum
prostate, seminal vesicles, and bulbourethral glands. It is ing a nd cri ss-crossing th e corpus cavernosu m . Irregular
alka line and may help to neutralize the acid environment The peni s consists principa ll y of two dorsal masses of smooth muscle bundles ar e o bser ved frequently as "suben-
of the urethra a nd the vagina. Semen also contains erectile t issue, t he corp01a cavernosa, an d a ventral mass dothelia l c ush io ns" surrounding irregu lar vascu lar spaces
prostaglandi ns that may influe nce sperm tran sit in both th e o f erectile tissue, the corpus spongiosum, in which the (Fig . 21.31). T he interstitia l connective tissue con tai ns
m a le a nd fe ma le rep roduc tive ducts an d that ma y have a spongy parl of the urethra is embedded. A d ense, fibro- ma ny nerve endings and lymphatic vessels. T he vascular
ro le in im plantatio n of a fertili zed ovum. elastic layer, the tunica albuginea, bind s t he t hree together spaces increase in size a nd rigid ity by fi lling wi t h b lood ,
FIGURE 21.30
The average ejacu late of semen h as a volum e of a bout 3 a nd forms a capsu le around each (Fig. 21.30). The co rpora principally d erived from the helicine arteries. T hese a rter- Photomicrograph of a histologic section of the penis. This photomi-
mL a nd normally conta ins up to 100 million sperm per cavernosa contain numerous wi de, irregularly shaped vas- ies d ilate d uring erection (see box) to increase th e blood crograph sllows a HeE-stained specimen of a cross section of the
mL. It is estimated that 20% o f the sperm in a n y e jaculate cular s paces lined w ith vascular endothelium. T hese spaces flow to the penis. An arteriovenous (AV) anast omosis ex- penis near the base of the organ. Note tile arrangement of tile cor-
are morphologically abnormal a nd nearly 25% a re im- ar e surrounded by a th in layer of smooth muscle t hat ists between the deep artery of th e pen is a nd the peripheral pora cavernosa and corpus spongiosum; the latter contains tile ure-
motile. fo rm s trabeculae w ithin the tunica a lbuginea interconnect- veno us system. thra. x 3.
-
FIGU RE 21.31
Photomicrograph of corpus spongiosum. a. This photomicrograph of the numerous irregularly shaped vascular spaces. Note the surround-
a H&E-stained section shows the corpus spongiosum and urethra. ing layer of smooth muscle (SM) form ing the subendothelial cush-
X20. b. This higher magnification of the corpus spongiosum shows ions: x135.
Erection of the penis is a vascular event initiated by the CNS and Sympathetic stimulation terminates penile erection by causing
maintained by complex interactions between vascular and neuro- contraction of the trabecular smooth muscle cells of the helicine ar-
logic events. The CNS responds to external and/ or internal stim uli teries. These events decrease the flow of blood to the corpora ca-
(sensory impulses, perception, desire, etc.) that involve the sympa- vern osa, reducing blood pressure in the erectile tissue to normal
thetic and parasympathetic inn ervation of the penis. venous pressure. The lower pressure w ithin the corpus caver-
Parasympathetic stimulation initiates erection by relaxation of nosum all ows the veins lead ing from the corpora cavernosa to
the t rabecular smooth muscle cells and dilation of the helicine ar- open and drain the excess blood.
teries. This leads to expansion of the corpora cavernosa and, to a Erectile dysfunction is an inability to achieve and maintain suffi-
lesser degree, the corpus spongiosum. Arterial blood accumulates cient penile erection to complete satisfactory intercourse. Adequate
in these erectile t issues by compression of the venules against the arterial blood supply is critica l for erection, therefore any disorder
nondistendible tun ica albuginea. This process is referred to as the that decreases blood flow into the corpora cavern osa may cause
corporal vena-occlusive mechanism. The tunica albuginea also erectile failure.
compresses the larger veins that drain blood from the corpora ca- Many cases of erectil e dysfunction that do not involve parasym-
vernosa so that venous outflow is also blocked, resulting in tumes- pathetic nerve damage can now be treated effectively with silde-
cence and rigidity of the penis. nafil citrate (Viagra). This compound enhances the relaxi ng effect of
Two neuromediators, acetylocholine and nitric oxide, are in- NO on smooth muscle cells of the corpora cavernosa by inhibiting
volved in the relaxation of smooth m uscle during the initiation and phosphodiesterase, which is responsible for degradation of cG M P.
maintenance of pen ile erection. As noted above, cG M P causes smooth muscle relaxation, which in
tu rn allows inflow of blood into the corpus cavernosum to initiate
Acetylcholine is released by the parasympathetic nerve end-
erection. However, wl1 en parasympath etic nerve damage has oc-
ings and acts primarily on the endothelial cells that line the
curred (e.g., as a complication of prostatic surgery), sildenafil citrate
vascular spaces of the corpora cavernosa. This causes the re-
w ill have no effect because the event involving parasympathetic
lease of vasoactive intestinal peptide (VIP) and, more impor-
stimulation and release of acetylocholine cannot occur. Without
tantly, nitric oxide.
acetylocholine, NO cannot produce cG MP. Without cGM P, smooth
Nitric oxide (NO) activates guanylate cyclase in the trabecular
muscle cells cannot relax to allow inflow of blood to fill the erectile
smooth muscle cells to produce cyclic guanosine monophos-
tissue.
phate (cG M P). cGMP causes t11e smoot11 muscle cells to relax.
712
PLATE 82. TESTIS I
l CHAPTER 21 lvinle Repmtluclive Sysle111 7I5
T he male reproductive system consists of the paired testes, epididymides, and genital ducts, as well as accessory repro-
ductive glands and the penis. The fu nctions of the testis are the production of sperm and the sy nthesis and secretion of andro-
gens, especially testosterone. The events of cell divi sion that lead to the mature sperm involve both normal cell division, mi-
tosis, and reduction divi sion, meiosis, to yield a haploid chromosome number and haploid DNA content. Androgen secretion
by the testis begins early in fetal development and is essential for continued normal development of the male fetus. At pubetty,
androgen secretion resumes and is responsible for initiation and maintenance of sperm production (spermatogenesis), secre-
tion by accessory sex glands (e.g. , prostate and seminal vesicle), and development of secondary sex characteristics.
Figure 1, testis, monkey, H&E x65. within the inner portion of the capsule, the part referred to
Figure 2, testis, monkey, H&E x400. and conspicuous nucleolus. The Sertoli cell cytoplasm ex-
KEY
BV, blood vessels Sc, spermatocytes X, tangential section of tubule with lumen
L, lobule Sg, spermatogonia obscured
LC, Leydig cells Sn, Sertoli nuclei arrows, spermatid nuclei displaying early
LP, lamina propria Sp, spermatids shape change
S, connective tissue septa TA, tunica albuginea
714
-
CHA PTE R 2 1 /\~ a le Reproduc live Sysle"' 7I7
Figure 1, testis, newborn human, H&E x 180; cleus. The cytoplasm takes little stain and usually appears
inset x360.
Prepubertal testis. The various germ cell types repre-
sentative of spermatogenesis in the mature seminiferous
as a light ring around the nucleus. This gives the gonocyte
a distinctive appearance in histologic sections (inset). Gen-
e rally, the gonocytes are found at the periphery of the cord,
tubules are not present in the testis before puberty or in the but many are also found more centrally. The gonocytes give
postpubertal undescended testi s. Instead, the "tubules" are rise to spermatogonia that begin to proliferate in males be-
represented by cords of cells in which a lumen is lacking. tween the ages of I 0 and 13 years. The seminiferous ep-
The seminifero us cords display the same tortuosity as in the ithelium then becomes populated with cells at various
adult; the tunica albuginea (TA) of the testis, though thinner, stages of spermatogenesis, as seen in the adult.
is of the same rel ative thickness. The epithelial cords are sunounded by one or two layers
The seminiferous cords are of considerably smaller di - of cells with long processes and flat nucle i. They resemble
ame te r than the tubules of the adult and are composed of fibrobl asts at the ultrastructural level a nd give rise to the
two cell types: the gonocyte, or first-genera tion spermato- myoid peri tubular cells of the adu lt.
gonium, derived f rom the primordial germ cell that mi- The interstitial cells of Leydig are conspic uous in the
grates fro m the yolk sac to the developing gonad in the em- newborn, a reflection of the residual effects of maternal hor-
bryo; and a cell that resembles the Sertoli cell of the adult. mones. Leydig cells, however, regress and do not become
The latter cell type predominates and constitutes the bulk of conspicuous again until puberty. In this preparation, the
the cord. The cells are columnar, and their nuclei are close Leydig cells ( LC) can be seen between the cords (inset).
to the basement membrane. The gonocytes (G) are the pre- They are ovoid or polygonal and are closely grouped , so that
cursors of the definitive germ cells, or spermatogonia. They adjacent cells are in contact with each other. Overall, they
are round cells that have a centrall y placed, spherical nu- have the same appearance as the Leydig cells of the adult.
Figure 2, testis, H&E x 65. and, fortuitously, the site where one of the seminiferous
Figure 3, testis, monkey, H&E x400. mous than cuboidal or, occasionall y, may be low columnar
KEY
AC, adipose cells LC, Leydig cells ST, seminiferous tubules
BV, bl ood vessels MT, mediastinum testis TA, tunica albuginea
G, gonocytes RT, rete testis TR, tubulus rectus
716
CH A PTER 2 1 A-lair Rc{1roductive Sy>lrlll 7 19
Figure 1, ductuli efferentes, monkey, H&E x 60; basal surface of the ductule, in contrast, has a smooth con-
E inset x360.
About 12 to 20 efferent ductules leave the testis and serve
as channels from the rete testis to the ductus epididymis. Each
of the efferent ductules undergoes numerous spiral windings
tour (see Fig . 2 and inset). Some of the cells, generally the
tall colu mnar cells, possess c ilia (C) (inset). Whereas the
cili ated cells aid in moving the contents of the tubule to-
ward the epididymis, the cells with the nlicrovilli are
and convolutions to form a group of conical structures; to- largely responsible for absorbing fluid from the lumen. In
gether they constitute the initial part of the head of the epi- add itio n to the columnar a nd cuboidal cells, basal cells are
didymis. When examined in a tissue section, the ductules ex- also present; thus, the epithelium is designated pseudostrat-
hibit a variety of irregular profiles due to their twisting and ified columnar. The basal cells possess little cytoplasm and
turning. This is evident on the right side of this nlicrograph. presumably serve as stem cells.
The epithelium that lines the efferent ductules is distinc- The efferent ductules possess a th in layer of circularly
tive in that groups of tall columnar cells alternate with arranged smooth muscle cells (SM, inset). The muscle is
groups of c uboidal cells, giving the luminal surface an un- close to the basal surface of the epithelial cells, being sep-
evenl y contoured appearance. Thus, small cup-like depres- arated from it by only a small amount of connecti ve ti ssue
sions are created where the epithelium contains groups of (CT, inset). Because of this c lose association, the smooth
cuboidal or low col umnar cells. Typically, these shorter muscle may be overl ooked or misidentified as connective
cells exhibit a brush border-like apical surface because of tissue. Smooth muscle facilitates movement of luminal
the microvilli that they possess (armwhead, inset). The conte nts of the ductule to the ductu s epididymis.
Figure 2, epididymis, monkey, H&E x 180. guished from the spherical nucle i of the basal cells that lie
KEY
AT, adi po~e tissue CT, connective tissue SM, smooth muscle
BY, blood vessel P, pigment arrowhead (inset), brush border
C, cil ia SC, stereocilia a r rows, " islands" of epithel ium in the lumen
..
718
CHAPTER 21 Male Reprod11clive Syslrm 72 I
B
Figure 1, spermatic cord, human, H&E x 80. a thick outer longitudinal layer (SM (L)), a thick middle cir-
A cross section through the ductus deferens and some of cul ar layer (SM (C)), and a thin ner inner longitudinal layer
the vessels a nd nerves that accompany the duct in the sper- (SM(L)). Between the epithelium and the inner longitudinal
mati c cord are shown in this figure. The wall of the ductus smooth muscle layer there is a moderately thi ck cell ular
defere ns is ex tremely thick, mostl y because of the presence layer of loose connective ti ssue, the lamina propria ( LP ).
of a large amount of smooth muscle. The muscle contracts The connective tissue immediately surrounding the ductus
when the tiss ue is removed, causing the mucosa to form deferens contains nerves and some of the smaller blood
longitudinal folds. For this reason, in histologic sections, vessels that supply the duct. In fact, some of these vessels
the lumen ( L) usually appears irregular in cross section. can be seen penetrating the outer longitudinal smooth mus-
The smooth muscle of the ductus deferens is arranged as cle layer (asterisks).
Figure 2, ductus deferens, human, H&E x 320; from the spermatic veins. These vessels receive the blood
B inset x 250.
The epithe lial lin ing of the ductus deferens consists of
pseudostratified columnar epithe lium with ste reocilia (ar-
rowheads). It resembles the epithelium of the epididy mis,
from the testis. (The pampiniform plexus a lso receives trib-
utaries from the epididymis.) The plexus is an anastomos-
ing vascular network that constitutes the bulk of the sper-
matic cord. Portions of several of these veins (BV) are
but the cells are not as tall. The elongated nuclei of the evident in the upper right of Figure 1 a long with a number
columnar cells are readily di stingui shed from the spherical of nerves (N). The unusual feature of the veins is their thick
nuclei of the basal cells (arrows). The epithelium rests on a muscular wall that, at a gla nce, gives the appearance of an
loose connective tissue that extends to the smooth muscle; artery rather than a vein . Care ful examination of these ves-
no submucosa is described. sels (inset) shows that the bulk of the vessel wa ll is com-
A unique feature of the spermatic cord is the presence of posed of two layers of smooth muscle-an outer circular
a plexus of atypical veins (pampiniform plexus) that ari se layer SM(C) and an inner longitudinal layer SM(L).
KEY
BV, blood vessels Lu, lumen of blood vessel arrowheads, stereoci li a
CT, connective tissue N, nerve arrows (Fig. 2), basal cell nucleus
L, lumen of ductus deferens SM(C), circular layer of smooth musc le asterisks (Fig. 1), small arteries supplying
LP, lamina propria SM(L), longitudinal layer of smooth muscle ductus deferens
720
l
I C H APTER 21 Male Rrprorlllclive Syste111 72 3
B
Figure 1, prostate, human H&E x47. epithelial surface. It should also be noted that many of the
A portion of the prostate gland in shown in this low- alveol i may appear rudimentary in structure (arrows).
magnification micrograph. A smal l section of the capsule These are simply in a n inactive state and are increasingly
(Cap) of the gland is seen in the upper left corner. The rest observed in older individuals. As noted above, aggregations
of the field is filled with the glandular and stroma l compo- of dead epithelial cells and precipitated secretions form
nents of the prostate. The secretory tubuloalveoli of the prostatic concretions (C) in the lumina of the alveoli; these
prostate gla nd vary greatly in form , as is evide nt in the fig- gradually increase in number a nd size with age. The con-
ure. They may appear as tubes, as isolated alveoli, as alve- cretions stain with eosin and may have a concentric lamel-
oli with branches, or as tubes with branc hes . Tangential lar appearance, as is clearly shown in the concretion in the
sections through alveoli may even produce the appearance lower right. With time, they may become impregnated with
of "epithe lial isla nds" (arrowheads) in the lumen of the calcium salts and thu s be easily recognized in x-rays of the
a lveoli. This is due to the extreme ly uneven contour of the lower abdomen.
stroma. Conc reti ons (C) are again evident in the lumina of
B
Figure 2, prostate, human, H&E x 178; upper in-
set x350; lower inset x650. alveoli, in one instance compressing the epithe lium to a de-
ln this higher magni fication view of a portion of the gree that makes it nearly unrecognizable. The lower inset,
prostate gland, the fibromuscular stro ma is clearl y seen co!Tesponding to the smaller rectangle, clearl y demon-
both immediately subtending the secretory epithelium of strates the pseudostratified columnar nature of the prostatic
the tubuloalveoli as well as in deeper, nonsecretory areas. epithelium (Ep). Well-delineated basal cells (anvwheads)
In the upper inset, corresponding to the larger rectangle, are seen along with the taller columnar secretory cells. A
the intensity of the staini ng of the smooth muscle (SM ) small blood vessel immediate ly subtending the epithelium
c learly distinguishes it from the fibrous stromal connective is recognizable by the red blood cells in its lumen. A lym-
tissue with wh ich it is intimate ly inte rming led . There are no phocytic infiltrati on appears to fill the stroma along the
clearly outlined bundles or layers of smooth muscle in the lower border of F igure 2, suggesting an inflammatory
prostate; rather, it is randomly arrayed thro ughout the process occurring in the prostate gland.
KEY
KEY E p, epithelium aJTows, inactive alveol i
BV, blood vessel L, lymphocytes arrowheads: Fig. I , "epitheli al islands";
C, prostatic concretion SM, smooth muscle Fig. 2, basa l cells
Cap, capsule
722
C H APTER 21 Mnlr Rrproductivr Syslr~u 72 5
Figure 1, seminal vesicle, human, H&E x30. plane of section is normal to the surface, the mucosal ridges
Figure 2, seminal vesicle, human, H&E x 220. liwn may not be readily recognized as pseudostratified. In
KEY
CT, connective !issue LP, lamina propria arrowhead, oblique sec1io n of epithelium
Ep, epithelium SM, smooth muscle arrows, mucosal arches
724
Female reproductive organs undergo regular cyclic changes
Q OVERVIEW OF THE FEMALE
22
from puberty to menopause
REPRODUCTIVE SYSTEM
The ovaries, uterine tu bes, a nd uterus of the sexua ll y
The female reproductive system consists of internal sex organs mature fema le undergo marked structural and functional
and external genital structures
changes related to neural activity and changes in hormone
levels during each menstrual cycle and during pregnancy.
UTERUS 743
Cyclic Changes During the Menstrual Cycle 746
s uspensory
Implantation 748 ligament of ovary
Cervix 750 uterine
cavity --:~f---_JJ fimbria
PLACENTA 751
VAGINA 755 hilum of ovary
EXTERNAL GENITALIA 757
MAMMARY GLANDS 758
Hormonal Regulation of the Mammary Gland 761 ligament of ovary
Involution of the Mammary Gland 763 mesometrium
Blood Supply and Lymphatics 763
Innervation 763
cervix - -- - - M":-
BOXES external os ---'~~~~~~C~~~
BOX 22.1. Clinical Correlations: Polycystic Ovarian Disease 735
BOX 22.2. Clinical Correlations: In Vitro Fertilization 739
BOX 22.3. Functional Considerations: Summary of Hormonal Regulation
of the Ovarian Cycle 741
BOX 22.4. Clinical Correlations: Fate of Mature Placenta at Birth 755
BOX 22.5. Clinical Correlations: Cytologic Pap Smears 757 FIGURE 22.1
Schematic drawing of female internal sex organs. This drawing uterine wall: tl1e inner layer, tl1e endometrium lining tl1e uterine cav
BOX 22.6. Functional Considerations: Lactation and Infertility 763
shows the posterior view of the female internal sex organs. Part of ity; the middle and tl1ickest layer, tl1e myometrium; and the outer
the wall of the uterus, uterine tube, and vagina has been removed to layer, tl1e perimetrium, wl1ich is the peritoneal covering of t11e uterus.
reveal their internal structure. Note the three distinct layers of t11e
726 72 7
728 CHAPTER 22 Fe111nle Rrf>rodH clive System CHAPTER 2 2 Femnl< RefJroduclr'vr Systew 72 9
C011:ex or cortical region found in the peripheral por- size of a follicle indicates the developmental state of the Follicle Development
'\lOVARY oocyte. Early stages of oogenesis occur during fetal life
tion of the ovary surrounding th e medulla. The cortex Histologically, three basic types of ovarian follicles can be
contains the ovarian follicles embedded in a richly cel- w hen mitotic divisions massively increase the number of
Production of gametes and steroid hormones are the two oogonia (see the section on oogenesis). The oocytes pres- identified on the basis of developmental state:
major functions of the ovary
lular connective tiss ue. Scattered smooth muscle fibers
are present in the stroma around the fo llicles. The ent at birth remain arrested in development at the first Primordial follicles
boundary between the medulla and cortex is indistinct. meiotic division (see page 69) . During puberty, small Growing follicles
Th e ovaries have two interrelated functions: the produc- groups of follicles undergo cycl ic growth and maturation. Mature or Graafian follicles
tion of gametes (gametogenesis) and the production of The first ovulation generally does not take place for a year
"Germinal epithelium" instead of mesothelium covers the Growing follicles are further subcategorized as primmy
steroids (stemidogenesis). In the female, the production of or more following menarche. A cyclic pattern of follicular
ovary and secondary (or antral) follicles . Some histologists iden-
gametes is called oogenesis. Developing gametes are ca lled maturation and ov ulation is then established that contin-
oocytes; mature gametes are called ova. ues in parallel with the menstrua l cycle. Normally, only tify add itional stages in the continuum of follicular devel-
Two major groups of steroid hormones, estrogens and The surface of the ovary is covered by a single layer of opment. In the cycling ovary, follicles are found at a ll stages
cubo idal and, in some parts, a lmost squamous cells. This one oocyte reaches full maturity and is released from the
progestogens, are secreted by the ovaries: ovary during each menstrual cycle. Obviously, the matu- of development, but primordial follicles predominate.
cellular layer, known as the germinal epithelium, is contin-
Estrogens promote growth and maturation of internal uo us with the mesothelium that covers the mesovarium. The ratio n and release of more than one egg at ovu lation may
and external sex organs and are responsible for the fe- lead to multiple zygotes. During the reproductive lifespan, The primordial follicle is the earliest stage of follicular
term genninal epithelium is a carryover from the past when
a woman produces only about 400 mature ova . Most of development
male sex characteristics that develo p at puberty. Estro- it was incorrectly thought to be the site of germ cell forma-
gens also act on mammary glands to promote breast de- tion during embryonic development. It is now known that the estimated 600,000 to 800,000 primary oocytes pres-
velopment by sti mulating ductal and stromal growth the primordial genn cells (both ma le and female) are of ex- ent at birth do not complete maturation and are gradua.lly Primordial follicles first appear in the ovaries during the
and accwnulation of adipose tissue. tragonadal origin and that they migrate from the embryonic lost thro ugh atresia, the spontaneous death and subse- third month of fetal development. Early growth of the pri-
Progestogens prepare the internal sex organs, mainly the yolk sac into the cortex of the embryonic gonad, where they quent r esorption of immature oocytes. This process begins mordial follicles is independent of gon adotropin stimu la-
uterus, for pregnancy by promoting secretory changes in differentiate and induce differentiation of the ova1y. A dense as early as the fifth month of fetal Jife and is mediated by tion. In the mature ovary, primordial follicles are found in
the endometrium (discussed in the section on cyclic connective tissue layet; the tunica albuginea, lies between apoptosis of cells surrou nding the oocyte (see page 69). the stroma of the cortex just beneath the tunica albuginea .
changes in the endometrium). Progestogens also prepare the germinal epithelium and the underlying cortex. Atresia reduces the number of primary oocytes in a loga- A single layer of sq uamous .follicle cells surrounds the
the mammary gla nd for lactation by promoting lobular rithmic fashion throughout life from as many as 5 million oocyte (Fig. 22.3). The outer surface of the follicle cells is
proliferation. Ovarian follicles provide the microenvironment for the in the fetus to less than 20% of that number at birth. The bounded by a basal lamina . At this stage, the oocyte and
developing oocyte oocytes that remain at menopause degenerate within a the surrounding fo llicle cells are closely apposed to o ne an-
Both hormones play an important role in the menstrual few years . other. The oocyte in the follicle measures about 30 J.Lm in
cycle by preparing the uterus for implantation of a fertilized
ovum. If implantation does not occur, the endometrium of Ovarian follicles of various sizes, each containing a sin-
the uterus degenerates and menstruation follows. gle oocyte, are distributed in the stroma of the cmtex. The
oocyte
follicle cells
Ovarian Structure
In nulliparas (woman who have not borne children), the secondary antral follicle basal lamina
ovaries are paired, almond-shaped, pi11kish w hite structures follicle approaching
atretic follicle
maturity
measuring about 3 em in length, 1.5 em in w idth, and 1 em late primary follicle
in thickness. Each ovary is attached to the posterior surface
of the broad ligament by a peritoneal fold, the mesovarium
(see Fig. 22.1 ). The superiM (or tubal) pole of the ovary is
E
attached to the pelvic wall by the suspens01)' ligament of the ::J
ovmy, which carries the ovarian vessels and nerves. The in- ~
0
ferior (01' uterine) pole is attached to the uterus by the ovar- (f)
(!)
dia meter a nd has a la rge, eccen tric nucleus that contains like zona pellucida, which is rich in glycosa minoglycans
fi nely dispersed chromatin and one or more large nucleoli. and glycoproteins and stains with the periodic acid-Schif
T he cytoplasm of the oocyte, referred to as ooplasm, con- (PAS) reaction.
tains a Balbiat1i body (Fig. 22.3a) . At the ultrastructura l
level, the Balbiani body is revealed as a loca lized accumu- Follicle cells undergo stratification to form the granulosa layer
lation of Golgi membranes and vesicles, endoplasmic retic- of the primary follicle
ul um, numerous mitochondria, and lysosomes. In addi-
tion, human oocytes contain annulate Lamellae, a nd T hrough rapid mitotic proliferation, the single layer of
n umerous small vesicles a re scattered throughout the cyto- follicle cells gives rise to a stratified epithelium, the mem-
plasm along with small, spherical mitochondria. Annu late brana granulosa (stratum granulosum), surrounding the
lamellae resem ble a stack of n uclear envelope profiles . oocyte. The follicle cells are now identified as granulosa
Each layer of the stack includes pore structures morpho- cells. The basal lamina retai ns its position between the out-
logically identica l to nuclea r pores. ermost layer of the follicle cells, which become columna r,
and the connective tissue stroma.
T he primary follicle is the first stage in the development of the During fo llicula r growth, extensive gap junctions de-
growing follicle velop between gran ulosa cells. Unlike Sertoli cells in the
testis, however, the basal layer of the granu losa cells does FIGURE 22.5
As a primordial follicle develops into a growing follicle, not possess elaborate tight junctions (zonulae occlu- Late primary follicle. a. Schematic drawing of a late primary follicle
cha nges occur in the oocyte, in the follicle cells, and in the dentes), indicating the absence of a blood- fo llicle bar- shows a multilayered mass of granulosa cells (differentiated from fol
licle cells) surrounding the oocyte. Note that the innermost layer of
adjacent stroma. Initially, the oocyte enlarges and the sur- rier. Movement of nutrients and sma ll informa tional
granulosa cells is adjacent to the zona pellucida, and the outermost
roundi ng flattened foll icle cells proliferate and become macromolecules from the blood in to the fo llicular flui d layer of these cells rests on the basal lamina, which is adjacent to the
cuboidal. At this stage, i.e., when the follicle cells become is essential fo r normal development of the ovum and stromal cells now called the theca folliculi. The Balbiani body at this
cu boidal, the follicle is identified as a primary follicle. As foll icle. stage reorganizes into multiple Golgi units, and cortical gran ules ap-
the oocyte grows, a ho mogeneous, deeply sta ining, aci- pear in the cytoplasm. The wedgeshaped enlargement depicts tile
dophilic refractile layer called the zona pellucida ap pears Connective tissue cells form the theca layers of the primary ultrastructure of an oocyte and adjacent follicle cells. Numerous mi-
between the oocyte and the adjacent follicle cells (Fig. follicle crovilli from the oocyte and slender processes from the granulosa
22 .4). T he zona pellucida is first apparent in the light mi- cells extend into the zona pellucida that surrounds the oocyte.
croscope when the oocyte, surrounded by a single layer of As the granulosa cells proli ferate, stromal cells immedi- stratum granulosum Processes of the granulosa cells contact the plasma membrane of
cuboidal or columnar fo llicle cells, has grown to a diame- ately surro unding the follicle form a sheath of connective the oocyte. b. Photomicrograph of a late primary follicle (monkey).
LATE PRIMARY FOLLICLE Multiple layers of granulosa cells (GC) can be seen surrounding the
ter of 50 to 80 JLm. The growing oocyte secretes the gel- tissue cells, known as the theca folliculi, just external to
primary oocyte. The zona pellucida (ZP) is present between the
oocyte and follicle cells. x 160.
follicle cells
forming the basa l lamina (Fig. 22.5). The theca foll iculi further dif- theca inte rna from the granulosa layer, which is avascular
zona
pellucid a ferentiates into two layers: during the period of foll icular growth.
The theca interna is the inner, highly vascularized layer
M aturation of the oocyte occurs in the primary follicle
of cuboidal secretory cells. T he fu lly differen tiated cells
of the theca interna possess ultrastructural features cha r-
The distribution of orga nelles changes as the oocyte ma-
acteristic of steroid-prod ucing cells. Cells of the theca in-
tures. M ultip le, dispersed Golgi elements derived from the
terna possess a large number of luteinizing hormone
single Balbiani body of the primordial oocyte become scat-
(LH ) receptors. In response to LH stimulation, they syn-
tered in the cytop.lasm. The number of free ribosomes, mi-
thesize and secrete the androgens that are the precursors
tochondr ia, small vesicles, and mul tivesicular bod ies and
of estrogen. In addition to secretory cells, the theca in-
the amount of rough endoplasmic reticu lum (rER) in-
terna contains fi broblasts, collagen bu ndl es, a nd a rich
crease. Occasiona l lipid droplets and masses of lipochrome
network of small vessels typ ical of endocrine organs.
pigment may a lso be seen. T he oocytes of ma ny species, in-
T he theca externa is the outer layer of connective tissue
cluding mammals, exhibit specialized secretory vesicles
cells. It conta ins mainly smooth muscle cells a nd bundles
a known as cortical grat1ules (see Fig. 22.5). T hey are lo-
of collagen fibers.
cated just beneath the plasma membrane (oolemma). The
PRIMARY FOLLICLE Boundaries between the thecal layers and between the granu les contain proteases that are released by exocytosis
FIGURE 22.4 theca externa and surrounding stroma are not distinct. when the ovum is acti va ted by the sperm (discussed in the
Early primary follicle. a. Schematic drawing of a
primary follicle In an cuboidal follicle cells surrounds the growing oocyte. b. Photomicro However, the basal lamina between the granulosa layer section on fertilization).
early stage of development. Note the formation of the zona pellucida graph of a pri mary follicle. Note the distinct layer of follicle cells (FC) and the theca interna establishes a disti nct bounda ry be- Numerous irregula r microvilli project from the oocyte
between the oocyte and tl1e adjacent follicle cells. A single layer of surrou nding the oocyte. x 640. tween these layers. It separates the rich capillary bed of the into the perivitelline space between the oocyte and the sur-
732 CHAPTER 22 Frmn lr Rrproduclivr Systrm C H APTER 22 Frmnlr Rrproductivr Syslrw 733
Cells of the cumulus oophorus form a corona radiata around The mature or Graafian follicle contains the mature secondary
the secretory follicle oocyte oocyte
As the seconda ry .follicle increases in size, the antrum, T he mature fo llicle, a lso known as a Graafian follicle, ha s
li ned by severa l layers of granu losa cells, a lso enlarges a diameter of 10 mm or more. Beca use of its large size, it ex-
(Fig. 22.7). T he stratum gran ulos um has a relatively uni- tends th rough the full thickness of the ovarian cortex a nd
form thickness except for t he region associated with the causes a bulge on th e surface of t he ovary. As the fo ll icle
oocyte. Here, the g ra nulosa cells for m a thickened mound, nears its maximum size, the mitotic activity of the gran ulosa
the cumulus oophorus, w hich projects into the antrum. cells decreases. The stratum granulosu m appears to become
The cells o f the cumulus oophorus that immediately sur- thinner as the a ntrum increases in size. As the spaces be-
round the oocyte and rema in with it at ovu lation a re re- tween the gran ulosa cell s continue to en large, the oocyte and
ferred to as the corona radiata. The corona radiata is com- cumu.l us cells are gradua lly loosened from the rest of the
posed of cumu lus cells that send penetrating m ic rovilli gra nulosa cells in preparation for ovulation. T he c umul us
throughout the zona pelluc ida to commu nicate via gap cells immediately surrounding the oocyte now form a single
junctions with m icrovilli of the oocyte. During fo llicular layer of cells of t he corona radiata. These cells and loosely
maturation, the number of surface microvill i of granulosa attached cumulus cells remain with the oocyte a t ov ul ation .
cells increases and is correlated w ith an increased number During thi s period of .follicle maturation, the thecal lay-
of LH receptors on the free antra l surface. Extrace llulat~ ers become more prominen t . Lipid drop lets appea r in t he
Secondary follicle. a. Schematic drawing of a secondary follicle
de nsely stain ing, PAS-pos itive material called Cali-Exner cyt oplasm of th e th eca interna cells, and t he cells demon-
showing the fluid-filled antrum, which arises by the coalescence of
small fluid-filled cavities among the granulosa cells. Note that this bodies (see Fig. 22.6) may be seen between th e gra nul osa strate u ltrastructural .features associated with steroid-
actively growing follicle has many dividing granulosa cells. Cali- cells. These bodies are secreted by granu losa cells a nd con- producing cells. In h umans, LH stimulates th e cells of the
Exner bodies appear at this stage. The wedgeshaped enlargement of tain hya luronic acid and proteoglycans. theca interna to secrete androgens, which serve as estro-
the shadowed area depicts the relationship of the gran ulosa cells,
basal lamina, and the theca interna and theca externa. The theca
interna cells differentiate into highly vascularized, steroid-producing
cells. The theca interna is surrounded by an outer layer of stromal
cells called the th eca externa. The basal lamin a separates the gran basal lam ina theca theca
granulosa cells
ulosa cells from the theca interna. b. Photomicrograph of a sec- antrum cells that will become
ondary follicle. The antrum (A), filled with follicular fluid, is visible filled with corona radiata afte r ovulation
within the stratum granulosum (GC). Multiple layers of theca interna follicular fluid
cells (TI) and theca externa cells (TE) can be seen outside the basal
lamina of the secondary follicle. xss.
zona pellucida a
SECONDARY FOLLICLE
rounding granulosa cells as t he zona pell ucida is deposited When the stratum granulos u m reaches a thickness of 6
(see Fig. 22.5). At the same time, slender processes from to 12 cell layers, flu id-fi lled cavities appear among th e
the g ra nulosa cells develop and project toward the oocyte, gra nul osa cells (Fig. 22.6). As the hya luronic acid-rich
intermingling with oocyte microvi lli and, occasionally, in- fluid called liquo1' folliculi contin ues to accumulate
vaginating into t he oocyte p l.asma m embrane. The amo ng the granu losa cell s, the cavities begin to coalesce,
processes may contact t he plasma membrane but do not even tu a ll y .forming a single, crescent-shaped cavit y called
esta bli sh cytoplasmic continuity between the cells. th e antrum. T he fo ll icle is now identified as a secondary
or antral follicle. The eccentrica ll y positioned oocyte,
The secondary follicle is characterized by a fluid-containing which has attained a diameter of about 125 JLm, under-
antrum goes no further g rowth . The inhibition of g rowth is
achieved by the presence of a sm a ll , 1- to 2-kDa peptide
The pr imary fo ll icle initially moves deeper into the cor- ca lled oocyte matumtion inhibitor (OMI), which is
tical stroma as it inc reases in size, mostly through prolife r- secreted by th e gra nul osa cells into the a ntra l flu id . A di- MATURE GRAAFIAN FOLLICLE
atio n of t he granu losa cells. Several factors are required for rect correlation is observed bet ween the size of th e sec-
FIGURE 22.7
oocyte and follicu lar growth: o ndary fo ll ic le and OMI concentratioti . The concentra-
Secondary follicle in a late stage of development. a. Schematic draw- filled antrum (A) and the cumulus oophorus (CO) containing the
tion is highest in sma ll follicles and lowest in mature ing of a mature (Graafian) follicle with a large antrum containing an oocyte. The remaining cells that surround the lumen of the antrum
Follicle-stimulating hormone (FSH) .follicles. The foll icle, which was 0 .2 mm in di a me ter oocyte embedded within the cumulus oophorus. The cells of the cu- make up the membrana granulosa (stratum granulosum, 5G). The sur-
Growth factors, e.g., epidermal growth factor, insulit1- as an early second ar y follicle w hen the fluid first ap- mulus oophorus immediately surrounding the oocyte remain with it face of the ovary is visible on the right. Note the presence of two pri-
like growth factor I (IGF-I) peared, continues to g row a nd reaches 10 mm or more in after ovulation and are referred to as the corona radiata. b. Pl1otomi- mary follicles (upper right). Tl, theca interna. X45.
Calcium iotts (Cal+) diameter. crograph of a mature secondary follicle. Note the large fluid-
734 CHAPTER 22 Feurnlr Rrproduclillr Systeur C HA PTER 22 f rurnlr Rrpmdllclillr Systeur 735
~~on of oogon;a
I I
I l
slow growth
of oogonia
I
I
deve lopment of
primordial follicle
FIGURE 22.10
Diagram illustrating changes that occur
fusion of during growth, maturation, and fertiliza-
c3' and pronuclei tion of the oocyte. In the initial develop
(in uterine tu ~
be~)~~~~~ ment of t11e primordial follicle, stromal
cells migrate to the oogonium and form a
surrounding layer. The oogonium then
enlarges to form the primary oocyte. Note
that the primary oocyte remains arrested
in prophase I of meiosis. The first meiotic FIGURE 22.11
or reductional division is completed only Photomicrograph of human corpus luteum. a. The corpus luteum is wall of the corpus luteum at higher magnification. The main cell mass
after the oocyte progresses to ovulation. formed from the collapsed follicle wall that contains the granulosa is composed of granulosa lutein cells (GLC). These cells llave a large
The second meiotic or equatorial division and theca cells. The granulosa lutein cells form a thick, folded layer spllerical nucleus and a large amount of cytoplasm. The tlleca lutein
is not completed unless the secondary around the former follicular cavity (Cav). Within the folds are cells of cells (TLC) also have a spherical nucleus, but the cells are considerably
oocyte is penetrated by a spermatozoon. tile theca interna (arrows). x 12. b. This photomicrograph shows the smaller tllan the granulosa lutein cells. x240.
second polar nonfunctional {Courtesy of Dr. Clark E. Corliss.)
body polar bodies
tero ne and estrogens. These hormones stimuJ ate the tolysis. A white scar, the c01pus albicans, is formed as in-
growth and secretory activity of the lining of th e uteru s, tercellular hyaline material accumulates among the degen-
CORPUS LUTEUM cells gives them a yellow appearance in fresh preparations. the endometrium, to prepare it for the implantation of the erating cells of the former corpus luteum (Fig. 22.13). The
The collapsed follicle undergoes reorganization into the corpus
At the ultrastr uctural level, the cells demonstrate features developing zygote in the event that fertilization occ urs. corpus albicans sinks deeper into the ovar.ian cortex as it
luteum after ovulation associated with steroid -secreting cells, namely, abundant slowly disappears over a period of several months.
sER and mitochondria with tubular cristae (Fig. 22.12) . The corpus luteum of menstruation is formed in the absence of
At ovulation, the follicu lar wall, composed of the re- Two types of 1ureal cells are identified: fertilization
maining gra nulosa and thecal cells, is tluown into deep Fertilization
folds as the follicle collapses and is transformed into the Granulosa lutein cells, la rge (about 30 f.tl11 in diameter),
centrally located cells derived from the granulosa cells
If fertiJization and implantation do not occur, the corpus
corpus luteum (yellow body), or luteal gland (Fig. 22.11a). luteum remains active only for 14 days; in this case it is Fertilization normally occurs in the ampulla of the uterine tube
At first, bleeding from the capillaries in tbe theca interna Theca lutein cells, smaller (abo ut 15 f.t111), more deeply
called the corpus luteum of menstruation. In the absence
into the follicular lumen leads to formation of the c01pus staining, peripherally located cells derived from the cells
of human chorioni c gonadotropin (hCG) and other lu- Usually, only a few hundred of the millions of sperma-
of the theca interna layer
hemorrhagicum with a central clot. Conn ective tissue from teotropins, the rate of secretion of progestogens and estro- tozoa in an ejaculate reach the site of fe rtilization, typically
the stroma then invades the former follicular cavity. Cells of As the corp us lu teum begins to form, blood and lym- gens declines, and the corpus luteu m begins to degenerate the ampulla of the uterine tube. On arrival, the spermato-
the granulosa and theca interna layers then undergo dra- phatic vessels from the theca interna rapidly grow into the about 10 to 12 days after ovulation. zoon penetrates the corona radiata, where the final steps of
mati c morphologic changes. These luteal cells increase in gra nulosa layer. A ric h vasc ular network is established The co rpu s luteu m degenerates a nd undergoes a slow in- capacitation occur. Capacitation invo lves the release of the
size and become filled with lipid droplets (Fig. 22.1lb). A within the corpus luteum . This highl y vasculari zed struc- volutio n after pregnancy or menstruation. The cells be- epididymal fluid glycoconjugate from the surface of the
lipid-soluble pigment, lipochrome, in the cytoplasm of the ture located in the cortex of the ovary secretes proges- come loaded with lipid, decrease in size, and undergo au- head of the spermatozoon. These surfa ce glycosides added
738 C HAPTER 22 Femn le Rrprocluclive Syslrm CHAPTER 22 Frwnle ReprocluctiPr Syslew 7 39
There are several indications for in vitro fertilization (IVF), but If ferti liza tion and implantatio n occur, the corpus lu-
the primary one is infertility due to surgically uncorrectable teum increases in size to form the corpus luteum of preg-
damage to, or absence of, the uterine tubes. To induce multiple nancy. The existence and functi on of the corpus luteum
follicle development and maturation, women selected for an depends on a combination of paracrine and endocrine se-
IVF procedu re undergo controlled hyperstimulation of the
cretions, collecti vely described as luteotropins.
ovaries. Hyperstimulation is achieved by different hormonal
Paracrine luteotropins are locally produced by the ovary.
therapies using human menopausal gonadotropins and
clomiphene citrate (Serophene), with or without FSH. They include
Mature preovulatory oocytes are collected from the
Estmgens
Graafian follicles by either laparoscopic or ultrasound-guided
percutaneous aspiration or transvaginal aspiration. Prior to in
IGF-I and IGF-II
semination, the oocytes are preincubated in a specialized Endocrine luteotropins are produced at a distance fro m
medium with serum complements for a time determined by
their target o rga n, the corpus luteum. They include
their stage of maturity.
The collected semen is placed in a special medium. The hCG, secreted by the trophoblast of the cho rion, w hich
oocytes are then added to the medium containing the col stimulates the corpus luteum and prevents its degenera-
lected semen for fertilization. Twelve to 16 hours later, the
tion
oocytes are examined with the differentia l Interference con
trast microscope to determine the presence of female and
LH an d prolactin, both secreted by the pituitary glan d
male pronuclei, the indication of successful fertilization. Gener Insulin, prod uced by the pancreas
ally, 80% of mature oocytes cultured In vitro are fertilized. High levels of progestero ne, produced fro m cho lestero l
At this point the embryo is transferred to a special growth
Cap medium for 24 to 48 hours, where it is allowed to grow to the
by the corpus luteum, block the cyclic development of
ovarian follicles . In early pregnancy, the corp us luteum
stage of four to six cells. Several em bryos are then transferred
measures 2 to 3 em, thus filling most of the ovary. Its func-
into the uterus via the vagina and cervical canal on the third
or fourth day after the initial aspiration of the oocyte. Prior to tion begins to decline gradu a lly after 8 weeks of pregnancy,
embryo transfer, the uterus has been prepared to receive the although it persists throu gho ut pregnancy. Althoug h the
embryo by administration of appropriate hormones. Embryos cor pus luteum remains acti ve, the placenta produces suffi-
FIGURE 22.12 are therefore placed into a hormonally prepared uterus under cient amounts of estrogens and progestogens fr om m ater-
Electron micrograph of theca lutein cells from the corpus luteum of conditions equivalent to those in normal Implantation (see nal and feta I precurso rs to take o ver the functio n o f the
a monkey. At this early implantation stage (day 10.5 of gestation), page 748). Intensive progesterone treatment is usually begun cor pus luteum after 6 weeks of pregnancy. hCG can be de-
FIGURE 22.13
membrane-bounded dense bodies are clustered near the Golgi appa just after the transfer, to mimic the function of tile corpus lu tected in the serum as ea rly as 6 da ys after conception a nd
Photomicrograph of the corpus albicans of a human ovary. Large teum of pregnancy.
ratus (G); most of the cytoplasm is packed with tubules of smooth en
amounts of hyaline material can be seen among the degenerating
in the uri ne as ea rl y as 10 to 14 da ys of pregnancy. Detec-
doplasmic reticulum (sER), lipid droplets (L), and mitochondria (M). In recent years, existing t reatment protocols have been op tion of h CG in the uri ne fo rms th e basis of most pregna ncy
cells of the former corpus luteum. The corpus albicans is surrounded timized to such extent that successfu l pregnancy and delivery
Note the capillary (Cap) and the closely apposed cell membranes of tests.
by ovarian stroma. X 125.
the theca lutein cells (arrows). x 10,000. (Courtesy of Dr. Carolynn B. with IVF programs have reached over 30% per embryo trans
Booher.) fer. Further improvements in pregnancy rates may be achieved
by the introduction of new drugs, sucll as recombinant FSH or Atresia
gonadotropin-releasing hormone (GnRH) antagonists that pro
d urin g sperm maturatio n in th e epididymis inhibit binding Several spermatozoa may penetrate the zona pellucida, but vide individualized hormonal treatment. On the other hand, Most ovarian follicles are lost by atresia mediated by apoptosis
to the zo na pellucida recepto r. After ca pacitation, the the occurrence of multiple pregnancies, which is tile main com
only one spermatozoon completes the fertilization process of granulosa cells
plication of IVF, may be limited by reducing tile number of
sperm atozoon can bind to the zona pellucida rece ptors.
transferred embryos.
Binding to the rece ptors o n th e zo na pellucida tri ggers As the fertilizing sperm atozoon penetrates the ooplasm, As stated, very few of th e ova ri an follicles tha t begin
th e acmsome reaction in which enzymes released from a t least three types of postfusio n reactions occur to prevent their differentiation in th e embryonic ovar y are destined to
th e acrosome enab le the spermatozoon to penetrate the other spermatozoa from entering the secondary oocyte complete their m aturation. Most of the follicles degenerate
zona pellucida. Penetration is accomplished by limited (po lyspermy) . T hese events include an d d isappear throu gh a process called ovarian folliculm-
proteolysis o f th e zona pell ucida in front of the adva ncing surfa ce a rea of the ov um an d reorga niza tion of the atresia. Atresia is med iated by apoptosis of g ran ul osa cells.
spenn a tozoon. Fast block to polyspenny. A large and long-lasting (up membrane. The co ntents of the cortical gra nul es are re- Large numbers of fo ll icles und ergo atresia d urin g feta l de-
T he nucleus of the sperm head tha t enters the second- to 1 minu te) depolariza tion of the oolemma creates a leased into th e perivitelline space. velopment, ea rl y postnatal life, and puberty. After puberty,
ar y oocyte fo r ms t he male pronucleus contai ning 23 transient electrica l block to polyspermy. Zona reaction. The released enzymes (proteases) of the gro ups o f follicles begin to mature durin g each menstrua l
paternal chro mosomes. After the fu sion of the two Cortical reaction. Changes in the po larity of th e cortica l gran ules not only degrade the glycoprotein cycle; no rm ally, o nly one fo llicle com pletes its matu ration .
pron ucl ei, th e res ulting zygote, with its diplo id (2n) com- oolemma th en trigger release of Ca 2 from the ooplas- oocyte plasma membrane receptor s for sperm binding Atresia is now th o ught to be a mechanism whereby a few
plement of 46 chromoso mes, und ergoes a mitotic d ivision mic stores. The Cal ' propagates a cortica l reaction but also for m the perivitelline ban'ier by cross-linking fo llicles are stimulated to m ainta in their development
or first cleavage. This two-cell stage ma rks the beginning wave, in which cortical granules move to the surface and proteins on the surface of the zona pell ucida. This event thro ugh the progra mmed death of the o ther foll icles. T h us,
of embryo nic develo pment. fuse with the oolemma, leading to a transient increase in creates the final and perm anent block to polyspermy. at any stage of its maturatio n a follicle may undergo atre-
740 CHAPTER22 Fewnle Re/lrodr~cliPe System CHAPTER 22 Female Reprodr~cti11e Systew 74 I
sia. The process becomes more complex as the follicle pro- separated by connective tiss ue. A ric h capillary n etwork
g resses toward ma tu ration. develops in the connect ive t issue. These atretic follicles,
In atresia of primordia l a nd sm a ll, growing fo llicles, the w hich resemble a n old corpus luteum, are called corpora
imma ture oocyte becom es sm a ller a nd degenera tes; similar lutea atretica.
changes occur in the g ra nulosa cells. Atretic fo ll icles shrink During each menstrual cycle, the ovary undergoes cyclic induced by a surge In the LH level, which occurs concomitantly
and eventually disappear from the stroma o f the ovary as changes that involve two phases: with a smaller increase in the FSH level.
The interstitial gland arises from the theca interna of the
The luteal phase begins immediately after ovulation, as the
a result of repeated apoptosis and phagocytosis by granu- atretic follicle Follicular phase
granulosa and thecal cells of the ruptured follicle undergo rapid
losa cells. As the cells a re reabsorbed and disappea r, the Luteal phase
morphologic transformation to form the corpus luteum. Estro-
s urro unding stromal cells migrate into th e space previously As atretic foUicles co ntinue to d egen erate, a scar with gens and large amounts of progesterone are secreted by the cor-
Ovulation occurs between the two phases (Fig. 22.14).
occup ied by t he follicle, leaving no trace of its existence. hya line streaks develops in the center of the cell mass, giv- The follicular phase begins with the development of a small pus luteum. Under the Influence of both hormones, but primarily
In a tresia of large, growing fo llicles, the degeneration of ing it the appearance of a sma ll corpus a lbicans. This struc- number of primary follicles (10 to 20) under the influence of FSH progesterone, the endometrium begins its secretory phase, which
the mature oocyte is delayed and appears to occur second - ture eventually di sappear s as th e ova rian stroma invades and LH. During the first 8 to 10 days of the cycle, FS H is the prin is essential for the preparation of the uterus for implantation in
ary to d egene rative c hanges in the fo ll icular wall. This de- the degenerating fo llic le . In the ovaries of a number of clpal hormone influencing the growth of the follicles. It stimulates the event that the egg Is fertilized. LH appears to be responsible
lay indicates that once the oocyte has achieved its maturity mamma ls the stra nds of lutea l cells do not degenerate im- the granulosa and thecal cells, which begin to secrete steroid for the development and maintenance of the corpus luteum dur-
an d competence, it is no longer sensi tive to th e same stim- mediatel y but become br oken up a nd scattered in the hormones, principally estrogens, into the follicular lumen. Late in ing the menstrual cycle. If fertilization does not occur, the corpus
uli that initiate the a tres ia in granulosa cells. The fo llicular the follicular phase, before ovulation, progesterone levels begin luteum degenerates within a few days as the hormonal levels
stroma . These cords of cells contribute to the interstitial
changes include the following sequent ial events: to rise under the influence of LH. Estrogens continue to accumu- drop. If fertilization does occur, the corpus luteum is mainta ined
gland of the ovar y a nd produce ster o id hormones. The de- and continues to secrete progesterone and estrogens. hCG, which
late in the follicular lumen, finally reaching a level that makes the
In it iatio n of apoptosis w ithin the granu losa cells, in di- velopme nt of the interstitia l gla nd is most extensive in an- is initially produced by the embryo and later by the placenta,
follicle independent of FSH for its continued growth and devel-
cated by cessa t ion of mitosis a nd expression of endo nu- ima l species that have large li tters. opment. The amount of estrogens In the circulating blood inhibits stimulates the corpus luteum and is responsible for its mainte-
cleases a nd other hydrolytic enzymes w ithin the gra n u- In the human ovary, the re are rela ti vely few interstitial fu rther production of FSH by the adenohypophysis. Ovulation is nance during pregnancy.
losa cells cells. They occur in the la rgest numbe rs in the first yea r
In vasion of the g ran ulosa layer by n eutrophils and of life and during the ea rly p hases of puberty, correspon- so~~--~---------.~-----------------,
ding to times of increased fo llic ul a r atres ia. At men arch e, pituitary ho rmones
macrophages 40 (in blood)
Invasio n of the gra nulosa layer by strand s of vascu la r- involutio n of the interstitial cells occurs; therefore, few
are present during the reproduc ti ve lifes pan a nd 30
ized connective tiss ue
Slo ug hing of the granulosa cells into the a ntrum o f the menopause. It h as been suggested that in humans the in- 20
follicle t erstitia l cells are an impo rta nt source of the estrogens
10
Hypert rophy of the theca in terna cells th at influence g rowth and d evelo pment of the seco nd a ry
O L-------------------r-----------------~
Collapse of the follicle as degeneration continues sex organs during the ea rly p hases of puberty. In other
s
Invas ion of connective tissu e into the cavity of the fo llicle s pec ies, th e interstitia l cells have been shown to pro duce
~
p rogesterone . ovarian cycle
R ecent studies indicate tha t several gene produc ts regu-
la te the p rocess of fo llic ular a tresia. One of these p roducts
In huma ns, cells called ovarian hilar cells a re fo und in @ @> ~ @ @
the hilu m of the ovary in association with vascu lar s paces w
is the go nadotropin-induced neural apoptosis inhibitory and n onmyelinated n er ve fi bers. These cells, w hich appea r I
protein (NAIF), w hic h inhibits and delays a poptotic I
to be struc tura lly re lated to th e interstitial cells of the I
changes in the g ra n u losa cell. N ArP gene expression is testis, contain Reinke aystalloids. The h ila r cells a ppea r to
p resent in a ll stages of the grow ing foll icle bur absent in respond to hormon a l ch a nges dur ing pregnancy and at t he 20
fo llicles undergo ing a tres ia . A hig h level of gonad otropins onset of men op a use. Resea rc h s uggests tha t the hilar cells ovaria n hormones
15 - (in blood)
inh ibi ts apoptosis in ova ria n follicles by increasi ng expres- secrete androgens; hyperplasia or tumo rs asso ciated with
sio n of NAIP in the ovaries. these cells us ua lly lead to mascu liniza tion .
10 - I
The oocyte und ergoes typical cha nges assoc ia ted w ith 5 -'------ estrogen :
degeneratio n a nd a utolysis, and the remna nts a re p ha go - 0 ~============~~~~~~----~
cytosed b y invad ing mac rophages. The zo na pellu cida, Blood Supply and Lymphatics
whi ch is resistan t to the auto lytic changes occurring in the
cells assoc iated w ith it, becomes fo lded and collapses as it Blood supply to the ovaries comes from two different sources:
is slowly b roken down w ithin the cavity of the fo ll icle . ovarian and uterine arteries
M ac rophages in the connecti ve tissue a re in volved in t he
phagocytosis o f t he zona pellucida a nd the re mnants o f t he The ovarian arteries are the bra nches o f the a bdom ina l
d egene ra t ing cells. The basement membrane be tween aorta that p ass to the ova ries th rough the s uspensor y liga- 0 5 10 14 20 25
t he fo llicle cells from the theca interna ma y separa te fro m ments a nd provide th e princ ipa l arteri?l su pply to the proliferative secretory
the fo llicle cells and increase in thickness, fo rming a wavy ovaries and uterine t u bes. T hese a rteries anastomose with phase phase
h ya line layer ca lled the glassy membrane. This struc ture is the second blood so urce to th e ova ry, the ovarian branches
FIGURE 22.14
cha racteristic o f fo llic les in la te stages of atres ia. of the uterine arteries, wh ich a rise from the interna l iliac Relationship of morphologic and physiologic events that occur in strual cycle. The pituita1y a nd ovarian hormones and their plasma
Enl argemen t of the cells of the th eca intern a occu rs in arteries. Relative ly large vessels arising from this regio n of the menstrual cycle. This diagram Illustrates the relation of the concentrations are indicated in arbitrary units. LH, luteinizing hor-
some atretic fo llicles. These cells are simila r to t heca lute in a nastomosis pass thro ug h the mesovarium and enter the morphologic changes in the endometrium and ovary to the pitu- mone; FSH, follicle-stimulating hormone.
cells a nd become organized into ra dia ll y a rranged strand s hilum of the ovary. T hese la rge arteri es a re called helicine ltaly and ovarian blood 11ormone levels that occur during the men-
742 CHAPTER 22 Femflle Re/noductitJe Sys tem CHAPTER 22 Fmwle Re/>roductitJe Sysle111 74 3
arteries because they branch and become highly coiled as the peritoneal cavity. The proximal end communicates
they pass into the ovarian medulla (see Fig. 22.2). with the ampulla. Fringed extensions, or (imb1iae, extend
Veins accompany the arteries and form a plexus, called from the mouth of the infundibulum toward the ovary.
the pampiniform plexus, as they emerge from the hilum. The ampulla is the longest segment of the tube, consti-
The ovarian vein is formed from the plexus. tuting about two thirds of the total length, and is the site
In the cortical region of the ovary, networks of lymphatic of fertilization.
vessels in the thecal layers surround the large developing The isthmus is the narrow, medial segment of the uter-
and atretic follicles and corpora lutea. The lymphatic ves- ine tube adjacent to the uterus.
sels follow the course of the ovarian arteries as they ascend The uterine or intramural part, measuring about 1 em
to paraaortic lymph nodes in the lumbar region. in length, lies within the uterine wall and opens into the
cavity of the uterus.
Ovaries are innervated by the autonomic ovarian plexus The uterine tube wall resembles the wall of other hollow
viscera, consisting of an external serosal layer, an interme-
Sensory and autonomic nerve fibers that supply the diate muscular layer, and an internal mucosal layer. How-
ovary are conveyed mainly by the ovarian plexus. Al - ever, there is no submucosa.
though it is clear that the ovary receives both sympathetic
and parasympathetic fibers, little is known about their ac- The serosa or peritoneum is the outermost layer of the
tual distribution. Groups of parasympathetic ganglion cells uterine tube and is composed of mesothelium and a thin
are scattered in the medulla. Nerve fibers follow the arter- layer of connective tissue.
ies, supplying the smooth muscle in the walls of these ves- The muscularis, throughout most of its length, is organ-
sels, as they pass into medulla and cortex of the ovary. ized into an innet; relatively thick circular layer and an
Nerve fibers associated with the follicles do not penetrate outer, thinner longitudinal layer. The boundary between
the basal lamina. Sensory nerve endings are scattered in the these layers is often indistinct.
stroma . The sensory fibers convey impulses via the ovarian The mucosa, the inner lining of the uterine tube exhibits
plexus and reach the dorsal root ganglia of the first lumbar relatively thin longitudinal folds that project into the lu-
spinal nerves. Therefore, ovarian pain is referred over the men of the uterine tube throughout its length. The folds
cutaneous distribution of these spinal nerves. are most numerous and complex in the amp ulla (Fig.
22.15 ) and become smaller in the isthmus. FIGURE 22.15
At ovulation, about 45 % of women experience midcycle Photomicrograph of a human uterine tube. a. This cross section is the uterine and ovarian arteries (BV) that travel along the uterine
pain ("mittelschmerz") . It is usua lly described as a sharp, The mucosal lining is simple columnar epithelium com- near the ampulla region of the uterine tube. The mucosa is thrown tube. Xl6. b. The lumen of the tube is lined by a simple columnar
lower abdominal pain that lasts from a few minutes up to posed of two kinds of cells, ciliated and nonciliated (Fig. Into extensive folds that project into the lumen of the tube. The mus- epithelium composed of ciliated cells (above the point of the arrow)
24 hours and is frequently accompanied by a small amount 22.15b). They represent different functional states of a sin- cularis is composed of a th ick inner layer of circularly arranged fibers and nonciliated cells (below the point of the arrow). X640.
of bleeding from the uterus. It is believed that this pain is gle cell type. and an outer layer of longitudinal fibers. Note several branches of
related to smooth muscle cell contraction in the ovary as
well as in its ligaments. These contractions are in response Ciliated cells are most numerous in the infundibulum
to an increased level of prostaglandin F 2" mediated by the and ampulla. The wave of the cilia .is directed toward the
surge of LH. uterus.
surface where rupture will occur. As the oocyte is re- '\1 UTERUS
leased, the ciliated cells in the infundibulum sweep it to-
Nonciliated, peg cells are secretory cells that produce
wa rd tht opening of the uterine tube and thus prevent The uterus receives the rapidly developing morula from the
the fluid that provides nutritive material for the ovum.
it from entering the peritoneal cavity. The oocyte is uterine tube. All subsequent embryonic and fetal develop-
'\1 UTERINE TUBES The epithelial cells undergo cyclic hypertrophy during transported along the uterine tube by peristaltic con- ment occurs with in the uterus, which undergoes dramatic
the follicular phase and atrophy during the luteal phase in tractions. The m echanisms by which spermatozoa and increases in size and development. The human uterus is a
The ute1ine tubes are paired tubes that extend bilaterally response to changes in hormonal levels, particularly estro- the oocyte are transported from opposite ends of the hollow, pear-shaped organ located in the pelvis between
from the uterus towa rd the ovaries (see Fig. 22.1 ). Also com- gens. Also, the ratio of ciliated to nonciliated cells changes uterine tube are not fully understood. Research suggests the bladder and rectum. In a nu llipa rous woman, it weighs
monly referred to as the Fallopian tubes, the uterine tubes during the hormonal cycle. Estrogen stimulates ci.liogenesis, that both ciliary movements and peristaltic muscular ac- 30 to 40 g and measures 7.5 em in length, 5 em in width
transport the ovum from the ovary to the uterus and provide and progesterone increases the mm1ber of secretory cells. At tivity are involved in the movements of the oocyte. The at its superior aspect, and is 2 .5 em thick. Its lumen, which
the necessary environment for fertilization and initial devel- about the time of ovulation, the epithelium reaches a height movement of the spermatozoa is much too rapid, how- is also flattened, is continuous with the uterine tubes and
opment of the zygote to the morula stage. One end of the of about 30 J.Lm and is then reduced to about one hal that ever, to be accounted for by intrinsic motility. Fertiliza- the vagina.
tube is adjacent to the ovary and opens into the peritoneal height just before the onset of menstrua~ion. tion usually occurs in the ampulla, near its ju nction with Anatomically, the uterus is divided into two regions:
cavity; tl1e other end conununicates with the uterine cavity. the isthmus. The ovum remains in the uterine tube for
Each uterine tube is approximately 10 to 12 em long and
Bidirectional transport occurs in the uterine tube about 3 days before it enters the uterine cavity. Several The body is the large upper portion of the uterus. The
can be divided into four segments by gross inspection: conditions that may alter the integrity of the tubal trans- anterior surface is a lmost flat; the posterior surface is
The uterine tube demonstrates active movements just port system (inflammati011, use of intrauterine devices, convex . The upper, rounded part of the body that ex-
The infundibulum is the funnel-shaped segment of the before ovulation as the fimbriae become closely apposed surgical manipulation, tubal ligation) may cause ectopic pands above the attaclm1ent of the uterine tubes is
tube adjacent to the ovary. At the distal end, it opens into to the ovary and localize over the region of the ovarian pregnancies and are thus clinically important. termed the fundus.
744 CHAPTER 22 Frmnlr Rr(ll'oductirr System
C H A PTER 2 2 Frmnlr Rr~rodu c ti11r System 745
Tbe cervix is the lower, barrel-shaped part of the uterus
ine cavity remains larger a nd the muscul ar wall remams basal layer of th e endo metrium w here they give off small
sep arated from the bo dy by the isthmus (see Fig. 22.1).
thicker tha n before pr egna ncy. straight arteries that supp ly this regio n of the en-
The lumen of the cervix, the cervical canal, has a con-
Com pa red w ith the body of the u terus, the cervix has d o metrium . Tbe m ain branch of t he radial a rtery continues
stricted opening or os at each end. The intemal os com-
more connective tiss ue and less smooth muscle. Elastic upwq rd and becomes highl y coiled; it is therefore called
municates with the cavity o f the uterus; the external os,
fibers are a bundan t in the cervix but a re found in appre- the spiral artery. Spiral arteries give o ff numero us arteri-
with the vagina .
ciable quantities only in the outer la yer of the m yometrium o les tha t often a nastomose as they supply a ri ch capillary
The uterine wa ll is composed o f three layers (Fig. of the bo d y o f the uterus. bed. The capillary bed includes t hin-walled di lated seg-
22. 16). From the lumen outw ard they are m ents called lacunae. Lacunae may a lso occu r in the ve-
The endometrium proliferates and then degenerates during a nous system that d ra ins the end o metriu m. The straight ar-
E11dometrium>th e mucosa of the uterus. menstrual cycle teries and the proximal part of t he spiral arteries do not
Myometrium, the thick muscula r layer. It is continuous cha nge during th e menstrual cycle. The distal portion of
with the muscle laye r of th e uterine tube and vag ina. The Th ro ug ho ut the r eproductive lifespa n, the endometrium the spiral arteries, und er the infl uence of estrogens and
smooth muscle fibers a lso extend into the liga ments undergoes cyclic changes each month t ha t prepare it for the
connected to the uterus. implan tation of the embryo and the su bsequent events o f
Perimetrium> the o uter sero us layer or viscera l peri- embryonic and feta l development. C hanges in the secretory
to neal covering o f the uterus. The perimetrium is con- activity of the endometr ium during the cycle are correlated
tinu ous with the pelvic a nd abdominal periton eum and with the maturation o f the o vari an follicles (see Fig. 22.14 ).
consists of a mesothelium and a thin layer of loose con- The end of each cycle is characteri zed by the partial d e-
necti ve tissue. Beneath the mesothelium, a layer of elas- struction and sloughing of the endometrium, accompan ied
tic tissue is usually p rominent. The perim etrium co ver s by bleeding from the m ucosal vessels. The dischar ge o f tis-
the entire posterior surface of the uterus but o nly part of sue and blood from the vagina, which usually continues fo r
the anterior surface. The r ema ining part of the anterior 3 to 5 d ays, is referred to as menstruation or menstrual
surface consists of connective tissue or adventitia. flow. T he menstrual cycle is d efined as beginning on the
day w hen menstrual Aow begins.
Both myometriu m and endo metrium undergo cyclic
During reproductive life, t he end ometr ium consists o f
cha nges each month to prepare the uterus fo r implantatio n
two layers or zones tb a t differ in structure and functio n
of an embryo. These changes constitute the menstrual cy-
(Fig. 22.17):
cle. If an embryo implants, the cycle stops, and both layers
undergo considera ble growth and d ifferentiati o n during Stratum ftmctionale o r functional layer. This layer is
pregnancy (descri bed below). t he thick pa rt o f the end ometri um, w hich is slo ughed off
at menstrua ti on .
The myometrium forms a structural and functional syncytium Stratum basale or basallaye1'. This layer is retained dur-
ing menstruati on and serves as the so urce for the regen-
T he myometri um is the thickest layer o f the uterine wall. eration of the stratum functi onale.
It is composed of three indistinctly defined layers o f
smooth muscle: The stratum functionale is the layer that proliferates and
-:.__perimetrium degenerates during the menstrual cycle
The middle muscle layer contains numero us la rge blood FIGURE 22.16
vessels (veno us p lexuses) and lymphatics and is called Photomicrograph of a sagittal section of a human uterus. This sec- D u ring the phases of the menstrual cycle, the eti-
the stm tum vasculare. It is the t hickest layer and has in- tion shows the three layers of the uterine wall: the endometrium, the d o metri um varies fro m .L to 6 mm in th ickn ess. It is lined
te rl aced sm ooth muscle bund les oriented in a circular or innermost layer that lines the uterine cavity; the myometrium, the by a simple columna r epithelium w ith a mixture o f secre-
spira l pattern. middle layer of smooth muscle; and the perimetrium, the very thin tory and cilia ted cells. The surface epithelium in vaginates
The smooth muscle bundles in the inner and outer lay- layer of peritoneum that covers the exterior surface of the uterus. The into th e underl ying la mina pro pria, the endometrial
ers are pred ominantly oriented pa rallel to t he long axis deep portion of the myometrium contains the larger blood vessels
stroma>fo rming the uterine glands. T hese simple tu bul ar
of the uter us. (BV) that supply the uterus. x a.
g lands, containing fewer ciliated cells, occasionally b ranch
As in most bulb-shaped ho llow o rga ns, such as the gall- in the deeper aspect of th e endo metrium. The end ometria l
bladder and urin ary bladder, muscular orientation is not strom a, which resembles mesenchyme, is highly cell ula r
distincti ve. The muscle bundles seen in ro utine histologic t he develo pment of new fibers through the div isio n o f ex- and conta in s abundant inter cellula r gro und substa nce. As
secti o ns appear to be rando mly arrayed. D ur ing uterine isting muscle cells and the d ifferentiation o f undifferenti- in the uteri ne tu be, no su bmucosa separates the en-
contraction, all three layers of t he myometrium work to- ated mesench ymal cells. T he amount of conn ective tissue dometriu m from t he myometri um.
FIGURE 2 2.17
gether as a fu nctional syncytium expelling the conten ts o f a lso increases. As pregnancy proceeds, the ute rine wa ll be- Schematic diagram illustrating arterial blood supply to the en-
The vasculature of the endometrium also proliferates and
the lumen thro ugh a narrow ori fice. comes progressively thinne r as it stretches because of the dometrium of the uterus. The two layers of the endometrium, the
degenerates during each menstrual cycle stratum basale and stratum functionale, are supplied by branches of
In the nonpregnant uter us, the smooth muscle cells are growth of the fetus. After pa rturition, the uterus r eturns to
abo ut 50 ,um lo ng. D uring pregnancy, t he uterus undergoes almost its o riginal size. Some muscle fibers degenerate, bu t the uterine artery. The spiral arteries located at the interface between
The endometrium co ntai ns a unique system of blood these two layers degenerate and regenerate during the menstrual cy-
enormous enlargement. The growth is prim arily due to the most ren trn to their origina l size. The collagen p roduced
vessels (see Fig. 22.1 7). The uter ine arter y gives off 6 to 10 cle under the influence of estrogens and progesterone. (Based on
h ypertrophy of existi ng smooth muscle cells, w hi ch may du ring pregnancy to strengthen the myometri um is t hen en-
arcuate arteries th at anastomose in the myomet rium . Weiss L, ed. Cell and Tissue Biology: A Textbook of Histology. 6th ed. Bal-
reach more th an 500 ,um in length, and seconda ril y due to zyma ti call y d egraded by the cells that secreted it. The uter-
Branches fro m these arteri es, the l'adial arteries, enter the timore: Urban & Schwarzenberg, 1988.)
746 C HA PTER 22 Female Rep.-odurliiJe Systm1 C H APTER 22 Frmnlr Retnoductive Systrm 74 7
progesterone, un der goes degenera tion and regene ra tio n cologie preparations, extraction of the glycogen gives an
with each menstru al cycle. empty appearance to the basal cytoplasm.
Cyclic Changes During the Menstrual Cycle The secretory phase of the menstrual cycle is regulated by
progesterone
Cyclic changes of the endometrium during the menstrual cycle
are represented by the proliferative, secretory, and menstrual Under the influence of progestero ne, d ra m atic changes
phases occur in the stratum func tionale, beginning a clay or two
after ovulation. The endometrium becomes edematous a nd
The menstrua l cycle is a continuum of d evelopmenta l may e ventually r each a thi ckness of 5 to 6 mm. The glands
stages in the functio nal layer of the endometrium. It is ulti- enlarge and become corkscrew shaped , a nd their lumina
mately co ntrolled by gonadotropins secreted by the p a rs di s- become sacculated as they fi ll with secretory p roducts (Fig .
ta lis of the pituita ry gland that r egulate the ste ro id secre- 22.18b). T he m ucoid .fluid pro duced by t he gland epithe-
tions of the ovary. The cycle normally repeats every 28 days, lium is rich in nut rients, p a rticu larly glycogen, required to
during w hic h the endometrium p asses through a seque nce support development if impla nta tion occur s. Mitoses are
of morphologic and fu nc tional changes. It is con venient to now rare. T he growth seen at thi s stage results from hy-
describe the cycle as having t hree successive phases: pertrophy of the epithelial cells, a n increase in vascularit y,
a nd edema of the endo metrium. The sp iral arteries, how-
Proliferative phase, occurring concurren tly with fo llicular ever, lengthen and become mor e coiled. They extend nea rly
matura t ion a nd influenced by ova ria n estrogen secret ion
to t he surface of the endometrium.
Secretory phase, coinciding with t he functio na l act ivity The sequential influe nce of est rogens a nd progester on e
of the corpus lu teum a nd primaril y influ enced by prog-
on the stromal cells e nables their transformation into de-
estero ne secretion
cidual cells. The stimulus fo r tra nsformation is t he im-
Menstrual phase, commencing as hormone production plantation of the blastocyst. Large, pale cells rich in glyco-
by the ovary declines with the degeneratio n of the cor-
gen result from this transformation . Although t he precise
pus luteum {see Fig. 22.14)
function of these cells is not known , it is clea r that they
T he phases a re part of a continuous process; there is no provide a fa vora ble enviro nment for the n ourishm ent o f
abrupt change from o ne to the next. the embryo a nd that t hey cr eate a specia lized layer tha t fa-
cilitates the separation of th e placen ta from the uterine
The proliferative phase of the menstrual cycle is regulated by wall a t the t ermination of pregna ncy.
estrogens
The menstrual phase results from a decline in the ovarian
At the end of the m enstrua l phase, th e endometrium secretion of progesterone and estrogen
co nsists of a thin ba nd o f connective tiss ue, about 1 mm
thick, conta ining the basa l porti ons of th e uterine glands The corpus luteum actively p rod uces hormones for
and the lower p ortio ns of the spi ra l a rteries (see Fig. about 10 da ys if fertil ization does not occur. As hormone
22.1 7). T h is layer is t he stratu m basale; the layer that was levels rapidly decline, changes occ ur in t he blood supply to
slo ughed off was the stra tum fu nction ale. Under the infl u- t he stra tum fu nct iona le. Initia lly, periodic contractions o f
ence o f estrogens, the proliferative phase is ini tiated . Stro - the wa lls o f t he spira l arteries, lasting for several hours,
mal, endothelial, a nd epi thelia l cells in the stra tum basa le ca use th e stratum functi o na le to become ischemic. The
prolifer ate ra p idly, a nd the following c ha nges ca n be seen: glands stop secreting, a nd th e endo metriu m shrinks in
height as the stro ma becomes less edem a tous. A fter about
Epithe lial cells in the basal porti on of the gla nds recon -
2 days, extended p eriods of arteria l contraction, w ith o nl y
stitu te the g la nds and migr a te t o cover th e de nuded en -
brief period s of blood flo w, ca use d isruption of the surface
dometria l surface. FIGURE 22.18
epithelium and rupt ure o f the b lood vessels. When the spi-
Stroma l cells p ro li ferate a nd secrete co ll agen a nd gro und Photomicrographs of the uterine lining in proliferative, secretory, thickness. The stratum basale (below the dashed line) exhibits less dra
ra l arteries close off, b loo d .flows into th e stratum basale
su bsta nce. and menstrual phases of the menstrual cycle. a. The upper panel matic changes in morphology. x 2 0. The lower panel shows uterine
but not into the stra tum functio na le. Blood , ute rine flu id,
Spi ral arteries lengthen as the endom etrium is reestab- shows the endometrium at the proliferative phase of the cycle. Dur glands that have been cut in a plane that is close to their long axes.
a n d slo ughing stroma l a nd epithelial cells fro m the stratum ing this pl1ase the stratum functionale (separated by the dashed line Note the pronounced corkscrew shape of the glands and mucous se
lished ; these a rte ri es are o nly slightly coiled and d o no t
fu nctio nale constitu te the vagina l d ischarge. As p atches of from the stratum basale) greatly thickens. x 15. The lower panel shows cretion (arrows). x 60. c. The upper panel shows the stratum tunc
extend into t he upper th ird of th e endo metrium.
t issue sep ara te fro m the endo metrium, t he torn end s of at higher magnification the endometrial glands that extend from the tionaie (above the dashed line). Much of the stratum fu nctionale has
The proli fe ra t ive ph ase continues until 1 d ay after o vu- veins, arteries, and gla nds are exposed (Fig . 22.1 8c). The stratum basale to the surface. x 55. b. The upper panel shows the en degenerated and sloughed away. x 15. The lower panel shows the ex
lation, wh ic h occurs a t about d ay 14 of a 28-day cycle. At desq uamation conti n ues u ntil onl y the stra tum basale re- dometrium at the secretory phase of the cycle. The glands have ac travasated blood and necrosis of the stratum functionale. x 55.
the end o f thi s p hase, the endome trium has reached a mains. C lotti ng of blood is inh ibited during th is period of quired a corkscrew shape as the endometrium increases further in
thic k ness o f a bo ut 3 mm. The g lan ds have narrow lum ina menstrua l .flow. Arterial bl ood flow is restric ted except for
a nd are re latively stra ig ht but have a slightly wavy a ppear- the brief perio ds of re laxa tio n of th e wa lls o f the spiral ar-
ance (Fig . 22.1 8a). Acc umulations of glycogen a re presen t teries. Blood contin ua ll y seep s from th e open end s of th e
in th e basa l p o rti o ns of the epithel ial cells. In ro utine his- vein s. T he perio d of menstru a l fl ow norma ll y lasts about 5
74 8 CHA PTER 2 2 I Fcwnlc Rrprodr~ctivr Sy strw C H APTER 22 Fewnlr Reprodu cti11e Sy stem 74 9
days. The average blood loss in the menstrua l phase is 35 trium is prevented, and the endometrium undergoes f ur- cavity. T his event defines the begin nin g of the blastocyst. invades the epitheliu m and under lying stroma of the en-
to 50 mL. Blood flow through the straight arteries main- ther development during th e firs t few weeks of pregnancy. As the blastocyst remains free in the uteri ne lumen for 1 or dometri um.
tains the stratum basale. 2 days and undergoes further mitotic di visions, the zona
As noted, this process is cyclic. Figure 22.14 shows a sin- Implantation is the process by which the blastocyst settles into pell ucida disappears. T he outer cell mass is now called the Throu~h the activity of the tro phoblast, the blastocyst is
gle cycle of the end ometrium and then dem o nstrates a the endometrium trophoblast, and the inner cell mass is referred to as the entirely embedded within the endo metrium on a bout the
gravid state as it is established at the end of a secretory embryoblast. 11th clay of development (further development of the syn-
phase. In th e absence of fertili zation, cessatio n of bleeding T he fertilized hmnan ovum undergoes a series of cytiotrophoblast a nd cytotrophoblast is described in the
wo uld accompany the growth a nd maturation of new changes as it passes through the uterine tube into the uter- Implantation occurs during a short period known as the section on the placenta).
ovarian follicles. T he epithelia l cells wou ld rapid ly prolif- ine cavity in preparation for becoming embedded in the implantation window The syncytiotrophoblast h as well-developed Golgi com-
erate and migrate to restore the sur face epithelium as the uterine mu cosa. The zygote undergoes cleavage, followed plexes, abu ndant sER and rER, numerous mitochondria,
proliferative phase of the next cycle begins. by a series of mitotic divisions wi tho ut cell growth, result- The attachment of the blastocyst to the endo metrial ep- and r elatively large numbers of lipid droplets. T hese fea -
In the absence of ovulation (a cycle referred to as an ing in a rapid increase in the n um ber of cells in the embr yo. itheli um occurs during the implantation window, the pe- tures a re consisten t with the secretion of progesterone, es-
anovulatory cycle), a cor pus luteum does not form, and Initially, th e em bryo is under th e control of maternal in- riod that the uterus is receptive for implantation of the trogens, hCG, and lactogens by this layer. Recent evidence
progesterone is not produced. In the absence of pr oges- fo rmational macromolecules th at have accumula ted in the blastocyst. This short period results from a series of pro- indicates that cytotrophoblast cells ma y also be a source of
terone, the endometrium does not enter the secretory phase cytoplasm of the ovum during oogenesis. La ter develop- grammed actions of progesterone and estrogens on the en- steroi.d h ormones and hCG .
and continues in the proliferative phase until menstruation. ment depends on activation of the embryo nic geno me, dometrium . Anti progesterone drugs, such as Mifepri stone
In cases of inferti lity, biopsies of the endometrium can be w hich encodes va rious growth factors, cell junction com- (RU 48 6) and its deriva tives, compete fo r the receptors in After implantation, the endometrium undergoes
used to di agnose such anovulatory cycles as well as other ponents, and other macromolecules r equired for norma l the endometri al epithel iu m, thus blocking hormone bind- decidualization
disorders of the ovary and endometrium. progression to the blastocyst stage. ing. The fa ilure of progesterone to ga in access to its recep-
T he cell mass resulti ng from the series of mitotic divi- tors prevents implan tatio n, thus effectively closing the During pregnancy, the portion of the endometrium that
sio ns is known as a morula [L. morum, mulberry], and th e in- window. In the huma n, th e impla ntatio n window begins undergoes morpho logic changes is ca lled the decidua or de-
Implantation o n day 6 after the LH sur ge and is completed by day 10. cidua graviditas. As its name imp lies, this layer is shed with
dividual cells a re known as blastomeres. During the third
day after fe rtili zatio n, the morula, w hich has reached a 12- As contact is made with the uterine wall by the tro- tbe placenta at parturitio n. T he d eci dua includes a ll but the
If fertilization and implantation occur, a gravid phase replaces to 16-cell stage and is still surrounded by the zona pellu- p hoblastic cells over the em bryoblast pole, the tropho blast deepest layer of the endometrium. T he stromal cells differ-
the menstrual phase of the cycle cida, enters the uterine cavity. The moru la remains free in rapidly proliferates and begins to invade the endometrium . entiate into large, rounded decidual cells (see page 745).
the uterus for about a day w hile continued cell divisio n T he invading trophoblas t differentiates into th e sy11cy- The uterine glands enlarge and become more coiled during
If fertilization a nd subsequent implantation occur, de- and development occur. The ea rly em bryo gives rise to a tiotrophoblast and the cytotrophoblast. the earl y part of pregnancy and then become thin and flat-
cline of the endometriurn is delayed unti l after pa rtur ition. blastocyst, a hollow sphere of cells w ith a centrally located tened as the growing fetus fills the uterine lumen.
The cytotrophoblast is a mi totica ll y active inner cell Three d ifferent regions of the deci dua are identified by
As the blastocyst becomes embedded in the uterine mucosa clump of cells. Th is inner cell mass w ill give rise to the tis-
layer prod ucing cells that fuse with tbe syncytiotro- their relatio nship to the site of implanta tion (Fig. 22.20):
in the ea rly part of the second week, cells in th e chorion of sues of the embryo proper; the surround ing layer of cells, phoblast, the o uter erosive layer.
the develo ping p lacenta begin to secrete h CG and other lu- the outer cell mass, will for m the trop hoblast and then the
The syncytiotrophoblast is not mitotica ll y active a nd Th e decidua basalis is th e portion of the endometrium
teotropins. These hormones main tai n the corpus luteum placenta (Fig. 22.19).
consists of a multi nu cleate cytoplasm ic mass; it actively that underlies the implan tation site.
an d stimulate it to continue the production o f proges- Fluid passes inward through the zona pellucida during
terone and estrogens. Thus, the decl ine of the endome- this process, forming a flu id-filled cavity, th e blastocyst
maternal
blood
embryoblast epithelium of
syncytiotrophoblast
cytotrophoblast placenta
vi lli
blastocyst extraembryonic decidua decidua
cavity somatic capsularis basalis
mesoderm decidua
decidua basalis
chorion
parieta lis
amnion
chorionic cavity
Cervix
The endometrium of the cervix differs from the rest of the uterus
FIGURE 22.22
Stratified squamous epithelium of the ectocervix. The stratified FIGURE 22.23
The cervical mucosa measures about 2 to 3 mm in thick- Transformation zone of the cervix. The site of the squamocolumnar
sq uamous epithelium and underlying fibrous connective tissue witl1in
ness and differs dramatically from the rest of the uterine en- the lower rectangle in Figure 22.21 is shown here at higher magnifica- junction from the upper rectangle in Figure 22.21 is shown here at
dometrium in that it contains large, branched glands (Fig. tion. The more mature epithelial cells have a clear cytoplasm (arrow higher magnification. Note the abrupt change from stratified squa-
22.21 ). 1t a lso lacks spiral arteries. The cervica l mu cosa un- 11eads), a reflection of their high glycogen content. Also, note the con- mous epithelium to simple columnar epithelium (arrow). Neoplastic
dergoes little change in thickness during the menstrua l cy- nective tissue papillae protruding into the epithelium (arrows). The changes leading to development of cervical cancer most frequently
cle and is not slo ughed during the peri od of menstru ation. bulk of the cervix is made up of dense, fibrous connective tissue with begin in this transformation zone. Within the connective tissue are
During each menstru al cycle, however, the cervical glands relatively little smooth muscle. x 120. the branched, mucus-secreting cervical glands (CG) composed of a
undergo important functional changes that are related to simple columnar epithelium that is continuous with the lining epithe-
lium of the cervical canal. x 120.
the transpo rt of spermatozoa within the cer vica l canal. The
amount and properties of the mucus secreted by th e gland
cells vary during the menstrual cycle under the influence of ------- external os - - - - marion zone resides in th e cervical cana l (Fig. 22.23 ). and veno us channels th at communicate with the lacunae
the ovarian hormones. At midcycle, the amount of mucus FIGURE 22.21 Metaplastic changes in this transitio n zone constitute pre- esta blishes directi o na l flo w fro m the arteries into the vei ns,
p rod uced increases 10- fold. This mucus is less viscous and Photomicrograph of a human cervix. This HaE-stained specimen is cancerous lesions of the cervix. The cervical epithelia l cells thereby establishing a primitive uteroplacental circul a tio n.
appea rs to provide a more favo rable enviro nment fo r sperm from a postmenopausal woman. Its lower portion projects into the are constantly exfoliated into the vagina. Stained prepara- Numerous pinocytotic vessels present in the syncytiotro-
migration. The cervical mucus at other times in th e cycle re- upper vagina where an opening, the external os, leads to the uterus tions of the cervica l cells (Papa nicolaou [Pap] smears) are phoblast indicate the transfer of nutrients from the mater-
through the cervical canal. The surface of the cervix is covered by used routinely for screening and diagnosis of precancerous
stricts the passage of sperm into the uterus. Thus, hormo nal nal vessels to th e embr yo.
stratified squamous epithelium (SSE) that is continuous with the ep-
mechanism s ensure that ovulation and changes in the cer vi- and cancerous lesions of th e cervix. Proliferation of th e cytotrophoblast, growth of chori-
ithelial lining of the vagina. An abrupt transition from stratified squa-
ca l mucus are coordina ted, th ereby increasing the possibil- mous epithelium to simple columnar epithelium (SCE) occurs at the
onic mesoderm, and blood vessel development successively
ity tha t fertili za tion will occur if freshly ejac ulated sperma - entry to the cervica l canal. In this specimen, the stratified epithelium give rise to
tozoa and the ovum arrive simultaneous ly at the site of has extended into the canal, an event that occurs with aging. Mucus- \}PLACENTA
fertili za tion in the uterine tube. secreting cervical glands are seen along the cervical canal. These are Primary chorionic villi, which are formed by the rapidly
Blockage of the openings of the mucosal glands results simple branched tubular glands that arise as invaginations of the ep- The developing fetus is maintained by the placenta, which proliferating cytotro pho blast. It sends cords or masses
in the retention of their secreti ons, leading to format ion of ithelium lining the canal. Frequently, the glands develop into Naboth- d evelops from fetal and maternal tissues of cells into the blood-filled trophoblastic lacunae in the
di lated cysts within the cervix, called Nabothian cysts. ian cysts as a result of retention of mucous secretion by blockage of syncytiotrop ho blast (see Fig. 22.19 b). The primary villi
Nabothian cysts develop frequentl y but are clinically im- the gland opening. The material marked by the X is mucus secreted The placenta consists of a fetal portion, formed by the ap pear between days 11 and 13 of develo pment.
portant only if nu mero us cysts produce ma rked enlarge- from the cervical glands. X10. cho rion, a nd a maternal portio n, fo rmed by the decid ua Seconda1'y chorionic villi, w hich are composed of a cen-
rnent o f the cerv ix. basa lis. The two parts are involved in ph ysio logic exchange tral core of mesenchyme, surrounded by an in ner layer of
of substances between the maternal and feral circulation. cytotropho blast an d a n o uter layer of sy ncytiotro-
The transformation zone is the site of transition between squamous epithelium (Fig. 22.22). An abrupt transition be- The uteroplacental circulatory system begins to develop phoblast. They develo p at a bout da y 16, w hen th e pri-
vaginal stratified squamous epithelium and cervical simple tween this sq uamous epithelium and the mucus-secreting around day 9, with development of vascul ar spaces ca lled mary chorionic villi become invaded by loose con11ective
columnar epithelium columnar epithelium of the cervica l canal, the endocervix, trophoblastic lacunae within the sy ncyti otrophoblast. Ma- tissue from cho rio nic mesench yme. The secondary villi
occurs in the transformation zone that during the repro- terna l sinusoids, w hich develop from ca pillaries of the ma- cover the entire surface of the cho rionic sac (Fig. 22.24a) .
The portio n of the cervix that projects into the vagina, ductive age of the woman is located just outside the exter- terna I side, a nastomose with the trophoblastic lacu nae Tertiary chorionic villi are formed by the end of th e
the vagin al part, the ectocervix, is covered with a stratified nal os. Before puberty and after menopa use the transfor- (Fig. 22.24 ). The differential pressure between the arterial third week as th e secondary villi become vascu larized by
752 C HAPTER 22 Female Rrpro1luclive SyslrHI CHAPTER 22 Female Rrproduclive Syslr111 753
Two types of cel ls a re recognized in the connective tissue Basal lamina of the trophoblast
stroma of the villi: mesenchymal cells and Hofbauer cells Connective (mesenchymal) tissue of the vill us
(Fig. 22.25). H ofbauer cells a.re more common in the early Basal lamina of the endotheliu m
secondary villus Endothelium of the fetal p lacental capillary in the terti-
placenta. They appear to be macrophages. The vacuoles in
these cells contain lipids, glycosaminoglycans, and glyco- ary vill us
syncytiotrophoblast
proteins. Recent studies of HIV-infected placentas indicate
cytotrophoblast that HIV is primarily loca lized within H ofbauer cells as T his barrier bears a strong resemblance to the air-blood
well as in the syncytiotrophoblast. barrier of the lung, with which it has an important paral-
lel function, namely, the exchange of oxygen and carbon
Early in development, the blood vessels of the villi become diox ide, in this case between the materna l blood and the
connected with vessels from the embryo fetal blood. It also resembles the air-blood barrier by hav-
ing a particular type of macrophage in its connective tis-
Blood begins to circu late through the embryonic cardio- sue, in this instance, the H ofbauer cell.
vascular system and the villi at abou t 21 days. The inter-
a villous spaces provide the site of exchange of nutrients, The placenta is the site of exchange of gases and metabolites
meta bolic products and intermediates, and wastes between between the maternal and fetal circulation
the materna l and feta l circulatory systems.
,...:,....___:_~- cytotrophoblastic
shell During the first 8 weeks, villi cover the entire chorionic Fetal blood enters the placenta through a pair of um-
surface, but as growth continues, villi on the decidua cap- bilical arteries (Fig. 22.26). As they pass into the pla-
~-+.-- tertiary villus
sularis begin to degenerate, producing a smooth, relatively centa, these arteries branch into several radiall y disposed
syncytiotrophoblast avascular surface called the chorimt Laeve. The villi adja- vessels that give numerous branches in the chorionic
cent to the decidua basalis rapidly increase in size a nd plate. Branches from these vessels pass into the villi,
number and become highly branched. T his region of the formi ng extensive capillary networks in close association
intervillous space chorion, which is the fetal component of the placenta, is with the inter villous spaces. Gases and metabolic prod-
called the chorion frondosum or villous chorion. The layer ucts are exchanged across the thin feta l layers that sep-
mate rnal blood of the placenta fro m which the villi project is called the arate the two bloodstreams at this level. Antibodies can
chorionic plate. also cross this layer and enter the feta l circulation to
During the period of rapid growth of the chorion fron- provide passive immunity against a variety of infectious
dosum, at abou t the fourth to fi fth month of gestation, the agents, e.g., those of diphtheria, small pox, and measles.
fetal part of the placenta is divided by the placental (de- Fetal blood returns through a system of veins that par-
cidual) septa into 15 to 25 areas ca lled cotyledons. Wedge- allel the arteries except that they converge on a single
FIGURE 22.24 Like placental septa for m the boundaries of the cotyledons, umbilical vein.
Schematic diagrams of sections through a developing human em- and because they do not fuse with the chorionic plate, ma- Maternal blood is supplied to the placenta through 80 to
bryo. a. This drawing shows the chorionic sac and placenta at 16 days ternal blood can circulate easily between them. Cotyledons 100 spiral endometrial arteries that penetrate the basal
of development. b. The same embryo at 21 days of development. The are visible as the bulgi ng areas on the maternal side of the plate. Blood from these spiral arteries flo ws into the base
diagrams illustrate the separation of the fetal and maternal blood ves- basal plate.
sels by the placental membrane, which is composed of the endothe- The decidua basalis forms a compact l aye1~ known as the
lium of the capillaries, mesenchyme, cytotrophoblast, and syncy-
basal plate, wh ich is the maternal component of the pla-
tiotrophoblast. (Based on Moore KL, Persaud TVN. The Developing FIGURE 22.25
centa. Vessels within this pa rt of the endometrium supply
Human, Clinically Oriented Emb1yo1ogy. Philadelphia: WB Saunders, Photomicrographs of a human placenta. a. This H&E-stained speci-
1993.)
blood to the intervillous spaces. Except for relatively ra re men shows the amniotic surface (A), the chorionic plate (CP), and, be-
r upturing of capi llar y walls, w hich is more common at de- low, the various-sized profiles of the chorionic villi (CV). These villi
li very, fetal blood and matern al blood do not mix. emerge from the chorionic plate as large stem villi and branch into
blood vessels that have developed in their connective tis- tile increasingly smaller villi. Blood vessels (BV) are evident in the
Fetal and maternal blood are separated by the placental larger villi. The smallest villi contain capillaries where exchange takes
sue cores (Fig. 22.24b)
barrier place. x 60. Upper inset. This higher magnification shows the simple
As the tertia ry villi are form ing, cytotrophoblastic ce lls cuboidal epithelium of the amnion and tile underlying connective tis-
Separation of the fetal and materna l blood, referred to sue. x 200. Lower inset. This higher magnification shows a cross-
in the villi contin ue to grow out through the syncytiotro-
as the placental ban-ier, is main tained primarily by the lay- sectioned villus containing several larger blood vessels and its thin
phoblast. When they meet the maternal endometrium, they surface syncytiotrophoblast layer. x 200. b. This H&E-stained speci-
ers of fetal tissue. Sta rting at the fourt h month, these lay-
grow laterall y and meet simila r processes growing from men shows the maternal side of tile placenta. The stratum basale
ers become very thin to fa cilitate t he exchange of p roducts
neighboring vi lli. Thus, a thi n layer of cytotrophoblastic (SB), the part of the uterus to which some of the chorionic villi (CV) an-
across the placental barrier. T he thinning. of the wall of the
cells, called the trophoblastic shell, is formed around the chor, is seen at the bottom of the micrograph. Also evident is a stro-
vi llus is due in part to the degenera tion of the inner cy-
syncytiotrophoblast. T he trophoblastic shell is interrupted mal connective tissue (CT) component, part of the stratum basale, to
totrophoblast layer.
only at sites where maternal vessels conunun icate with the which many of the chorionic villi are also attached. Within the stra-
At its thinnest, the placental barrier consists of the
intervillous spaces. Future growth of the placenta is ac- tum basale and the connective tissue stroma are clusters of cells, the
complished by interstitial growth of the trophoblastic Syncytiotrophoblast decidual cells (arrows), which arose from connective tissue cells. x 60.
shell . Discontinuous inner cytotrophoblast layer Inset. Decidual cells seen at higher magnification. x 200.
754 CHAPTER 22 I Frultllr Reproductive Syslfw
CHAPTE~ 22 Fttunlr Rcprorluclivr Systrm 7 55
MATERNAL CIRCULATION placenta produces eno ugh p rogeste rone by the en d of the IGF-I and IGF-II are produced by and stimulate prolif-
eighth week to maintain pregnancy if the corpus luteum is eration and differentiatio n of the cytotrophoblast.
surgically rem oved or fai ls to function. In the production E1tdothelial gmwth factor (EGF) exhibits an age-
stump of main .....,+-~ of placental estrogen, the fetal adrenal cortex p la ys an es- dep~ndent dual action o n the early placenta . In the 4-
stem vi lli sential role, providing the precu rsors needed for estrogen to 5-week-o ld placenta, EGF is synthesized by the cy-
septa synthesis. Because the placen ta lacks the enzymes needed totropho blast and stimulates proliferation of the tro-
for the p roductio n of estrogen precursors, a cooperative phoblast. In the 6- to 12-week-old placenta, synthesis
decid ua parietalis main stem villus fetoplacental (endocrine) unit is esta blished . Cli nically, the of EGF is shifted to the syncytiotrophoblast; it then
uterine monitoring of estrogen production during pregnancy can stimulates and maintains the function of the differen-
cavity umbilical arteries cotyledons
be used as an index of fetal development. tiated trophoblast.
amnion placenta The following peptide hormones are secreted by the pla- Relaxin is synthesized by decidual cells and is involved
centa: in the "softening" of the cervix and the pelvic ligaments
chorion decidua
basalis
in preparation for parturition.
hCG, the synthesis of which begins a ro und day 6, even Leptin is synthesized by syncyti otrophoblast, particu-
endometrial
spiral artery before syncytiotrophoblast formation. hCG exhi bits larly during the last month of gestation. Leptin appears
umbilical vei
marked homology to pituitary th yroid-stimulating hor- to regulate maternal nutrient storage to the nutrient re-
mone (T SH ) and stimulates the m aterna l thyroid gland quirements of the fetu s. It is also involved in transport-
endometrial to increase secretion of tetraiodothyron ine (T 4 ). It also ing nutrients across the placental barrier from m other to
vein mai ntai ns the corpus lu teum d uring early pregnancy. the fetus.
M easurement of hCG is used to detect pregnancy and Other growth factors sti mulate cytotrophoblastic
assess early embryonic development. growth (e.g., fibroblast growth factor, colony-stimulat-
Huma11. chorionic somatomammotmpin (hCS) , a lso ing factor [CSF-1 ], platelet-derived growth factor, and
known as human placental lactogen (hPL), is closely re- interleukins [IL-l and IL-3 J) or inhibit tropho blast
lated to human growth hormone. Synthesized in the syn- growth and proliferation (e.g., tumor necrosis factor).
cyti otrophoblast, it promotes general growth, regulates
FIGURE 22.26
glucose metabolism, and stimulates mam mary duct pro-
Schematic diagram of mature human placenta. Th e sagittal section exchange of gases and metabolic products occurs. Tile maternal
li feration in the m aternal breast. hCS effects on m ater-
\/VAGINA
of the uterus (left) with the developing embryo shows the most com- blood finally leaves the Intervillous space (black arrows) through en-
mon location of the placenta. The mature placenta (right) Is divided dometrial veins. The fetal blood enters the placenta through the um- nal metabolism are significant, but the role of this hor-
The vagina is a fibromuscular tube that joins internal
Into cotyledons by placental septa that are formed by outgrowths of bilical arteries that divide into a series of radially disposed arteries mone in fetal development remains unknown.
reproductive organs to the external environment
the decidua basalis. Maternal blood enters the placenta through nu- within tile chorionic plate. Branches from the vessels pass into the
merous endometrial spiral arteries that penetrate t he basal plate. As main stem villi and there form extensive capillary networks. The
the blood enters the cotyledon, it is directed deep into the intervillous
The vagina is a fib romuscula r sheath extending from rhe
veins within the villi then carry the blood back through a system of
spaces {red arrows). It then passes over the surface of the villi, where veins that parallels the fetal arteries. cervix to the vestibule, which is the area between rhe labia
minora. In a virgin, the opening into the vagina may be
surrounded by the hymen, fo lds of muco us membrane ex-
tending into the vaginal lumen. T he hymen or its r emn ants
are derived fr om the endodermal membrane that separated
of the in tervillo us spaces, which contai n about 150 mL of Before the establishment of blood flow thro ug h the p la- the developing vagina from the cavity of the definitive uro-
The mature placenta measures about 15 to 20 em in diameter
matern a l blood that is exchanged 3 to 4 times per minute. centa, the growth of the em bryo is su pported in part by genita l sinus in the em bryo.
and 2 to 3 em In thickness, covers 25 to 30% of the uterine sur
The blood press ure in the spir al a rteries is much higher metabolic products that are synthesized by or transported face, and weighs 500 to 600 gat term. Tile surface area of the The vaginal wa ll (Fig. 22.27) consists of an
th an that in the in tervillous spaces. As blood is injected through the trophoblast. T he syncytiotro pho blast synthe- villi in the human placenta Is estimated to be about 10m2 . Tile Inner mucosal layer, which has numerous transverse
into these spaces at each pulse, it is di1ected deep into the sizes glycogen, cholesterol., and fat ty acids, as well as other microvilli on the syncytiotrophoblast Increase the effective
folds or ru gae (see Fig. 22.1) and is lined with stratified
spaces. As the pressure decr eases, the blood fl ows back nu trients used by the embryo. area for metabolic exchange t o more than 90 m2 After birth,
squamo us epithelium (Fig. 22 .28) . Connective tiss ue
over the surfaces of the villi and eventua lly enters endome- the uterus continues to contract, reducing tile luminal surface
papillae fro m the underlying lamina propria project into
tr ial veins a lso located in the base of the spaces. The placenta is a major endocrine organ producing steroid and and inducing placental separation from the uterine wall. The
entire fetal portion of the placenta, fetal membranes, and the the epithelia l layer. In humans and other primates, kera-
Exchange of gases and metabolic pr oducts occurs as the protein hormones
Intervening projections of decidual tissue are released. During tohyalin gra nules may be presen t in th e ep ithelial cells,
blood passes over the villi. Normall y, water, ca rbon diox-
uncomplicated labor, the placenta is delivered approximately but under normal cond itions, keratinizatio n does not
ide, metabolic waste products, and hormones are tra ns- The placenta also functions as an endocrine organ, pro-
30 minutes after birth. occur. Ther efore, nuclei can be seen in epithelial cells
fened from the fetal blood to the maternal blood; water, du cing steroid and peptide hormones as well as
After delivery of the placenta, the endometrial glands and th rougho ut the thickness of the epithelium.
oxygen , metabolites, electrolytes, vitamins, horm ones, and prostaglandins that play an important role in the onset of stroma of the decidua basalis regenerates. Endometrial regen- Intermediate muscular layer, which is organized into
some antibodies pass in the opposite direction. T he placen- labor. Immunocytochemical studies i11dicate that the syn- eration is completed by the end of tile third week postpartum two sometimes indistinct, intermingli ng smooth muscle
tal barrier does not exclude many po tentiall y dangero us cytiotrophoblast is the site of synthes is of these hormones. except at the placental site, where regeneration usually ex- layers, an outer longitu din al layer and an inner circular
agents, such as alcohol, nicotine, viruses, drugs, exogenous The steroid hormones, progesterone and estrogen, have tends through t he next 3 weeks. During the first week after de- layer. The o uter layer is continuo us with the correspon-
hormones, and heavy metals. Therefore, dur ing pregnancy, essential roles in tbe ma intena nce of pregnancy. As preg- livery, remnants of the decidua are shed and constitute the
ding layer in the uterus and is much thicke r than the in -
exposure to or ingesti on of such agents should be avo ided nancy proceeds, the placenta takes over the major rol e in blood-tinged uterine discharge known as the lochia rubra.
ner layer. Striated muscle fibers of the bulbospongiosus
to red uce the risk of injury to the embryo or fetus . the secretio n of these steroids fr o m the corpus luteum. The muscle are present at the vag.inal opening.
756 CHAPTER 22 Fe111nle Reproductive Sy ste111 C H APTER 22 Fe111nle Ref>rodllclivr Syslr111 7 57
Labia majora. The labia majora are two lar ge longitu- vestibular glands (also called Skene's glands ), are pres- 22.31). The lobes, separated by fibrous ba nds of co nnec- ends in a lactifemus duct th a t opens through a con-
dinal fo lds of skin, homologous to th e sk in of the scro- ent primarily near th e clitoris an d around the external tive tissue, radiate from the mammary papilla, or nipple, stricted orifice onto the nipple. Beneath the areola, the
tum, that extend from the mons pubis and form the lat- urethral orifice. The large, paired greater vestibular a nd are further subdivided into numerous lobules. Some of pigmented a r ea surrounding t he nipple, each duct has a
eral bounda ries o f the urogenital cleft. They contain a glands (also called Bartholin's glands) are homologous the fib rous bands, called suspensory or Cooper's liga- dilated portion, t he lactiferous sinus. Near their open-
th in layer of smooth m uscle that r esem bles the dartos to the male bulbo urethral g lands. These t u boalveolar 11tents, connect w ith the derm is. Abundant ad ipose tissue ings, the lactiferous ducts are lined with stratified sq ua-
muscle of the scrotum and a large amount of su bcuta- glands are a bo ut 1 em in di amete r an d a re located in the is present in the dense connective tissue of the interlobular mous epithelium. T he epithelia l lining of the duct shows
neous adipose tiss ue. The outer surface, like that of the lateral wal l of the vestibule posterior to the bulb of the spaces. The intralobular connective tissue is much less a grad ua l tra nsition from stratified squamous to two la y-
mons pubis, is covered with pubic h a ir. The inner sur- vestibule. The greate r vestibular glands secrete lubricat- d ense and contains little fat. ers of c uboid al cells in the lactiferous sinus and fin ally
face is smooth and devoid of hair. Sebaceo us and sweat ing muc us. The ducts o f these glands open into the The epidermis of the adult nipple a nd areo la is highly to a sing le layer of columnar or cuboidal cells through
g lan ds are present on both surfaces (Fig. 22.30) . vestibule near the vagin al opening. pigmented and somewhat wrinkled a nd has long dermal the rema inder of the duct system. Myoepithelial cells o f
Labia minora. The labia minora are pa ired, hairl ess papillae invading into its dee p surface (Fig. 22.32). It is ectoderm al o rig in lie within the epithelium between th e
Numerous sensory nerve e ndings are present in the ex -
folds of skin that border the vestibule a nd are h omolo- covered by keratinized stratified squa m ous epithelium. The smface epithelia l cells and the basal lamina. These cells,
ternal genitalia:
gous to the skin of the p enis. Abunda nt melanin pigment pigmentation of th e nipple increases a t puberty, and arranged in a baske t-like network, are present in the se-
is prese nt in the deep cells of the epithelium. The core of Meissner's corpuscles are particularly abu ndant in the the nipple becomes more prominent. DL1r ing pregnancy, cretory portion of the gland but are more apparent i.n
co nnecti ve tiss ue within each fold is d evoid of fat but skin over the mons pubis and labia m a jora. the areola becomes larger and th e degree o f pigmentation the larger ducts.
does contain munerou s blood vessels a nd fine elastic Pacinian corpuscles a re d istri buted in the deeper layers inc reases further. D eep to the a reola and n ipple, bundles of
fibers. Large sebaceous gla nds a re present in the stroma. of th e connective tissue and a re found in the labia ma- smooth muscle fibers are arranged radiall y and circumfer- The morphology of the secretory portion of the mammary
Clitoris. The clitoris is an erectile structure th at is ho- jora and in associatio n with the erectile tiss ue. The sen- entially in t he dense connective tissue and longitudina lly gland varies with the menstrual cycle
mologous to the penis. Its body is composed of two sory impulses fro m these nerve endings play a n impor- a long the lactiferous duc ts. These muscle fibe rs allow the
small erectile bodies, t he corpora cavernosa; the glans tant role in the physio logic response during sexua l n ipple to become e rect in response to va ri o us stimu li. In the inactive gland, the gland u lar component is
clitoris is a small, ro unded t ubercle o f e rectile tissue. T he arousa l. The areo la contains se baceous glands, sweat glands, spa rse a nd consists chiefl y of duct elements (Fig. 22.33 ).
skin over the glans is very thin, for ms the prepuce of the Free nerve endings are present in large numbers and a re and modified mamma r y glands (gla nds of Montgomery). During the menstrua l cycle, the inactive breast und ergoes
clito ris, a nd contains num erous sensory ne rve endings. equally distributed in the skin of the external genitalia . These glands, have a structure intermediate between slight cyclic cha nges. Early in the cycle, the ducts appear
Vestibule. The vesti bule is lined with stra tified squ am o us sweat gla nds and true mammary g lands, and produce as cords with little or n o lumen. Under estrogen stimu-
epithelium. Nu merous small mucous g lands, the lesser sma ll eleva tions on the surface of the a reola. Numerous lation, at about the tim e of ovulation, tl1e secretory cells
Q MAMMARY GLANDS senso ry nerve endings are present in the nipple; the a re- increase in height, lumina ap pear in the ducts as small
o la contains fewer sensory ne rve endings. The tubu - amounts o f secreti o ns accumulate, a nd fluid accumulates
The ma mma ry g lands, or breasts, are a distinguishin g fea- loalveola r glands, derived from modified sweat glands in in the connective tissue.
ture of ma mmals. During embryo logic development, the epidermis, l ie in th e subc uta neous tissue. Each gland
growth and development of breast tissue occur in both Mammary glands undergo dramatic proliferation and
sexes. Multiple gla nds develop a long paired epidermal development during pregnancy
thickenings, ca lled mammmy ridges (milk lines), wh ich
extend from the d eveloping axilla to the developing in- The mammary gla nds exhibit a n um ber of ch a nges in
guinal region . L1 huma ns, no rma ll y only o ne group of cells prep a ratio n for lactation. The ch anges in the gla ndul a r
develops into a b reast on each side. An extra breast (po ly- tissue are accompanied by a decrease in the amount of
mastia) or nipple (polythelia) may occur as an inherita ble connecti ve tissue and ad ipose tissue. Plasma cells, lym-
conditi o n in about 1% of the fema le population. These rel- p hocytes, a n d eosinophils infiltrate the fibrou s comp o-
a tively rare conditions may a lso occur in ma les. nent of th e connective tissue as the breast develops. The
In males, little add itional d evelopment of t he ma mmary development of the glandular tissue is not w1iform, a nd
gla nds normally occu rs in postnata l life, a nd the glands re- variation in th e degree of d evelopment is seen even
main rudimentary. In fema les, the mammary g lands un - w itl1in a single lo bul e. T he cells va ry in shape from flat-
dergo further d evelopment under hormonal influence. They tened to low columnar. As the cells proliferate by mitotic
are also influenced by cha nges in ovaria n hormon e levels di vision, the ducts bra nch and alveoli begin to develop.
during each menstru al cycle. The actual initia tion of milk In the later stages o f pregn a ncy, a lveolar development
secretio n is induced by prolactin secreted by the adeno hy- becomes more p romi ne nt (Fig. 22.34). The actua l pro-
pophysis. The ejection o f the mi lk from t he breast is stimu- liferation of the stromal cells declines, a nd subseq uent
lated by oxytocin released from the neurohypoph ysis. With en la rgement of the breast occurs through hypertrophy of
the c hange in the ho rmon al environ ment a t menopa use, the the secretory cells and accu mula tion of secr etory prod-
g la ndu la r component of the b reast regresses o r involutes uc t in t he alveo li .
FIGURE 22.30
a nd is replaced by fat a nd con nective tissue. lobules of tubuloalveolar glands
Photomicrograph of the inner surface of the labia majora. This low-
power H&E-stained specimen of the labia majoras inner surface FIGURE 22.31
Both merocrine and apocrine secretion are involved in
shows its nonkeratinized epithelium (Ep} and abundant sebaceous Mammary glands are modified apocrine sweat glands that Schematic drawing of the human breast as seen during lactation. production of milk
glands (SG). Two sebaceous ducts (SD) are also evident. Note the con develop under the influence of sex hormones The breast is composed largely of branched tubuloalveolar glands
tlnu ity of the duct epithelium with the epithelium of the skin and the contained within an extensive connective tissue stroma and variable The secreting cells contain abundant granular e ndo-
sebaceous gland epithelium. At this magnification, several smooth The inactive adult ma mmar y g la nd is composed of 15 to amounts of adipose tissue. (Modified from Warwick R, Williams PL, p lasmic retic ulum, a mode rate number of la rge mitoc hon-
muscle bundles can be just barely discerned (arrows). 20 irregular lobes of bra nc hed tubuloa lveolar g lands (Fig. eds. Gray's Anatomy. 35th ed. Edinburgh : Churchill Livingstone, 1973.) dria, a supranuc lea r Go lg i apparatus, a nd a number of
I
I C HAPTER 22 Fruwle Reproductive Syslew 76I
I
I
I
I
I
I
i
I
I
I
FIGURE 22.32 I
Photomicrographs of a section through the female nipple. a. This
low-magnification micrograph of a H&E-stained sagittal section
two cell layers. As it approaches the tip of the nipple it changes to a
stratified squamous epitl1elium and becomes continuous w ith the
I
through the nipple shows the wrinkled surface contour, a thin strati-
fled sq uamous epithelium, and associated sebaceous glands (arrows).
epidermis. x 175. c. A higher magnification of the sebaceous gland
from the rectangle in a. Note how the glandular epithelium is continu-
I
The core of the nipple consists of dense connective tissue, smooth ous with the epidermis (arrows) and the sebum is being secreted onto
muscle bundles, and the lactiferous ducts that open at the nipple sur- the epidermal surface. x 90. d. A higher magnification showing bun-
face. x 6. b. The wall of one of the lactiferous ducts is shown here at
higher magnification. Its epit11elium is stratified cuboidal, consisting of
dles of smooth muscle in longitudinal and cross-sectional profiles.
X 35Q.
I
l
FIG URE 22.34
Photomicrograph of an active mammary gland during late preg- Outside the lobules Is a large excretory duct. x 6 0 . b. A higher mag-
nancy. a. This low-magnification H&E-stalned specimen shows the nification of an area in a. The secretory alveolar cells are mostly
marked proliferation of the duct system, giving rise to the secretory cuboidal here. A myoepithelial cell (mEp) as well as a number of
alveoli that constitute the major portion of the lobules. The intralob- plasma cells (arrows) can be identified in the adjacent loose connec-
ular duds are difficult to identify, as their epithelium also secretes. tive tissue. x ?OO.
dense lysosomes (Fig . 22.35). Depend ing on t he secretory The sec re tion released in the first few clays after chi ld-
sta te, large lipid drop lets and secretory vesicles ma y be birth is known as colostrum. T h is premjl k is a n alkaline,
p rese nt in th e apical cytoplasm. T he secretory cells pro- ye llowish secretion w ith a highe r protein, vitamin A,
duce two d istinct pr oducts th at are released by different sodiu m , a nd c hl oride content a nd a lower lip id, ca r bo-
mec ha nisms: hydrate, a n d potass iu m co n ten t th a n mi lk. It conta ins
co ns ider able a mo unts of antibod ies t h at p r ovid e t he
Merocrine secretion. The protein com po nent of th e newb orn with so me deg ree o f passive immu nity. T he an-
milk is synthesized in t he rER, packaged into mem- ti bodies in the co lostr um are believed to be p r oduced by
br ane- limited secretory vesicles for tra nsport in t he the lymp ho cytes and plasma cells t hat in filtrate the loose
Golgi appa ratus, and released from t he cell by fusion co nnective tissue of t he b reast d ur ing its p ro liferatio n
of the ves icle's limi ting m embrane with th e plasma and de ve lopme n t and are secreted across the glandula r
mem b rane. cells as in saliva ry g la nds and in testine. As these wan-
Apocrine secretion. T he fatty or lipid component of t he dering cells decrease in n umber a fter parturition, t he
mi lk a r ises as lipid droplets free in the cytoplasm. prod uction of colostru m sto ps, a nd l ipid-rich m ilk is
T he lipid coalesces to form large d roplets t hat pass to prod ucecl.
the apica l region of the cell and project into the lumen
of the acin us. The droplets a re invested with an envelope
Hormonal Regulation of the Mammary Gland
FIGURE 22.33
of p lasma membra ne as they a re released . A thi n layer of
Photomicrograph of an inactive m am mary gland. a. This low- of the area in the rectangle of a. The epithelial cells of the duds are cytoplasm is trapped between t he plasma mem brane and T h e initial growt h and development of the mammary
magnification H&E-stained specimen shows several lobules within columnar and exhibit interspersed lymphocytes (arrows) that have lipid droplet and is released w ith th e li pid, b ut t he cyto- gland at puberty occur under t he influence o f estrogens
the dense connective tissue of the breast. The epithelial component entered the epithelium. The surrounding stained material (arrow plasmic loss in this process is minimal. and progesterone produced by th e matur ing ova ry. Su b-
consists of a branclling duct system that makes up the lob ule. The /leads) represents the myoepit11elial cells (MEp) and collagen bundles
clear areas (arrows) are adipose cells. X60. b. A l1igl1er magnification in the adjacent connective tissue. x?OO.
762 CHAPTER 22 Female Rcproducliue Sy stem CHAPTER 22 Femnle Refnodu ctipe Systen1 763
c
FIGURE 22.35
Photomicrographs and diagram of a lactating mammary gland. the secretory cells of the alveoli as well as in the alveolar lumin a. The
a. Low-magnification micrograph of a fast green-osmium-stained sec- arrows indicate plasma cells within the interstitial spaces. X480. c. Di-
tion of a lactating mammary gland. Portions of several large lobules agram of a lactating mammary gland epithelial cell. (Redrawn after
and an excretory duct are seen. Many of the alveoli exhibit a promi- Bloom W, Fawcett DW. A Textbook of Histology. lOth ed. Philadelphia:
nent lumen, even at this magnification. x60. b. A higl1er magnifica- WB Saunders, 1975.)
tion of an area in a shows lipid droplets (black circular profiles) within
sequent to this initial development, slight changes in the gresses. Immediately after birth, however, the sudden loss
morphology of the glandular tiss ue occur during each of estrogen and progesterone secretion from the placenta
ovarian cycle. During pregnancy, the corpus luteum and and corpus luteum allows the prolactin to assume its lac-
placenta contin uous ly produce estrogens and proges- togenic role. Production of milk also requires adequate se-
terone. Estrogen present in the circulation stimulates pro- cretion of growth hormone, adrenal glucocorticoids, and
liferation of th e lactifero us duct components, and proges- parathyroid hormones.
terone stimulates growth of alveo li. It is now believed The act of suckling during breast-feeding initiates sen-
that the growth of the mammary glands also depends on sory irnpulses from receptors in the nipple to the hypo-
the presence of prolactin, produced by the adenohypop h- tha lam us. T he impulses inhibit the release of prolactin-
ys is; h CS, prod uced by the placenta; and adrenal gluco- inh.ibiting factor, and prolactin is then released . from the
corticoicls. adenohypophysis. The sensory impulses also cause the
release of oxytocin in the neurohypophysis. Oxytocin
Lactation is under the neurohormonal control stimulates the myoepithelial cells that smround the base
of the adenohypophysis and hypothalamus of the alveolar secretory cells and the pase of the cells
in the larger ducts, causing them to contract and eject
Although estrogen and progesterone are essential for the the milk from the alveoli and the d ucts. In the absence
physical development of the breast during pregnancy, both of suckling, secretion of milk ceases, and the mammary
of these hormones also suppress the effects of prolactin glands begin to regress. The glandu lar tissue then returns
and hCS, the levels of wh.ich increase as pregnancy pro- to an inactive condition.
CHAPTER 22 Female Reprod11ctivc System 76 5
Figure 1, ovary, monkey, H&E x120. nica albuginea (TA); under the tunica albuginea are the pri-
The cortex of an ovary from a sex ually mature individ- mordial follicles ( PF). It is not unusual to see follicles at
ual is shown here. On the surface, there is a single layer of various stages of development or atresia in the ovary. In thi s
epithelial cells desi gnated the germinal epithelium (GEp). figure, along with the large number of primordial follicles,
This epithelium is continuous with the serosa (peritoneum) there are four growi ng follicles (SF), an atretic follicle
of the mesovarium. Contrary to its name, the epithelium (A F), and part of a large fol licle on the right. The region of
does not give rise to the germ cells. The germinal epithe- the large follicle shown in the fig ure includes the theca in-
lium covers a dense fibrous connective tissue layer, the tu- terna (Tl), granulosa cells (GC), and part of the antrum (A).
Figure 2, ovary, monkey, H&E x450. ered. A follicle undergoing these early changes is called a
When a primordial follicle begins the changes leading to prima1y follicle. Thus, an early primary follicle may still be
the formation of a mature follicle, the layer of squamous unilaminar, but it is surrounded by c uboidal cells, and this
follicular cells becomes cuboida l, as in this figure. In addi- distingu ishes it from the more numerous unilaminar pri-
tion , the follicular cells proliferate and become multilay- mordial follicles that are surrounded by squamou s cells.
Figure 3, ovary, monkey, H&E x 450. eluded in the plane of section , as in the oocyte marked X.
This figure shows several primordial fo llicles at hi gher The group of epithelioid-appearing cells (a nvwhead) are
magni fication. Each follicle consists of an oocyte sur- follicu lar cells of a primordial follicle that has been sec-
rounded by a single layer of squamou s follicula r cells (F). tioned in a plane that just grazes the follicular surface. Jn
The nucleus (N) of the oocyte is typically large, but the this case, the follicular cells are seen en face.
oocyte itself is so large that the nucleus is often not in-
Figure 4, ovary, monkey, H&E x450. Surrounding the follicles are elongate cells of the highl y
The primary follicle in this figure shows a multilayered cellular connective tiss ue, referred to as stromal cells. The
mass of follicular cells (FC) smTounding the oocyte. The in- stromal cells surrounding a secondary follicle become dis-
nermost layer of follicular cells is adjacent to a thick posed into two layers designated the theca interna and the
eosinophilic layer of extracellular homogeneous material theca externa. As seen in Figure I , stromal cells become ep-
called the zona pellucida (ZP). At this stage of development, ithelioid in the cell-rich theca interna (TI).
the oocyte has also enlarged slightly. The entire structure
surrounded by the zona pellucida is acLUally the oocyte.
KEY
A, antrum N, nucleus of oocyte TI, theca interna
AF, atretic follic le PF, primordial follicles X, oocyte showing only cytoplasm
F, fo llic le cells, primordial SF, growi ng follic les ZP, zona pell ucida
FC, folli cle cells TA, tunica albuginea arrowhead, follic le cell s seen en face
GEp, germinal epithelium
764
C H APTER 2 2 Fewnle Refnoduclivr Syslrw 76 7
Figures 1 and 2, ovary, monkey, H&E x 120. follic ul ar cells, it is appropriate to classify it as a primary
Two follicles growi ng under the influe nce of FSH are follicle. In both folli cles, but partic ul arly in the larger folli -
shown in Figure 1. The more advanced follicle is a second- cle with the antrum, the surrounding stromal cells have be-
ary follicle. The oocyte in th.is follicle is surrounded by sev- come altered to form two distinctive layers designated
eral layers of follicular cells ( FC) that, at this stage, are theca interna (Tf) and theca externa (TE). The theca inte rna
identified as granulosa cells. At a slightly earl ier time, small is a more cellular layer, and the cells are e pithelioid. Whe n
lakes of fluid formed between the follic ular cells, and these seen with the electron microscope, they di splay the charac-
lakes have now f used into a well-de fi ned larger cavity teristics of endocrine cells, particularly steroid-secreting
called the follicular antrum (FA), which is evident in the fig- cells. In contrast, the theca externa is a connective tissue
ure. The antru m is also filled with fluid and stai ns with the layer. Its cells are more or less spindle shaped.
periodic acid- Schiff (PAS) reaction, although only lightly. In Figure 2, a later stage in the growth of the secondary
The substance that stains with the PAS reaction has been re- follicle is shown. The antrum (FA) is larger, and the oocyte
tained as a n eosi nophilic precipitate in the antra of the sec- is off to one side, surrounded by a mound of follicular cells
ondary follicles shown here and in Fi gure 2. Immediately called the cumulus oophorus. The remaining follicular cells
above the obvious secondary follicle is a slightly smaller that surround the antral cavity are referred to as the mem-
folli cle. Because no antral spaces are evident between the brana granulosa (MG), or sim ply gran ulosa cells.
Figure 3, ovary, monkey, H&E x 65. (see Fig. 4). The two larger, more advanced follicles do not
Atretic follicles (AF) are show n he re and at higher mag- display the remains o f a zona pellucida, but they do di splay
nification in Figure 4. The two smaller atre tic follicles can other fea tu res of follic ular atresia.
be identified by virtue of the re tai ned zona pellucida (ZP)
Figure 4, ovary, monkey, H&E x 120. me mbrane. Thus, the glassy me mbrane (arrows) separates
In atresia of a more advanced follicle, the foll icular cells an outer layer of remai ning theca interna cells from the de-
tend to degenerate more rapidly than the cells of the theca generati ng inner follicu lar cells. T he re maining theca intern a
interna, and the basement membrane separati ng the two be- cells may show cytologic integri ty (RTf); these intact theca
comes thicke ned to form a hyal inized membrane, the glassy cells remain temporarily functional in steroid secretion.
Figure 5, ovary, monkey, H&E x 120. the atresia in these follicles is we ll advanced, so me of the
Additional atre tic folli cles (AF) are shown here. Again, cells extern al to one of the glassy membranes still retain
some show re mnants of a zona pell ucida (ZP), and two their epithelioid characte r (armwhead). These are persist-
show a glassy membrane (arrows). N ote that even though ing theca inte rna cells.
KEY
AF, at retic follicle RTI, remaini ng theca interna cells ZJ>, zona pellucida
FA, antrum of folli cle TE, theca ex terna arrowhead, persisting theca interna cells
FC, folli cle cells TI, theca interna arrows, g lassy membrane
MG, membrana granulosa
766
1 C HAPTER 22 Female Rc~ rotlucli !JC Syste111 769
TLC _-'/"
Figure 1, corpus luteum, human, H&E x20. corpus luteum develops. As the corpus luteu m becomes
1 \r.
'........
-
granulosa has become plicated, and the g ranul osa cells, the blood vessels into the outermost depressio ns of the pli-
now transforming into cells of the corpus luteum, are called cated structure. These theca interna cells become trans-
granulosa lutein cells (TC). The plication of the membrana formed into cells of the corpu s luteum called theca lutein
g ranulosa begins just before ovulation and continues as the cells.
Figure 2, corpus luteum, human, H&E x20. mind that the theca interna was derived from the connective
Figures 3 and 4, corpus luteum, human, H&E x65 than nuclei of adjacent granulosa lutein cells. The connec-
KEY
BV, blood vessels FC, former fo lli cular cavity T C, granul osa cells transforming into cor-
CT, connecti ve tissue GLC, granulosa lutein cells pus luteum cells
TLC, theca lutein cells
768
CHAPTER 22 Frrunlr Rrproduclivr Systw1 77 I
Figure 1, oviduct, human, H&E x40. The muscularis consists of smooth muscle that forms a
Figure 2, oviduct, human, H&E x 160; inset x320. also called peg cells (PC), are readily identified by the ab-
KEY
BV, blood vessels Ep, epithelium Muc, mucosa
C,cili a L, lumen Mus, muscularis
CT, connective tissue Lym, lymphatic vessel PC, peg cells
770
C HAPTER 22 f r"wlr Reproductive Syste111 77 3
Figure 1, uterus, human, H&E x 25; inset x120. ilarity to the glandular epi thelium (GI). The endometrium is
Figure 2, uterus, human, H&E x25; inset x 120. tionale (SF) to reach the surface. The stratum basale (SB)
KEY
BV, blood vessels M, myometrium SEp (inset, Fig. 1), surface epithelium
Gl, glands SB, stratum basale SF, stratum functionale
772
CHAPTER 22 Fenwlr Rrfnod llclive System 7 75
Figure 1, uterus, human, H&E x25. shallow sacculations that give the profile of the glandular
Figure 2, uterus, human, H&E x30; inset x120. them to dilate. Typically, the glands of the secretory en-
KEY
GI, glands SB, stralllm basale ai'I'OW, glandular opening at uterine surface
M, myometrium SF, stratum functionale al'l'owheads, stromal cells
774
CHAPTER 22 Fe"'"le ReJlrodllctiue System 777
r .
\
" _; .......
~
supravagi nal portion of the cervix (portio supravaginali s). The mucosa (Muc) of the cervix differs according to the
Fig ure 2 shows the supravagi nal cervix at a slig htly higher cavity it faces. The two rectangles in Figure I delineate rep-
.. ,,
level than in Figure 1. The plane of section in both figures resentative areas of the mucosa that are shown at higher
passes through the long axis of the cervical canal. The cer- magnification in Fig ures 3 and 4, respectively.
vical canal (CC) is narrowed and cone shaped at its two Figure 2 e mphasizes the nature of the cervical glands
ends. The upper end, the internal os, communicates with (Gl). The glands differ fro m those of the uterus in that they
the uterine cavity, a nd the lower end, the extemal os (Os), branch extensively. They secrete a muco us substance into
communicates w ith the vagina. (For purposes of orienta- the cervical canal that serves to lubricate the vagina.
Figure 3, cervix, human, H&E x240. epithe lium. Another similarity is that the epithe lial surface
Figure 4, cervix, human, H&E x240. the transition zo ne, which is shown at hi gher magnification
occurs at the opening of the cervical canal (exte rnal os). pare w ith Fig. 3).
The Lower rectangle in Fig ure I marks this site, known as
Figure 5, cervix, human, H&E x 500. shape of the nuclei (asterisk) seen at the upper part of one
KEY
BV, blood vessels G l, cer vical glands SSEp, stratified sq uamous epithelium
CC, cervical canal Muc, mucosa asterisk (Fig. 5), tangential cut o f the ep-
CEp, colu mnar epithelium Os, ostium of the uterus ithelial surface
776
CHAPTER 22 Fewnlr Reprod11clive System 7 79
B
Fig ure 1, placenta, human, H&E x 16. semble the vessels of the um bilical cord. Although their
A section extend ing from the a mniotic s urface into the identification as blood vessels is relatively simple, it is dif-
substance of the placenta is shown here. T hi s includes the fi cult to disting uish whi ch vessels are branches of an um-
amnion (A ), the chorionic plate (CP), and the chorionic villi bilical artery and wh ich are tributaries of the vein.
(CV). The a mnion consists of a layer of simple cuboidal ep- The ma in substance of the placenta consists of chorio nic
ithelium and an underlying layer of connecti ve ti ssue. The villi of different sizes (see Plate 96). These emerge from the
connective ti ss ue of the amnion is contin uous with the con- c horionic plate as large stem villi that branch into increas-
nective ti ss ue of the chorionic plate as a result of their fu- ingly smaller vi lli . Branches of the umbil ical arteries and
sion at an earlier time. The plane of fu sion, however, is not vein ( BVv, Fig. 2) enter the stem villi and ramify through
evident in H&E sections; the separati on (asterisks) in parts the branching villous network. Some villi extend from the ~
of this figure in the vic inity of the fusion is an artifac t. chorionic plate to the material side o f the placenta and \
The chorionic plate is a thick connective tissue mass that make contact with the maternal ti ssue; these are called an-
contains the rami fications of the umbilical arteries and vein. choring villi. Other villi, the free villi, simply arbori ze
These vessels (BVp) do not have the distinct organi zational within the substance of the placenta without anchoring onto
features characteristic of arteries and veins; rather, they re- the maternal side.
*
Figure 2, placenta, human, H&E x70; inset x370. fo und in clusters and have an epithelial appearance. B e-
'
KEY
A, amn ion CP, c horion ic plate SB, stratum basale
BVp, blood vessels in chorionic plate
BVv, blood vessels in c horionic villi
CV, chorionic villi
DC, decidual cells
asterisk, separation that is actually an arti-
fact '
.2:
778
CHAPTER 22 Female Rrprodlictivc System 78 I
D
Figure, placenta, human, H&E x280. The syncytiotrophoblast contains microvilli that project
A section through the substance of a full-term placenta into the intervillous space. These may appear as a striated
shows chorioni c villi (CV) of different sizes and the sur- border in paraffin sections, but they are not always ade-
rounding inter villous space ( IS). The connective ti ssue of quately preserved and may not be evident.
the villi conta ins branches and tributaries of the umbil ical In earlier placentas, the cytotrophoblasts form an almost
arteries and vei n (BV). The smallest villi contain only cap- complete layer of cells inm1ediately deep to the syncy-
illaries; larger vi lli contain correspondingly larger blood tiotrophoblast. Cytotrophoblasts are the source of the syn-
vessels. The intervillous space contains maternal blood. cyti otrophoblast. Cell division occurs in the cytotro-
Maternal blood was drained from the specimen before its phoblast layer, and the newly formed cells become
preparation, and therefore, few maternal blood cells are incorporated into the sy ncytial layer. In this full-term pla-
seen in the section. centa, onl y occasional cytotrophoblasts (Cy) can be dis-
The nuclei of the syncytiotrophoblast may be more or cerned.
less evenl y di stributed, givi ng thi s layer an appearance (in Most of the cells within the core of the villus are typical
H&E sections) similar to that of cuboidal epithelium. The re connective tissue fibroblasts. The nuclei of these cells stain
are, however, sites where the nucle i are gathered in clusters well with hematoxylin, but the cytopl asm cannot be di stin-
(arrowheads), as well as regions of syncytium relatively gui shed from the delicate intercellular fibrous material.
free of nucl ei (arrows). These stretches of sy ncytium may Other cells have a recognizable amount of cytoplasm sur-
be so attenuated as to give the impression that the villous rounding the nucleus. These are considered to be phagocy-
surface is devoid of a covering. It is thought that the nuclear totic and are named Hofbauer cells. The Holbauer cells
c lusters and the adjacent cytoplasm may separate from the (HC) show n in the figure do not co ntain any di stinctive cy-
vi llus and e nter the maternal blood pool. toplasmic inclusions.
KEY
BV, blood vessels HC, Hofbauer cells arrows, attenuated syncytial cytopl asm
CV, chorionic villi IS, intervill ous space asterisk, tangentially sectioned villus
Cy, cytotrophoblasts arrowheads, clusters of syncytial tro-
phoblast nuclei
CHAPTER 22 Frmnlr Reproducfil!r System 783
Figure 1, vagina, human, H&E x90. vaginal e pithelium. Thus, nucle i can be observed through-
The mucosa of the vagina consists of a stratified squa- out the e ntire thickness of the epithelium despite the fact
mous epithelium (Ep) and an underlying fibro us connective that the cytoplasm of most of the cells above the basal lay-
ti ssue (CT) that often appears more cellular than othe r fi- ers appears empty. T hese cells are norma lly filled with large
brous connective tissue. The boundary between the two is deposits of glycogen th at is lost in the processes of fi xation
readil y identified because of the conspicuous sta ining of the and embeddi ng o f the tissue. The rectangle outli nes a por-
closely packed small cells of the basal layer (B) of the ep- tion of the epithel ium and connective ti ssue papillae that is
ithelium. Connective tissue papillae project into the under- exami ned at higher magnification in Figure 2. The muscu-
side of the epithelium, giving the epithelial-connective tis- lar layer of the vaginal wall consists of smooth muscle
sue juncti on an uneven appearance. The papillae may be c ut arranged in two ill-de fined layers. T he outer layer is gene r-
obliquely or in cross secti on and thus may appear as con- ally said to be longitudinally arranged (SML), and the inner
nective tissue islands (arro ws) within the lower portion of layer is generally said to be circ ularly arranged (SMC), but
the epithelium. The epithelium is characteri stically thick the fi bers are more usually organized as interlacing bundles
and a lthough keratohyaline granules may be fo und in the surrounded by connective tissue. Many blood vessels (BV)
superficial cells, keratinization does not occur in human are seen in the connective tissue.
Figure 2, vagina, human H&E x 11 0. islands in the epithelium are more clearly seen here ( ar-
This is a higher magnification of the epithe li um that in- rows), in some instances outlined by the surrounding
cludes the area outlined by the rectangle in Figure 1 (turned closely packed cells of the basal epithelial cell layer. Note,
90). The obliquely c ut and cross-sectioned portions of again, that the e pithel ial cells even at the surface still retain
connecti ve tissue papillae that appear as connective tissue their nuclei and there is no evidence of keratinization.
Figure 3, vagina, human H&E x225. become less regularly arranged as they move towards the
This is highe r-magn ification mi crograph of the basal surface. T he highly cellular connective (CT) tissue immedi-
portion of the epithe li um (Ep) between connective tissue ately beneath the basal layer (B) of the epithelium typically
papillae. Note the regul arity and de nse packing of the basa l contai ns many lymphocytes (L). T he number of lympho-
epithelial cells. They are the ste m cells for the stratifi ed cytes varies with the stage of the ovarian cycle. Lymp ho-
squ amous epithe lium. Daughter cells of these cells migrate cytes invade the epithe lium around the time of menstruation
toward the surface and begin lo accumulate glycogen and and appear a long with the epithelial cells in vaginal smears.
Figure 4, vagina, human, H&E x 125. muscle cut in cross section (SMC). T his bund le abuts on a
This higher- magnification micrograph of the smooth long itudi nally sectioned lymphatic vessel (LV). To the left
muscle of the vagina l wall e mphasizes the irregularity of of the lymphatic vessel is another longitudinal bundle of
the arrangeme nt of the muscle bundles. At the ri ght edge of smooth muscle (SML). A valve ( Va) is seen in the lymphatic
the fig ure is a bundle of smooth mu scle c ut in a lo ngitudi- vessel. A sma ll vein (V) is present in .the circular smooth
na l section (SM L). Adjacent to thi s is a bundle of smooth muscle close to the lymphatic.
KEY
B, basal layer o f vaginal epithelium L , lymphocytes V, vein
BV, blood vessels LV, lymphatic vessel Va, valve in lymphatic vessel
CT, connective tissue SM C, smooth m uscle, cross section arrows, con nective tissue islands in epithe-
Ep, epithelium SML, smooth muscle, lo ngitud inal section lium
-.......-
xao.
B
Figure 1, mammary gland, human, H&E gether, the ducts and surrounding connective tissue consti-
This figure is a section through an inactive gland. The tute a lobule. Two lobules (L) are bracketed in tlus figure.
parenchyma is sparse and consists mainly of duct elements. Beyond the lobule, the connective ti ss ue is more dense
Several ducts (D) are shown in the center of the field. A (CT(D)). The two types of connective tissues can be distin-
small lume n can be seen in each. The ducts are surrounded guished at the low mag11ification of this figure.
by a loose connective tissue (see CT(L), Fig. 2), and to-
Figure 2, mammary gland, human, H&E x200; in- verse, a simple examination of equal areas of loose and
B set x400.
Additional detail s are evident at higher magnification. In
di stingu islung between the loose and dense connective tis-
sue, recall that both extracellular and cellular features show
dense connective tissue will, by far, show fewer cells in the
dense connective tissue. Characteristically, the dense con-
nective tissue contains numerous aggregates of adipocytes
(A).
differences that are evident in both the figure and the inset. The epithelial cells within the resting lobule are regarded
Note the thicker collagenous fi bers in the dense connecti ve as being chiefly duct elements. Usually, alveoli are not
tissue in contrast to the much thinner fibers of the loose fo und; their precursors, however, are represented as cellular
connective tissue. The loose connective tissue contai ns far thickenings of the duct wall. The epithelium of the resti ng
more cells per unit area and a greater variety of cell types. lobule is cuboidal; in addition, myoepithelial cells are pres-
This figure shows a c luster of lymphocytes (L) and, at still ent. Reexamination of the inset shows a thickening of the
highe r magnification (inset), plasma cells (P) and individ- epithe lium in one location, presumably the precursor of an
ual lymphocytes (L). Both plasma cells and lymphocytes alveolus, and myoepithelial cells (M) at the base of the ep-
are cells with a rounded shape, but plasma cells are larger itheUum. As elsewhere, the myoepitheUal cells are on the
and show more cytoplasm. In addition, regions of plasma epitheUal side of the basement membrane. During preg-
cell cytoplasm display basophilia. Elongate nuclei in spin- nancy, the glands begin to proliferate. This can be thought
dle-shaped cells belong to fibroblasts. In contrast, although of as a dual process in which ducts proliferate and alveo li
the cell types in the dense con nective tiss ue may also be di- grow from the ducts.
KEY
A, adipocytes D, ducts M , myoepithel ial cells
CT(D), dense connective tissue L: Fig. 1, lobules; Fig. 2 and inset, lympho- P, plasma cells
CT(L), loose connective tissue cytes
784
T
Figure 1, mammary gland, late proliferative stage, ithelium. The cells of both components are secretory. The
Figure 2, mammary gland, lactating, human, small droplets within the epithe lial cells. These droplets be-
KEY
D, interlobu lar duct P, plasma cell arrow, union of intralobular duct with inter-
L, lobule S, connective tissue septa lobular duct
Ly, lymphocyte asterisks, sites of merg ing alveoli
M, myoepi thelia l cell
within the orbit. T he extraocu lar muscles a re coord inated has a p ro m inence or convexity. The cornea is contin uous
so that the eyes move sym metrically about their own cen- with the sclera (Gr. sk/eros, hard). The sclera is composed of
tral axes. dense fi brous connective tissue that p rovides attachment
fo r the extrinsic m uscles of the eye. The sclera constitutes
Layers of the Eye the "whi te" of the eye but has a slightly blue ti nt in chil-
dren beca use of its thin ness and is yellow in the elderl y be-
Eye The wall of the eye consists of three concentric layers or coats
\1 OVERVIEW OF THE EYE Because the eyes are paired, two somewhat differe nt and
overlapping images (visua l fie lds) a re sent to the brain.
Complex neural mechanisms coordina te eye movements
The eye is a comp lex sensory organ that provides the sense
and inter pr et the slightly different images. Binocular visio n
of sight. In many ways, the eye is similar to a d igita l cam-
ena bles us to perceive depth and d istance to ac hieve a
era. Li ke the optical system of a camera , the cornea a nd
three-dimensio nal image.
lens of the eye capture and foc us light. T he light detector
in a digital camera, called the charge-co upled device
(CCD), consists of closely spaced photodiodes that cap- \1 GENERAL STRUCTURE OF THE EYE
ture, collect, and convert the light image in to a series of
electrica l im pulses. Similarly, the photoreceptors in the The eye measu res approximately 25 mm in d iameter. It is FIGURE 23.1
retitta of the eye detect light intensity and colo r and encode suspended in the bony orbita l socket by six extr ins ic mus- Schematic diagram of the layers of the eye. Tile wa ll of tile eyeball is coat or uvea (pink) ; and (c) an inner photosensitive layer, tile retina
these para meters into electrical impu lses fo r transm issio n cles that control its movement. A thick layer of adipose tis- organized in tl1ree separate concentric layers: (a ) an outer supporting (yellow).
to the bra in via the optic nerve. sue parti ally surrou nds and cushi ons the eye as it moves layer, tile corneoscleral coat (clear and blue); (b) a middle vascular
790 CHAPTER 23 Eyr CHAPTER 23 Eye 79 I
the iris. It appears black because one looks through the Vitreous chamber, the space between the posterior sur- jects. The aqueous humor and vitreous body have only mi- cup. After the lens vesicle detaches from the surface ecto-
lens toward the heavily pigmented back of the eye. In the face of the lens and the neural retina (Fig. 23 .2). The nor roles in refraction. H owever, the aqueous humor plays derm, this same site again thickens to form the corneal ep-
process of adaptation, the pupil changes in size to conu-ol cornea, the anterior and posterior chambers, and their a n important role in providing nutrients to two avascular ithelium. Mesenchymal cells from the periphery then give
the amount of light that passes through the lens to reach contents constitute the anterior segment of the eye; the str uctures, the lens and cornea . In add ition to transmitting rise to the corneal endothelium and the corneal stroma.
the retina. vitreous chamber, visual retina, RPE, posterior sclera, light, the vitreous body helps maintain the position of the Grooves containing blood vessels derived from mes-
and uvea constitute the posterior segment. lens and helps keep the neural retina in contact with the enchyme develop along the inferior surface of each optic
The retina consists of two components, the neural retina and RPE. cup and stalk. Called the choroid fissures, the grooves en-
pigment epithelium The refractile media components of the eye alter the light path able the hyaloid artery to reach the inner chamber of the
to focus it on the retina eye. This artery and its branches supply the inner chamber
Development of the Eye
The retina is a thin, delicate layer (Fig. 23.1c) consisting of the optic cup, lens vesicle, and mesenchyme within the
of two components: As light rays pass through the components of the eye, To appreciate the unusual structural and functional rela- optic cup. T he hyaloid vein returns blood from these struc-
they are refracted. Refractio n focuses the light rays on the tionships in the eye, it is helpful to understand how it tures. The dista l portions of the hyaloid vessels degenerate,
Neural retina, an inner layer that contains .light-sensitive
pbotoreceprors of the retina. Four tra nsparent components forms in the embryo. but the proximal portions remain as t be central artery and
receptors and complex neurona l networks
of the eye, called the refractile (or dioptric) media, alter veil-t. By the end of the seven th week, the edges of the
Retinal pigment epithelium (RPE), an outer layer com-
the path of the light rays: The tissues of the eye are derived from neuroectoderm, choroid fissure fuse, and a round opening, the future pupil,
posed of simple cuboidal melanin-contai ning cells
surface ectoderm, and mesoderm is formed over the lens vesicle.
Cornea, the anterior wi ndow of the eye
Externally, the retina rests on the choroid; intern ally, it The outer la yer of the optic cup forms a single layer of
Aqueous humor, the wa tery fluid located in the an ter ior
is associated w ith the vitreous bod y. The neural retina con- By the 22nd day of development, the eyes are evident as pigmented cells (Fig. 23 .3c) Pigmentation begins at the end
and posterior chambers
sists largely of photoreceptor cells, called retinal rods and shallow grooves, the optic sulci or grooves, in the neural of the fifth week. The inner layer undergoes a complex dif-
Lens, a tra nsparent, crystalline, biconcave structure sus-
cones, and interneurons. Visual information encoded by folds at the cran ial end of the human embryo. As the neu- ferentiation into the nine layers of the neural retina. The
p ended from the inner surface of the ciliar y body by a
the rods and cones is sent to the brain via impulses con- ral tube closes, the paired grooves form outpocketings photoreceptor (rod and cone) cells as well as the bipolar,
r ing of rad ia lly oriented fi bers, the zonule of Zinn
veyed along the optic nerve. ca lled optic vesicles (Fig. 23 .3a). As each optic vesicle amacrine, and ganglion cells and nerve fibers are present
Vitreous body, composed of a transparent gel substance
grows laterally, the connection to the forebrain becomes by the seventh month. The macular depression begins to
that fills the vitreous cha mber. It conta ins hyaluronic
constricted into an optic stalk, and the overlying surface develop during the eighth month and is not complete until
Chambers of the Eye acid, widely dispersed collagen fibrils, and other pro-
ectoderm th ickens and forms a lens placode. T hese events about 6 months after binh.
teins and glycoproteins. T he fluid component of the vit-
are followed by concomitant invagination of the optic vesi- D uring the third month, growth of the optic cup gives
The layers of the eye and the lens serve as boundaries for reous body is ca lled the vitrous humor.
cles a nd the lens placodes. The invagination of the optic rise to the ciliary body and the future iris, w hich forms a
three chambers within the eye vesicle results in the formation of a double-layered optic
The cornea is the chief refractive element of the eye. It double row of epithelium in front of the lens. The meso-
has a refractive index of 1.376 (air bas a refractive index cup (Fig. 23.3b). The inner layer becomes the neural derm located external to this region becomes the stroma of
The chambers of the eye are of 1.0). The lens is second in impor tance to the cornea in retina. T he outer layer becomes the RPE. the ciliary body and iris. Both epithelial layers of the iris
Antel'ior chamber, the space between the cornea and the the refraction of light rays. Because of its elasticity, the Invagination of the central region of each lens placode re- become pigmented. In the ciliary body, however, only the
lrtS shape of the lens can undergo sligh t changes in response to su lts in the formation of the lens vesicles. By the fifth week outer layer is pigmented. At birth, the iris is light blue in
Posterior chambel', the space between the posterior sur- the tension of the cilia ry muscle. T hese changes are impor- of development, the lens vesicle loses contact with the sur- fair-skinned people because pigment is usually not present.
face of the iris and the anterior surface of the lens tant in accommodation for proper foc usi ng on near ob- face ectoderm and comes to lie in the mouth of the optic The dilator and sphincter pupillary muscles develop during
choroid
sclera
superior rectus muscle pigmented retinal
forebrain epithelium
optic cup
anterior
chamber
irldopupillary
membrane
lens
cornea
placode invaginating
FIGURE 23.2 ectoderm
lens vesicle
anterior retinal arterioles Schematic dlagam illustrating the internal struc-
chamber and venules
tures of the human eye. The retina consists of pho-
pupil optic nerve papilla
tosensitive and nonphotosensitlve regions that dif- ciliary body
.Jt?M:?<~~~ optic nerve
cornea fer in their function. Note that the photosensitive
m~!!illll~i:L-central retinal
region of the retina occupie? the posterior part of
hyaloid
artery and vein artery vitreous
the eye and terminates anteriorly along the ora
posterior body outer vascu lar
serrata. The non photosensitive region of the retina chamber
chamber i retinal pigment
is located anterior to the ora serrata and lines the FIGURE23.3
lens capsule '~ epithelium
c. T11e eye as seen in a 15-week fetus. All the layers of the eye are es-
inner aspect of the cil iary body and the posterior Schematic drawing illustrating the development of the eye. a. Fore-
surface of the Iris. The other layers of the eyeball bra in and developing optic vesicles as seen in a 4-mm embryo. b. Hi- tablished, and the hyaloid artery traverses the vitreous body from the
as well as the attachment of two of the extraocu- layered optic cup and invaginating lens vesicle as seen in a 7.5-mm optic disc to the posterior surface of the lens. (Modified from Mann IC.
lar muscles to the sclera are also shown. embryo. The optic stalk connects the developing eye to the brain. The Development of tl1e Human Eye. New York: Grune fr Stratton, 1974.)
792 CHAPTER 23 Eye CH AP TE R 23 Eye 793
Source Derivative
Surface ectoderm Lens
Epithelium of the cornea, conjunctiva, and lacrimal gland and its drainage system }- Bowman's membrane
Neural ectoderm Vitreous body (derived partly from neural ectoderm of t he optic cup and partly from mesenchyme)
Epithelium of the retina, iris, and ciliary body
Sphincter pupillae and dilator pupillae muscles
Optic nerve
-
Mesoderm Sclera
Stroma of the cornea, ciliary body, Iris, and choroid
Extraocular muscles - comeal stroma
-
t he sixth month as d er ivatives of the neuroectoderm of the
o uter layer of th e optic cup.
m ous at the surface. The basal cells are low columnar with
ro und, ovoid n uclei; the surface cells acq uire a squamous - corneal stroma
The embryonic origins of th e indi vid ual eye structures
are su mmarized in Table 23. 1.
o r discoid shape and their n uclei ar e flattened and p yknotic
(see Fig. 23.4b). As t he cells migrate to the surface, the cy-
toplasmic orga nelles g raduall y disap pear, indicating a p ro-
-
~ endothelium 7
.. ..
::E- Descemet's membrane
C
..-..~
Corneoscleral Coat the comeoscleral limbus, t he juncti on of the cornea and FIGURE 23.4
sclera. The m icroenviro nment of the limbus is important in Photomicrograph of the cornea. a. This photomicrograph of a sec- stroma, are low columnar in contrast to the squamous surface cells.
The cornea consists of five layers: three cellular layers and two maintaining the population of stem cells t hat also act as a tion through the full thickness of tl1e cornea shows the corneal Note that one of the surface cells is in the process of desquamation
noncellular layers "barrier" to conj un ctiva l epithelial cells an d normally pre- stroma and the two corneal surfaces covered by different types of (arrow). x 2BO. c. A higher-magnification photomicrograph of the
vent their m igration to the cornea l surface. The corneal ep- epithelia. The corneal stroma does not contain blood or lymphatic posterior surface of the cornea covered by a thin layer of simple
The transparen t cornea (see Figs. 23 .1 and 23 .2) is only ithelial stem cells may be partially or totally depleted by vessels. X l 40. b. A higher magnification of the anterior surface of squamous epithelium (cornea l endothelium). These cells are in direct
0.5 mm thick at its center and about 1 mm thi ck peripher- disease or extensive injmy, resulting in abnormal ities of the the cornea showing the corneal stroma covered by a stratified squa- contact with the aqueous humor of the anterior chamber of the eye.
all y. It consists o f three cellular layers th at are distinct in mous (corneal) epithelium. The basal cells that rest on Bowman's Note the very thick Descemet's membrane (basal lamina) of the
corn eal surface t hat lead to "conjunctivalization" of the
both appearance and orig in. These layers a re separated by membrane, which is a homogenous condensed layer of corneal corneal endothelial cells. x 280.
cornea, characterized b y vascularization, appear ance of
two important mem branes that appea r homogeneous goblet cells, and an irregula r and unstable epithelium.
when viewed in the light microscope. Thus, t he fi ve layers These changes cause ocular discomfort and reduced v ision.
o f the cornea seen in a transverse secti on are Mi nor inj ur ies o f th e corneal surface heal rapi dly by in-
duci ng stem cell proliferation and m igra tion of cells from d imi nish light transmissio n. Instead, it has recently been as a barrier to the spread o f infections . It does no t regen-
Comeal epithelium the corn eoscleral limbus to fi ll the defect. shown that corneal epithelial cell n uclei con tain ferritin, erate. T herefore, if d am aged, an opaq ue sca r forms tha t
Bowman's membmne (anterior basement membmne) Numerous free nerve endi ngs in the corneal epit heli um an iron-storage p rotein. Experimenta I studies with avian may impair visio n. In add ition, changes in Bowma n's
Comeal stroma provide it with ext reme sensitivity to touch. Stimulation of corneas have shown that nuclear ferritin protects the DNA membra ne ar e associated with recurrent comeal erosions.
Descemet's membmne (posterior basement membrane) these nerves, e.g., by sma ll. foreign bodies, elicits blin k ing in the corneal epithe lial cells fro m free ra d ical d amage d ue
Comeal e1tdothelium of the eyelids, flow of tea rs, and, sometimes, severe pain . to UV light expos ure. The corneal stroma constitutes 90% of the corneal thickness
Microvilli p resent on the surface epithelial cells help retain
The corneal epithelium is a nonkeratinized stratified squamous
the tear film over t he enti re corneal surface. Drying of the Bowman's membrane is a homogeneous-appearing layer on T he cornea l stroma, a lso called substantia propria, is
epithelium which the corneal epithelium rests composed o f about 60 thin la mellae. Each lamella consists
corneal surface may cause ulceration.
of para llel bundles of co llagen fi brils. Located betw een
The corneal epithelium (Fig. 23 .4) consists of approxi- DNA in corneal epithelial cells is protected from UV light Bowman's membrane (anterior basement membrane) is lamellae are nea rl y complete sheets of slender, flattened fi-
ma tely five layers o f no nkerat inized cells and measures damage by nuclear ferritin a homogeneous, fain tly fi br illar lamina that is approxi- bro blasts. The fi brils measu re approx imately 2 3 nm in di -
about 50 p,m in average t hickness. It is conti nuous wi th the matel y 8 to 10 (.Lm th ick. It lies between the cornea l ep- ameter and up tO 1 em in length. The co llagen fi brils in each
conj unctival epit helium th at overl ies the adjacent sclera. Despite consta nt exposure of the corneal epitheli um to ithelium and the underlying co rn eal stroma and ends lamella are a rranged a t approx imate right angles to those in
T he epithelia l cells adhere to neighboring cells via desmo- UV light, ca ncer of this epi theli um is extremely ra re. Un- abr uptly at the corneoscleral limbus. The collagen fibri ls o f the adjacent la mellae (Fig. 23.5 ). The ground su bstance
somes th at are present o n shor t interdigitating processes. like the epidermis, wh ich is a lso ex posed to UV l ight, Bowman's m embrane have a diameter of abo ut 18 nm and con tains comeal proteoglycans (lu mican ), w hich are sul-
Like o ther stratified epithelium, such as that of the skin, melani n is not present as a defense mechanism in corneal a re randomly oriented. Bowman's membra ne imparts fated glycosa minoglycans (chiefly, kera tan sulfate and
the cells proliferate from a basal layer and becom e sg ua- epith el ium . The presence of melan in in t he cornea would so me strength to the corn ea , but m o re sign ifica ntly, it acts chondro itin sulfa te) cova lently bo und to protein (decorin ).
794 CHAPTER 23 I Eyr CH A PTE R 23 Eye 79 5
curvature of the cornea by exerting tension on Descemet's The sclera is divided into three rather ill-defined layers: liUin at this site th ickens from th ~ 5 cell layers of the
membrane. cornea to the 10 to 12 cell layers of the conjunctiva. The
Episcleral layer (episclera), the external layer, is the
loose connective tissue adjacent to the periorbital fat. surface of the limbus is composed of two distinct types of
The corneal endothelium provides for metabolic exchange epithelial cells: one type constitutes the conjunctival cells
between the cornea and aqueous humor
Substantia propria (sclera proper, a lso called Tenon's
capsule ), the investing fascia of the eye, is composed of and the other corneal epithelial cells.
a dense network of thick collagen fi bers. At this junction, the corneal lamellae become less reg-
The corneal endothelium is a single la yer of squamous ular as they merge with the oblique bundles of collagen
cells covering the surface of the cornea that faces the ante-
Suprachorioid lamina (lamina fusca), the inner aspect
of the sclera, is located adjacent to the cho roid and con- fibers of the scl.era. An abr upt transition fro m the avas-
rior chamber (see Fig. 23 .4). T he ce.lls are joined by well- cular cornea to the well-vascu larized sclera also occurs
tains thinner collagen fibers and elastic fibers as well as
developed zonulae adherentes, relatively leaky zonulae oc- here.
.f ibroblasts, melanocytes, macrophages, and other con-
cludentes, and desmosomes. Virtually all of the metabolic The limbus region, specifically, the iridocorneal angle,
nective tiss ue cells.
exchanges of the cornea occur across the endothelium. The contains the apparatus for the o utflow of aqueous humor
endothelial cells conta in many m itochondria and vesicles Episcleral space (Tenon's space) is located between the (Fig. 23. 7) . In the stromal layer, endothelium-lined chan-
and an extensive rough endoplasm ic reticul um (rER) and episcleral layer an d s ubstantia propr ia of the sclera. This nels ca lled the trabecular meshwork (or spaces of
Golgi apparatus. They demonstrate endocytotic activity space and the surrou nding periorbital fat allow the eye to Fontana) merge to form the scleral venous sinus (canal of
and are engaged in active transport. Na+JK+-activated ro tate freely wi thin the orbit . The tendons of the extraoc- Schlemm). This s inus encircles the eye (Figs. 23.6 and
ATPase is located on the lateral plasma membrane. ular muscles attach to the su bstantia propria of the sclera. 23. 7). The aqueous humor is produced by the ciliary
Transparency of the cornea requires precise regulation processes that border the lens in the posterior chamber of
of the wa ter content of the stroma. Physical or metabolic The corneosclerallimbus is the transitional zone between the the eye. The flu id passes from the posterior chamber into
damage to the endotheli um leads to rapid corneal swelling cornea and sclera the anterior chamber through the valve-like potential
FIGURE23.5 and, if the damage is severe, corneal opacity. Restoration opening between the iris a nd lens. The fluid then passes
Electron micrograph of the corneal stroma. This electron micrograph of endothelial integrity is usua lly followed by deturges- At the junction of the cornea and sclera (Fig. 23.6), through the openings in the trabecula r meshwork in the
shows parts of three lamellae and a portion of a corneal fibroblast cence, although corneas can swell beyond their ability for Bowman's membra ne ends abruptly. The over lying epithe- limbus region as it continues its course to enter the scleral
(CF) between two of the lamellae. Note that the collagen fibrils In ad-
self-repair. Such swelli ng can resu lt in permanent focal
jacent lamellae are oriented at right angles to one another. Xl 6,700.
opacities caused by aggrega ti on of collagen fibrils in the
swollen cornea. Essen tial sulfated glycosaminoglycans that
It is believed that th e unifor m spacing of collagen fi- no rmally separate the corneal collagen fibers are extracted
brils and lamellae, as well as the orthogonal m-ray of the fro m the swollen cornea.
lamellae (a lternating layers at ri ght angles), is responsible Human cornea l endothelium has a limited prolife rati ve anterior cham
for the tra nsparency of the corn ea. Proteoglycans, a long capacity. Severely damaged endo theliu m can only be re-
with collagen type V, regulate the p recise diameter an d paired by tr ansplantation of a do no r cornea. Recent stud- corneoscleral limbus
spacing of the collagen fibrils. Swell ing of the cornea fo l- ies indicate that the per iphery of the cornea represents a re-
lowing injury to the epithelium or endothelium disrupts generative zone of the corneal endothelial cells. However,
this precise a rray and leads to translucency or o pacity of soon after corneal transpla ntati o n, endothelial cells exhibit
the cornea. contact in hi bition when exposed to the extracellular ma-
Norma lly, the cornea conta ins no blood vessels o r p ig- trix of Descemet's membrane. This find ing that inhibitory
ments. During an inflam matory response involving the factors released by Descemet's membrane prevent prolifer-
cornea, large nwnbers of neutrophilic leukocytes and lym- atio n of endothelial cells has focused some current corneal
phocytes migrate fro m blood vessels of the corneosclera l r esearch o n reversal or prevention of this inhibition with
limbus and penetrate between the stro ma l lamellae. exogenous growth factors.
Descemet's membrane is an unusually thick basal lam i na The sclera is an opaque layer that consists predominantly of
dense connective tissue
FIGURE 23.6
Descemet's membrane (posterior basement membr ane) Schematic diagram of the struc
is the basa l la mina of cornea l endothelial cells. It is in- T he sclera is a thick fibrous layer containing flat co lla- ture of the eye. This drawing shows
tensely periodic acid-Schiff positive and ca n be as much as gen bundles that pass in various directions and in planes a horizontal section of the eyeball
10 fLm thick. Descemet's membrane has a felt-like appear- para llel to its surface. Both the collagen bundles and fib rils with color-coded layers of its wall.
ance and consists of an interwoven meshwork of fibers and that form them ar e irregula r in diameter and arrangement. Upper inset. Enlargement of the
pores. Interspersed between the collagen bundles are fine net- anterior and posterior chambers
It separates the corneal endothelium from the adjacent works of elastic fibers and a moderate amount of grou nd shown in more detail. Note the di-
corneal stroma. Unli ke Bowman's membrane, Descemet's substance. Fibroblasts are scattered among these fibers. rection of the flow of aqueous hu-
mem brane readily regenerates after injury. It also slowly The opaci ty of the sclera, like that of o ther dense con- mor (arrows), which is drained by
the scleral venous sinus (canal of
thickens w ith age. nective tiss ues, is prima ri ly due to the irregularity of its
Schlemm) at the iridocorneal angle.
Descemet's membr ane extends periphera ll y beneath the structure. The sclera is pierced by blood vessels, nerves,
Lower insets. Typical organization
sclera as a meshwork ca lled the pectinate ligame1tt. and the optic nerve (see Fig. 23.2) . It is 1 mm thick poste- of the cells and nerve fibers of the
Strands from the pectinate ligament penetrate the cil iary r iorly, 0.3 to 0.4 m m thick at its equator, a nd 0.7 111m thick fovea centralis (left) and the retina
muscle a nd sclera and may help to maimain the norm al at the corneoscleralmargin o r " limbus." (rigl7t).
796 CHAPTER 23 Eye C HAPTER 23 Eye 797
The anterior surface of the iris reveals numerous ridges light enter s the eye. Two muscles actively involved in a d ap-
canal of Schlemm and groves, wh ich can be seen in clinical examination tation are
w ith the o phtha lmoscope. W hen this s urface is examined
Sphincter pupillae muscle, a circular band of smooth
in the light microscope it appear s as a discontinuous layer
muscle cells. This muscle is innervated by parasympa-
o f fibroblasts and melanocytes. The numbe r o f
thetic nerves carried in the oculomotor nerve (cra nia l
melanocytes in the strom a is responsible for varia tion in
nerve III) and is responsible fo r reducing pupillary size in
eye color. The function of these pigment-containing cells
response t o bright light (see Fig . 12.8). Failure of the
in the iris is to a b sorb light rays. If there are few
pupil to respond w hen light is shined into the eye-
melanocytes in the stroma, eye color is derived from light
"pupil fixed a nd dilated"-is an importa nt clinical sign
reflected from the pigm ent present in the cells of the pos-
of the lack of nerve or brain hmction.
terior surface of the iris, giving it a blue appearance. As
Dilator pupillae muscle, a thin sheet of radially oriented
the amount of pigment present in t h e stroma increases, t h e
pigmented myoepithelial cells constituting the a nterior
co lor changes from blue to shades of g reenish blue, gray,
pigment epithelium of the iris. This muscle is innervated
and, finally, brown.
by sympa thetic nerves from the superior cer vica l gan-
glion and is responsible for increasing pupillary size in
The sphincter pupillae is innervated by parasympathetic
response to dim light.
nerves; the dilator pupillae muscle is under sympathetic
nerve control
The ciliary body is the thickened anterior portion of the
The size of the pupil is controlled by contraction of the vascular coat and is located between the iris a nd choroid
sphincter pupillae an d dilator pupillae muscles . The
process of adaptation (increasing or decreasing the size of The ciliary body extend s a bout 6 mm from the root of
the pupil ) ensures that only the appropriate amount of t he iris posterolaterally to the ora serrata (see Fig. 23 .2) . As
FIGURE 23.7
Photomicrograph of the ciliary body and iridocorneal angle. This for the production of aqueous humor. Anterior to the ciliary body, be-
photomicrograph of the human eye shows the anterior portion of tile tween tile iris and the cornea, is the irid ocorneal angle. The scleral ve-
ciliary body and parts of the iris and sclera. Tile inner surface of the nous sinus (canal of Schlemm) located in close proximity to this angle
ciliary body fo rms radially arranged, ridge-shaped elevations, the cil- drains the aqueous humor to regulate intraocular pressure. x 120. The
iary processes, to which the zonular fibers are anchored. The ciliary inset shows that the cili ary epithelium consists of two layers, the outer
body contains the ciliary muscle, connective tissue with blood vessels pigmented layer and the inner nonpigmented layer. x480.
of the vascular coat, and the ciliary e pithel ium, which is responsible
venous sinus. Collecting vesse ls in the sclera, called aque- (Fig. 23 .8) . The basal lamina of these cells faces the pos-
ous veins because they convey a queous humor instead of terior c hamber of the eye. T he degree of pigmenta tion is
blood, transport the aqueous humor to (b lo od) ve ins lo- so g rea t that neither th e nucle u s n or character of the cy-
ca ted in the sclera . toplasm can be seen in the li ght mi croscope . Located be-
nea th this layer is a layer of myoepithelial cells, the ante-
rial' pigment myoepithelium. The apica l (posterio r)
Vascular Coat (Uvea) portions of these myoepithelial cells are la d en with pigment-lade n macrop hage myoepithelial
melanin g ranu les, which effec tively obscu re their bound- cells a
The iris, the most anterior part of the vascular coat, forms a ari es with the adjacent posterior p igment epithelia l cells .
contractile diaphragm in front of the lens The basa l (a nterior) portio n s of myoe pithelia l cells pos- FIGURE 23.8
sess processes containing contractile elements that extend Structure of the iris. a. This schematic diagram shows the layers of posterior chamber of tile eye. Because of intense pigmentation, the
The iris arises from the anterior border of the c iliary the iris. Note that the pigmented epithelial cells are reflected as occurs llistologic features of these cells are not discernable. Just anterior to
radially and collectively m a ke up the dilator pupillae
b ody (Fig. 23.7) and is attached t o the sclera about 2 mm at the pupillary margin of the iris. The two layers of pigmented ep- these cells is the anterior pigment myoepithelium layer (the dashed
muscle of the iri s. The contractile processes ar e enclosed line separates the two layers). Note that the posterior portion of the
ithelial cells are in contact with the dilator pupillae muscle. The in-
posterior t o the corn eosclera l junction. The pupil is the by a basal la mina that separates them fr om the a dj acent complete layer of fibroblasts and stromal melanocytes is ind icated on myoepithelial cells contains melanin, whereas the anterior portion
central aperture of this thin disc. The ixis is pushed stroma . the anterior surface of the iris. b. Photomicrograph of the iris show- contains contractile elements form ing the di lator pupillae muscle of
s lightl y for ward as it ch a nges in size in respo nse to light Con striction of the pupil is produced by smooth muscle ing the histologic features of this structure. The lens, which lies pos- the iris. Tile constrictor pupillae muscle is evident in the stroma. The
intensity. It consists of highl y vascularized conn ective tis- cells located in the stroma of the iris near the pupilla ry terior to the iris, is included for orientation. The iris is composed of a color of the iris depends on the number of stromal melanocytes scat-
sue stroma that is covered o n its p os terio r surface by marg in of the iris. These circumferentia lly o riented cells connective tissue stroma covered on its posterior surface by the pos- tered throughout the connective tissue stroma. At the bottom, note
h ighly pigmented cells, the posterior pigment epithelium collectively compose t he constrictor pupillae muscle. terior pigment epithelium. The basal lamina (not visible) faces the the presence of the lens. x 570.
798 CHAPTER 23 I Eye C HA PTE R 23 Eye 799
seen from behind, th e lateral edge of t he ora serrata bears cells, the ciliary epithelium, tha t was originally derived The choroid is attached firm ly to t he sclera at the margin vide nutrients to the cells of the retina. The fenestrated
17 to 34 grooves or crenulations. These grooves mark the from th e two layers of the optic cup. The ciliary epithelium of the optic nerve. A potential space, the perichoroidal capillaries have lumina that are large and irregular in
anterior limit of both th e retina and the ch oroid. The ante- has three principal functions: space (between the sclera and retina ), is traversed by thjn shape. In the region of the fovea, the choriocapillary
rior third of t he ciliary body has about 75 radial ridges or Lamellae or st rands that pass from the sclera to the cho roid. layer is thicker, and the capillary network is denser. T his
Secretion of aq ueous humor These lamellae originate from the suprachoroid lamina layer ends at the ora serrata.
ciliary processes (see Fig. 23 . 7). T he fibers of the zon ule
Participation in the blood-aqueous barrier (part of (lamina fusca) and consist of large, flat melanocytes scat- Bruch's memb1'ane measures 1 to 4 p,m in th ickness and
arise fro m t he grooves between the cilia ry processes.
the blood-ocular banier, see below) tered between connective tissue elements including collagen lies between the choriocapillary layer and the p igment ep-
T he layers of t he ciliary body a re similar to those of t he
Secretion and anchoring of the zonular fibers that and elastic fibers, fibroblasts, macrophages, lymphocytes, ithelium of the retina. It is a thin, amorphous refractile
iris and consist of a strom a an d an epitheli um. T he stroma
fo r m the suspensory Ligament of the Lens plasma cells, and mast cells. The lamellae pass inward to layer, also called the Lami1ta vitrea. With the transm ission
is divided into two layers:
The inner cell layer of the ciliary e pitheli LUn h as a surrou nd the vessels in the remainder of the choroid layer. electron microscope (T EM), five different layers are identi-
An o uter layer of smooth muscle, the cilia1y m uscle, fied in Bruch's membra ne:
basal lamina facing t he posterior and vitreous chambers. Free smooth m uscle cells, not associated with blood vessels,
w hich ma kes up t h e bulk of the ciliary body
The cells in this layer are nonpigmented. The cell layer are present in this tissue. Lymphatic channels called epi-
An in ner vascular regio n that extends into t he cil iar y The basal lamina of the endothelial cells of the chorio-
th at h as its basal lamina facing t he connective tissue choroid Lymph spaces, long and short posterior ciliary ves-
processes capillary layer
stroma of th e ciliary body is heavily p igmented and is sels, and nerves on their way to the front of t he eye are also
A layer of collagen fibers approximately 0 .5 p,m thick
The epithelial layer covering the internal surface of the d irectly continuous w ith the pigmented epithelial layer of p resent in the suprachoroid lamina.
A layer of elastic fibers approximately 2 p,m thick
ciliary body is a direct con tin uation of the two layers of the the retina. The double-layered ciliary epithelium contin- Most of the blood vessels decrease in size as they ap-
A second layer of collagen fibers (thus forming a "sand-
reti nal epithelium (see Fig. 23 .1 ). ues over the iris where it becomes the posterior p ig- proach the retina. The largest vessels continue forward
wich" around the intervening elastic tissue layer)
mented epithelium and anterior pigmented m yoepithe- beyond the ora serrata into the ciliary body. These ves-
The basal lamina of the retinal epithelial cells
The ciliary muscle is organized into three functional portions lium. The zonu lar fibers exte nd from the basal lamina of sels ca n be seen with an ophtha lmoscope. T he large ves-
or groups of smooth muscle fibers t he nonpigmen ted epi thelial cells of the ciliary processes sels a r e mostly veins that course in whorls before pass-
and insert into t he lens capsule (the thickened basal la m- ing obliquely thr ough the sclera as vortex veins. T he Retina
The smooth m uscle of the ciliary body has its origin in ina of the lens) . inner layer of vessels, arranged in a single plane, is called
The cells of the n onpigmented layer have all the charac- the choriocapillary Layer. The vessels of this layer pro- The retina represent s the innermost layer of the eye
the scleral spu r, a r idge-li ke projecti on o n t he in ner surface
of t he sclera a t the corneoscleral junction. T he m uscle teristics of a fluid-tra nsporting epi t helium, including com-
plex cell-to-cell junctions with a well-developed zon ular The retina, derived from the inner and outer layers o f the
fibers spread o ut in severa l directions and are classified
occludens, extensive la teral a nd basal p lications, a nd lo- optic cup, is the in nermost of the three concentric layers of
into three functional gro ups o n th e basis of t heir directio n
calization of Na +fJ(+ -ATPase in the lateral plasma mem- the eye (see Fig. 23.1c). It consis ts of two basic layers:
and insertio n:
br a ne. In ad dition, they have an ela borate rER and Go lgi Neural 1'etina or retina proper, the inner layer that con-
Meridional (or longitudinal) p011ion consists of the complex consistent with t heir role in secreting t he zonular ta ins the p h otoreceptors
outer muscle fibers that pass posteriorly into the stroma fibers. The cells of the pigme nted la yer have a less devel-
Glaucoma is a clinical condition resulting from Increased In- RPE, the o u ter layer t hat rests on and is firmly attached
of the choroid. These fibers function chiefly in stretchi ng oped junctional zone and often ex h ibit la rge, irregular lat-
traocular pressure. It can be caused by excessive secretion of to the chori ocapillary layer of the choroid
the choroid . It also may help open the iridocorneal an- eral intercellular spaces. The apical surfaces of the two cell
gle and facilitate drainage of the aqueous humor. aqueous humor or impedance of the dra inage of aqueous hu-
layers are held together by both desmosomes an d gap junc- A potential space exists between the two layers of the
mor from the anterior chamber. The internal tissues of the eye,
Radial (or oblique) portion consists of deeper muscle tions, creating discontinuous "luminal" spaces called cil- retina. The two layers may be separated mechanically in
particularly the retina, are nourished by the diffusion of oxy-
fiber bund les that radiate in a fan-like fashion to insert iary channels. the preparation of histologic specimens. Separation of the
gen and nutrients from the intraocular vessels. Blood flows
in the ciliary body. Its contraction causes t he lens to flat- T he aqueous humor is similar in io nic composition to normally through these vessels (including the capillaries and layers, "retinal detachment" (see Box 23 .2 ), also occurs in
ten a nd t hus focus for d istant vision. plasma but contains less tha n 0.1% pr otein (compared with veins), when the hydrostatic pressure within the vessels ex- the li ving state as a result of eye disease or trauma.
Circular (or sphincteric) portion consists of in ner m us- 7% p rotein in plasma). The aqueous humor p asses from t he ceeds the intraocular pressure. If the drainage of the aqueous In the neural retina, two regions or portions that d iffer
cle fiber bundles oriented in a circu la r pattern fo rming a ciliary body toward t he lens, then between the iris and Ieos, humor Is impeded, the intraocular pressure increases because in function are recognized:
sphincter. It red uces the tension o n the lens, ca using the before it reaches the a nterior c ha m ber of t he eye (see Fig. the layers of the eye do not allow the wall to expand. This in-
creased pressure interferes with normal retinal nourishment The nonphotosensitive region (nonvisual pa11), located
lens to accom mo date for n ear vision. 23 .6). In th e a nterior chamber of the eye, the aqueous hu-
and function. Visual deficits associated with glaucoma include anterior to the ora senata, which lines the inner aspect
mor passes laterally to the angle fo rmed between the cornea blu rring of vision and impaired dark adaptation (symptoms of the ciliary body and the posterior surface of the iris
Examination of a histologic p repara ti on does not clearly and iris. Here, it penetrates the tissues of the limbus as it en- that Indicate loss of normal retinal function) and halos around (th is portion o f the reti n a is described in the sections on
revea l t he arra ngement of the m uscle fi bers. Rather, the or- ters the labyrinthine spaces and fi nally reaches the canal of lights (a symptom indicating corneal endothelial damage). If the iris and ciliary body)
ganizational grouping is based on mjcrodissection tech- Schlemm, which co mmunicates with the vei ns of the sclera . the condition is not treated, the retina will be permanently The photosensitive region (optic part), wh ich lines the
nJques . damaged and blindness will occur. Treatments are directed to- inner surface of the eye posterior to the ora serrata ex-
The choroid is the portion of the vascular coat t hat lies deep ward lowering the intraocular pressure by decreasing the rate cept where it is pierced by the optic nerve (see Fig . 23.1)
Ciliary processes are ridge-like extensions of the ciliary body to the ret ina of production of aqueous humor or eliminating the cause of
f rom which zonular fibers emerge and extend to the lens the obstruction of normal drainage. Recently, carbonic anhy- The site where the optic nerve joins t he retina is called
drase inhibitors that specifically inhibit carbonic anhydrase the optic papilla or disc. Because the optic papilla is de-
The choroid is a da rk-brown vascular sheet onl y 0.25 Isoenzyme CA-ll, which plays an important role In the produc- void of photoreceptors, it is a blind spot in the visua l field.
Cilia ry processes are t hickenings of th e inner vascula r
mm thick posteriorly an d 0.1 mm thick anteriorly. It lies tion of aqueous humor In humans, are used as the pharmaco- The fovea centralis is a shallow depression located about
regio n of the ciliary body. They are contin uo us w it h th e
between the sclera and retina (see Fig . 23 .1 ). logic treatment of choice. Dorzolamlde and brlnzolamide are 2.5 nun lateral to the optic disc. It is the area of greatest vi-
vascula r layers of the c horoid. Scattered macrophages con-
Two layers can be identified in the c horoid : two carbonic anhydrase inhibitors that are currently available sual acuity. The visual axis of the eye passes through the
ta ini ng me lanin pigment granules a nd elastic fibe rs ar e
as eyedrops to treat glaucoma. fovea. A yellow-pigmented zone called the macula Lutea
p resent in t hese processes. The p rocesses and the ciliary Choriocapillary Layer, an in ner vascular layer
body are covered by a d o u ble layer of columna r epithelial Bruch's membra11e, a th in, amorp hous hya line mem brane su rrounds the fovea . In relati ve terms, the fovea is the re-
800 CHAPTER 2 3 Eye C H APTER 23 Eye 801
gion of the retina that contains the highest concentration Association and other neurons- horizontal, centrifugal, 5. Oute1' plexiform layer-contains the processes of many of these processes. They aggregate on the side of the
and most precisely ordered arrangement of the visual and amacrine retinal rods and cones and processes of the hori- cell nearest the rods and cones and are the most prominent
elements . Supporting cells-Muller's cells and neuroglial cells zontal, amacrine, and bipolar cells that connect to feature of the cells. The nucleus with its many convoluted
The specific arrangement and associations of the nuclei them infoldings is located near the basal plasma membrane ad-
LAYERS OF THE RETINA and processes of these cells result in the retina being or- 6. Inner nuclear layer- contains the cell bodies (nu- jacent to Bruch's membrane. The cells also contain mate-
ganized in ten layers that are seen with the light micro- clei) of horizontal, amacrine, bipolar, and Muller's rial phagocytosed from the processes of the photoreceptors
Ten layers of cells and t heir processes constitute t he neural scope. The ten layers of the retina, fro m outside inward, cells in the form of lamellar debris contained in res idual bodies
retina are (Figs . 23.9 and 23.10) 7. Inner plexiform layer- contains the processes of or phagosomes. A supranuclear Golgi apparatus and an
horizontal, amacrine, bipolar, and ganglion cells extensive network of smooth endoplasmic reticulum (sER)
Before discussing the ten layers of the retina, it is im- 1. Pigment epithelium-the outer layer of the retina, that connect to each other surround the melani n granules and resid ual bodies that are
portant to identify the types of cells fo und there. T his iden- actua lly not part of the neural retina but intimately 8. Ganglion cell layer-contains the cell bodies (nu- present in the cytoplasm.
tification will aid in understanding the fu nctional rela tion- associated with it clei) of ganglion cells The RPE serves several important functions including
ships of the cells. Studies of the retina in primates have 2 . Layer of rods and cones-contains the outer and 9. Layer of optic nerve fibers- contains processes of
inner segments of photoreceptor cells ganglion cells that lead from the retina to the brain A bsorption of light passing through the neural retina to
identified at least 15 types of neurons that for m at least 38
3. Outer limiting membrane-the apical boundary of 10. Inner limiting membrane-composed of the basal prevent reflection and resultant glare.
different types of synapses. For con venience, neurons and
Muller's cells lamina of M iiller's cells Isolation of tbe retinal cells from blood-borne sub-
supporting cells can be classified into four groups of cells
4. Outer nuclem layer-conta ins the cell bodies (nu- stances. It ser ves as a ma jor component of the blood-
(Fig. 23 .9):
clei) of retinal rods and cones Each of the layers is more fully described in the follow- retina barrier via tight junctions between RPE cells.
Photoreceptors-the retinal rods and cones ing sections (see corresponding num bers). Participation in restoration of photosensitivity to visual
Conducting neurons-bipolar and ganglion cells pigments tha t were dissociated in response to light. T he
The cells of the RPE (layer 1) have extensions that surround the metabolic apparatus fo r vis ual pigment resynthesis is
processes of the ro ds and co nes present in the RPE cells .
Phagocytosis and disposal of membranous discs from
incident light T he RPE is a single layer of cuboidal cells about 14 f.LlTI the rods an d cones of the retinal photoreceptor cells.
Inner limiting membrane w ide and 10 to 14 p.m tall. T he cells rest on Bruch's mem-
optic nerve
fiber layer ~~~ brane of the choroid layer. The pigment cells are tallest in
the fovea and adjacent regions, which accounts for the
darker color of this region .
The rods an d cones of t h e photoreceptor cell (layer 2) ext end
from t he outer layer of the neur al retina to the pigment
epithelium
Adjacent RPE cells are connected by a junctional com-
plex consisting of gap junctions and elaborate zonulae oc- The rods and cones are the outer segments of photore-
inner Muller's cludentes and ad herentes. This junctional comp lex is the ceptor cells w hose nuclei form the outer nuclear layer of
cells
plexiform site of the "blood-retina banier." the retina (Figs. 23.10 and 23 .11). The light that reaches
layer T he pigment cells have cylindrical sheaths on their api-
lo--- - 1 - - amacrine the photoreceptors must first pass through all of the inter-
cells cal surface that are associated with, but do not directly nal layers of the neural retina. T he rods and cones are
contact, the tip of the photoreceptor processes of the adja- arranged in a palisade manner; therefore, in the light mi-
cent rod and cone cel ls. Complex cytoplasmic processes croscope, they appea r as vertica l striations.
bipolar
cells project for a short distance between the photoreceptors of The retina conta ins approximately 120 million rods and
the rods and cones . Numero us elongated melanin gran- 7 million cones. The rods are about 2 p.m thick a nd 50 p.m
ules, unlike those found elsewhere in the eye, are present in long (ranging from about 60 p.m at the fovea to 40 p.m pe-
ripherally). The cones vary in length from 85 p.m at the
fovea to 25 p.m at the periphery of the retina.
Functiona ll y, the rods are more sensitive to light and are
the receptors used during periods of low light intensity
(e.g., at dusk or at night) . The visual image provided is
outer outer one composed of gray tones ("a black and white pic-
limiting 1-b--- +--- segment ture"). In contrast, the cones exist in three classes : L, M,
membrane of cone A potential space exists in the retina as a vestige of t he space
and rod between tile apical surfaces of the two epithelial layers of the and 5 (long-, midd le-, and short-wavelength sensitive, re-
optic cup. If this space expands, tile neural retina separates spectively) that cannot be distinguished morphologically.
~~~;;,~~,!;~~~~~~::::::._pigment They are less sensitive to low light and have maxima l sen-
epithelium from the pigment epithelium. This condition is ca lled r etinal
rod cone detachment. If not corrected, blindn ess results. More com- sitivity to the reel, green, or bl ue region of the visual spec-
FIGURE 23.9 FIGURE 23.10 monly, as til e vitreous body ages (i n t11e sixth and seventh trum . They provide a visual image composed of color,
Schematic drawing of the layers of the retina. Tile interrelationship decades of life), it tends to shri nk and pull away from the neu- which is believed to permit better visual acuity. T he speci-
Photomicrograph of a human retina. On tile basis of histologic fea-
of tile neurons is indicated. Light enters tile retina and passes through ral retin a, w hich causes single or multiple tears in the neural ficity of the cones provides a functional basis to explain
tures that are evident in this micrograpll, the retina can be divided
t11e inner layers of tile retina before reaching the photoreceptors of retina. Retinal detachment is repaired by cryosurgery or laser color blindness that is believed to resu lt fro m the lack of
into ten layers as indicated on th is photomi crograph. Note that
til e rods and cones that are closely associated with t11e pigment surgery to prevent visual loss.
Bruch's membrane (lamina vitria) separates the inner layer of the vas- red-, green-, or (much less commonly) blue-sensitive
epitllelium . cular coat (chorioid) from tile pigment epithelium. X440. cones.
802 CHAPTER 23 Eye C HA PTER 23 Eye 803
ionic permeability of the p lasma membrane and cause Discs are shed from both rods and cones The outer nuclear layer (4) cont ains the nuclei of t he retinal synaptic connections with rod spherules, cone pedicles,
the photoreceptor to become hyperpolarized, thus initi- rods and cones and bipolar cells. This electrical coupling of cells is thought
ati ng imp ulses that are conveyed to the bra in . In r ods, after a period of sleep, a burst of disc shedding to affect the functiona l thresho ld between rods and cones
occurs as light first enters the eye. T he time of disc shed- The region of the rod cytoplasm that contains the nu- and bipola r cells. The processes of a11tacrine cells branch
In rods, absorbed light energy causes conformational changes ding in cones is more varia ble. T he shedding of discs in cleus is separated from the inner segment by a tapering extensively to provide sites of synaptic connections with
in retinal. converting it to retinol cones also enables the recep tors to elimina te superfl uous process of the cytoplasm. In cones, the nuclei are located axonal endings of bipolar cells and dendrites of ganglion
membrane. Al though not fully understood, the shedding close to the outer segments, a nd no tapering is seen. The cells.
The conversion of retinal to retinol results in its release process in cones also alters the size of the discs, so that the cone nuclei stain lightly and are larger and more oval than In the peripheral regions of the retina, the axo ns of bipo-
from scotopsin (a reaction called " bleaching") . The cell be- conical for m is maintained as discs are released from the rod nuclei. R od nuclei are surrounded by only a thin rim lar cells pass to the inner plexiform layer w here they
comes hyperpolarized as calcium diffuses from the recep- distal end of the cone. of cytop lasm. In contrast, a relatively thick investment of synapse with several ganglion cells. In the fovea, they ma y
tor cell a nd reduces its permeability to sodium. The visual cytoplasm surrounds the cone nuclei (see Fig. 23 .11 ). synapse with a single ganglion cell, again reflecting the
pigment is then reassembled, and ca lcium is transported The outer limit ing membrane (layer 3) is formed by a row greater visual acuity in th is region. Amacrine cell processes
back into the cell. The energy for this process is pr ovided of zonulae adherentes between MLlller's cells The outer plexiform layer (5) is formed by the processes of the pass inward, contrib uting to a complex interconnection of
by the mitochondria located in the inner segment. Miiller's photoreceptor cells and neurons cells. They synapse in the inner plexiform layer with bipo-
cells and pigment epithelial cells also participa te in the in- The outer lim iting mem brane is not a true membrane. lar, ganglion, and other amacrine cells (see Fig. 23.9).
terconversion of retinal and retinol and the reactions nec- It is a row of zon ulae adherentes that attaches the apica l The outer plexiform layer is formed by the processes of
essa ry fo r the resynthesis of rhodopsin. ends of Muller's cells (i .e., the end that faces the pigment retinal rods and cones and the processes of horizontal, The inner plexiform layer (7) consist s of a complex array
During normal functioning of the photoreceptors, the epitheli um) to each other and to the ro ds and cones amacrine, and bipolar cells. The processes allow the elec- of intermingled neuronal cell processes
membranous discs of the outer segment are shed and (see Fig. 23 .10). Because Muller's cells end at the base of trical coupling of photoreceptor cells to these specialized
phagocytosed by the pigment epithelial cells (Fig. 23.13). the in ner segments o f the receptors, they ma rk the loca- interneurons via synapses. A thin process extends from the The inner plexiform layer consists of a complex inter-
It is estimated that each of these cells is capa ble of phago- tion of this layer. Thus, the supporting processes of region of the nucleus of each rod or cone to an inner ex- mingling of the processes of the amacrine, bipolar, and
cytosing a nd disposing of a bout 7500 discs/day. T he discs M iiller's cells on w hich the rods and cones rest are panded portion with several lateral processes. The ex- ganglion cells. T he course of these processes is parallel to
are constantly turning over, a nd the production of new p ierced by the inner an d outer segments of the photo- panded portion is called a spherule in a rod and a pedicle the inner limiting membrane, thus giving the appearance of
discs must equal the rate of disc shedding. receptors. in a cone. Normally, many photoreceptors converge onto horizontal striations to this layer (see Fig. 23.1 0).
one bipolar cell and form interconnecting neural networks.
Cones located in the fovea, however, synapse with a single The ganglion cell layer (8) consists of the cell bodies of large
bipolar cell. The fo vea is also un iq ue in that the compact- multipolar neurons
ness of the inner neural layers of the retina causes the pho-
toreceptors to be oriented obliquely. H orizontal cell den- The cell bodies of large m ultipolar nerve cells, measur-
dritic processes synapse with photoreceptors throughout ing up to 30 J.Lm in diameter, constitute the ganglion cell
the retina and further contribute to the elaborate neuronal layer. These nerve cells have lightly staining round nuclei
connections in this layer. with promi nent nucleoli and have Nissl bodies in their cy-
toplasm. An axonal process emerges from the rounded cell
The inner nuclear layer (6) consists of the nuclei of horizontal. body, passes into the nerve fiber layer, and then goes into
amacrine, bipolar, and MLlller's cells the optic nerve. The dend rites extend from the opposite
end o f the cell to ranufy in the inner ple.xiform layer. In the
Mi.iller's cells form the scaffolding for the entire retina. peripheral regions of the retina, a single ganglion cell may
T heir processes invest the other cells of the retina so com- synapse with a hundred bipolar cells. In marked contrast,
pletely that they fill most of the extracellular space. The in the macular region surrounding the fovea, the bipolar
basal and apical ends of Miiller's cells form the inner and cells are smal.ler (some authors refer to them as "midget"
outer limiting membranes, respectively. Microvilli extend- bipolar cells), and they tend to make one-to-one connec-
ing from their apical border lie between the photoreceptors tions with gangli on cells. O ver most of the retina, the gan-
of the rods and cones. Capillaries from the retinal vessels glion cells are only a single layer of cells. At the macula,
extend only to this layer. The rods and cones carry out however, they are piled up to eight deep, although they are
their meta bolic exchanges with extracellula r fl uids trans- absent over the fovea itself. Scattered among the ganglion
ported across the blood-retina barrier of the RPE. cells are small neuroglia l cells with densel y staining nuclei
The three types of conducting cells- bipolar, horizon- (see Fig. 23.10).
tal, and a11tacrine- found in this la yer have dis tinct orien-
tations (see Fig. 23.9). The processes of bipolar cells ex- The layer of optic ner ve fibers (9) contains axons
tend to both the inner and outer plexiform layer. Through of the ganglion cells
these connections, the bipolar cells establish synaptic con-
FIGURE 23.13
Electron micrograph of the retinal pigment epithelium in associa- cone cells. The retinal pigment epithelial cells contain numerous ml- nections with multiple cells in each layer except in the The axonal processes of the ganglion cells form a flat-
tion with the outer segments of rods and cones. Retinal pigment ep- tocllondria and phagosornes. Til e arrow indicates the location of the fovea, where the number of interconnected cells is reduced tened layer running parallel to the retinal surface. This
Ithelial cells (RPE) contain numerous elongated melanin granules that junctional complex between two adjacent cells. x 20,000. (Courtesy to prov ide greater visual acuity. The processes of horizon- layer increases in depth as the axons converge at the optic
are aggregated in the apical portion of the cell, where the microvilli of Dr. Toichiro Kuwabara.) tal cells extend to the outer plexiform layer where they in- disc. The axons are thin, nonmyelinated processes measur-
extend from the surface toward the outer segments of the rod and termingle with processes of bipolar cells. The cells have ing up to 5 J.Lm in diameter (see Fig. 23 .10 ).
806 C H AP TER 2 3 Eye CHAPTER 23 Eyr 807
ameter. Except for the photoreceptor layer, most of the lay- vessels form a capillary plexus that does not extend be-
ers of the retina are markedly reduced or absent in th is re- yond the inner nuclear layer. The branches of the central
gion (see Fig. 23.6). Here, the photoreceptor is composed retinal artery do not anastomose and therefore are classi-
Age-related macular degeneration (ARMD) Is the most common the formation of "blind spots in the visual field (Fig. 23.14). Wet entirely of co nes tha t are longer and more slender and rod- fied as anatom ic end arteries. Evaluation of the retinal ves-
cause of blindness In older individuals. Although the etiology of ARMD is a complication of dry ARMD caused by neovasculariza- like than they are elsewhere. T he adjacent pigment epithelial sels and optic disc during the physical examination of a pa-
this disease Is still unknown, evidence suggests both genetic and tion of blind spots of the retina in the large drusen. These newly cells an d choriocapillaris are also thickened in this region. tient not only provides important information on the state
environmental (UV irradiation, drugs) components. The disease formed, thin, fragile vessels frequently leak and produce exudates T he macula lutea is the area surrounding the fovea . It is of the eye but also provides early clinical signs of a num-
causes loss of central vision, w hile peripheral vision remains un- and hemorrhages in the space j ust beneath the retina, resulting in yellowish d ue to the presence of yellow pigment (xantho- ber of conditions, including elevated intracranial pressure,
affected. Two forms of ARMD are recognized: a dry (atrophic, fibrosis and scarring. These changes are responsible for the pro- phy ll ). R etinal vessels are absent in this region. H ere, the hypertension, glaucoma, and diabetes.
nonexudative) form and a wet (exudat ive, neovascular) form. The gressive loss of centra l vision over a short time. The treatment of
r etinal cells and their processes, especially the ganglion
latter is considered a complication of the first. Dry ARMD is the wet ARMD includes conventional laser treatment therapy; how-
cells, a re heaped up on the sides of the fovea so that light
most common form {90% of all cases) and Involves degenerative ever, new su rgical methods such as macular translocation have
lesions localized In the area of the macula lutea. The degenerative been recently Introduced. In this procedure, the retina is detached,
m ay pass unimpeded to this most sensitive area of the Crystalline Lens
lesions include a focal thickening of Bruch's membrane called translocated, and reattached in a new location, away from the retina .
T he lens is a transparent, avascula r, biconvex structure. It
"drusen; atrophy and depigmentation of RPE, and obliteration of chorioid neovascular tissue. Conventional laser treatment is then is suspended between the edges of the ciliary body by the
capillaries in the underlying chorioid layer. These changes lead to applied to destroy pathologic vessels w ithout destroying central VESSELS OF THE RETINA zonular fibers. The pull of the zonular fibers keeps the lens
deterioration of the overlying photosensitive retina, resulting in vision.
in a flattened condition . Release of tension causes the lens
T he central retinal artery and vein, the vessels that can be
to fatten or accomm odate to bend light rays originating
seen and assessed with an ophthalmoscope, pass through
close to the eye so tha t they focus on the retina .
the center of the optic nerve to enter the bulb of the eye at
T he lens has three principal components (Fig. 23.15 ):
the optic disc (see Fig. 23.2 and pages 791 to 792, the sec-
tion on the developing eye). The artery branches immedi- Lens capsule, a th ick basal lamina measuring approxi-
ately into upper and lower branches, each of which divides mately 10 to 20 J.Lm, produced by the anterior lens cells
again. Veins undergo a similar pattern of branching. The Subcapsular epithelium, a cu boidal la yer of cells present
vessels initially lie between the vitreous body and inner only on the anterior surface of the lens
lim iting membrane. As the vessels pass laterally, they pass Lens fibers, structures derived from subcapsular epithe-
deeper with in the inner retinal layers. Branches from these lial cells
germinal zone
-
lens capsu le
(basal lamina)
sub cap sular epitheli~m -~
FIGURE 23.14
Photograph depicting the v isual field In individuals w ith age- maximize their remaining vision, individuals with this cqndition
related macular degenerat ion. Note that central vision is absent are instructed to use eccentric fixation of their eyes.
because of the changes in the macula region of the retina. To
a
FIGURE 23.15
The in ner limiting membrane (layer 10) consists of a basal SPECIALIZED REGIONS OF THE RET INA Structure of the lens. a. This schematic drawing of the lens indicates magnification photomicrograph of the germinal zone of the lens
lamina separating the retina from the vitreous body its structural components. Note that the capsule of the lens is formed (near its equator) shows the active process of lens fibers formation
T he fovea appears as a shallow depression located at the by the basal lamina of the lens fibers and the subcapsular epithelium from the subcapsular epithelium. Note the thick lens capsule and the
The inner limiting membrane is th e basal lami na of posterior pole of the optical axis of the eye. Its centra l re- located on the anterior surface of the lens. Also note the location of underlying layer of nuclei of lens fibers during their differentiation.
Mi.iller's cells (see Fig. 23.10). gion, know n as the fovea centralis, is abo ut 200 p.m in di- the germinal zone at the equatorial area of the lens. b. Th is high- The mature lens fibers do not possess nuclei. x570.
808 CHAPTER 2 3 Eye
8( The lens capsule, composed p rimarily of type IV colla- C HA PTER 23 Eye 809
gen and proteoglycans, is elastic. It is thickest at the equa-
tor where the fibers of the zonule attach to it. reous humor), collagen, glycosaminoglyca ns (principally
hyaluronic acid), and a small population of cells called
Gap junctions connect the cuboidal cells of the s ubcap-
hyalocytes. These ceiJs are believed to be responsible for
sular epithelium. They have few cytoplasmic organelles
synthesis of collagen fibrils and glycosaminoglycans.
and stain faintly. The apical region of the cell is directed to-
H yalocytes in routine hematoxylin and eosin (H&E)
ward the internal aspect of the lens and the lens fibers with
preparation are difficult to visualize. Often, they exhibit a
which they form junctional complexes. The lens increases
well-developed rER and Golgi appa ratus. Fibroblasts and orbital} lacrimal gland
in size during normal gr owt11 and then continues to pro-
tissue macrophages are sometimes seen in the periphery of palpebral accessory lacrimal
duce new lens fibers at an ever-decreasing rate throughout tarsal muse Ie
the vitreous body. The hyaloid canal (or Cloquet's canal) , gland (of Krause)
life. Th e new lens fibers develop from the subcapsular ep -
which is not always visible, runs through the center of the
ithelial cells located near the equator (see Fig. 23.15). Cells
vitreo us body from the optic disc to the posterior lens cap-
in this region increase in height and then differentiate into
lens fibers. sule. It is the remnant of the pathway of the hyaloid artery
of the developing eye.
As tile lens fibers develop, they become highly elongated
and appear as thin, flattened structures. They lose their nu-
clei and other orga nelles as they become filled with pro-
teins called crystal/ins. Mature lens fibers attain a length of Accessory Structures of the Eye
7 to 10 mm, a width of 8 to 10 ,um, and a thickness of
2 ,um. N ear the center of the lens, in the nucleus, the fibers The conjunctiva lines the space between the inner surface of
are compressed and condensed to such a degree that indi- the eyelids and the anterior surface of the eye lateral to the
vidual fibers are impossible to recognize. Despite its den- cornea
sity and protein content, the lens is normally transparent
(see Fig. 23.15 ). The high density of lens fibers makes it
The conjunctiva is a thin, transparent mucous mem-
difficult to obtain routine histologic sections of the lens brane that extends from the corneoscleral limbus located
that are free from artifacts.
on the lateral margin of the cornea across the sclera (bul- palpebral conj unctiva
Changes in the lens are associated with aging
bar conjunctiva) a nd covers the internal surface of the eye-
lids (palpebral conjunctiva). It consists of a stratified aprocrine glands of a . sebaceous glands . b
eyelids (of Moll) of eyelashes (of Zes)
columnar epithelium containing nu merous goblet cells and
Wit11 increasing age, the lens gradually loses its elasticity rests on a lamina propria composed of loose connective tis-
and ability to accommodate. This condition, called pres- FIGURE 23.16 . . schematic drawing of the eyelid sho_ws
cle tissue (i.e., orbJcul~lls o_c
sue. The go bler cell secretion is a component of rl1 e tears . . uli muscle) stains yellow, and tile epithe
that bathe the eye. Structure of the eyelid. a. TillS scles tendons, connective d glandular epithelium are green.
byopia, us ually occurs in the fourth decade of life. It is eas-
assoc~ate
. d kn appendages, mu , d lial cells of skin, conjunctiva, an I ds within the eyelid. The
ily corrected by wearing reading glasses or using a magni- tile skin, . s I te the distribution of multiple small glan s f t l numerous g an
fyi11g lens. tissue ' and conJ Note tile presence o le I d and it is located wltllln
. un ctiva. lid
Noand observe th e reflection of the palpebral
d . the largest g an '
The primary function of the eyelids is to protect the eye associated With the eye . I ac to become the bulbar tarsal (Meibomian) glan IS
Loss of transparency of the lens or its capsule is also a . . f . of the lacruna s .d . r ue of the t arsa I plates This sebaceous gland
conJunctJva Ill the orlllx 'ttal section of the eyell the dense connective ISS l'd s X20 Inset. Higher mag-
relatively common condition associated with aging. This ograpll of a sag1 . 1g onto the eye 1 .
The skin of the eyelids is loose and elastic to accommo- conjunctiva. secretes into ducts openu . tl boxed area, showing the typica
condition, called cataract, may be due to conformational . b.. PhotomiCI
. id for bette!. VISU
. allzation of epithelial. campo-
nification of a tarsal gland flom le 1
date their movement. Within each eyelid is a flexible sup- stained With p1CIIC ac lands. In this preparation, mus- structure of a holocrine gland. X 60.
changes or cross-linking of proteins. The development of a nents of the skin and the numerous g
port, the tarsal plate, consisting of dense fibrous and elas-
cataract may also be related to disease processes, meta- tic tissue. Its lower free margin extends to the lid margin,
bolic or hereditary conditions, trauma, or exposure to a and its superior border serves fo r the attachment of
deleterious agent (s uch as ultra violet radiation) . Cataracts smooth muscle fibers of the supe1ior tarsal muscle (of I ds re duces an oi ly layer on the . . I the Iacnma
. I gI and s by a< . conunon
that significa ntly impair vision can usua lly be corrected cretion of the tarsal g an l p. - t ds the evaporation of is synch ronized Wltl . . t stinal polypeptide (VIP ).
Muller). The undersurface of the tarsal plate is covered by sur face Of the tear film tla t r e ar . t . vasoactive 111 e d f
surgically by removing the lens and replacing it with a neurotransnut er, f I ost anterior e ge o
the conjunctiva (Fig. 23.16). The orbicularis oculi muscle, l I
The eye asJ?es en lerge .rom t 1e m . s of the Met o-'b
plastic lens implanted in the posterior chamber. the normal tear layer. I h (. lands of Zeis), small,
a facial expression muscle, forms a thin oval sheet of cir- l nds of eye as es g d l . . f ont of the opemng d
Sebaceous g a I d tl at are connecte Wlt 1 the lid margm, m r I t stiff curved hairs an
cularly oriented skeletal muscle fibers overlying the tarsal mian gla nds. The lashes are_ sjlor. ' s . The las hes on the
modified sebaceous g _a n s to, the follicles of the eye-
Vitreous Body plate. In addi tion, the connective tiss ue of the eyelid con- and empty then secretion ll1 . . d ble or tnp e row . d d.
tains tendon fibers of the levator palpebrae superioris
may occur
same eyelid mmargmOl~ ma y Ilave d'1.fferent lengths an !-
muscle, which open the eyelid (see Fig. 23.16) lashes l . h (glands of Moll), sma ll
Apoc1'i1te glan~s of eby~ asl e~ inuous tubules tha t be-
a meters.
The vitreous body is the transparent jelly-like substance
that fills the vitreous chamber in the posterior segment In addition to eccrine sweat glands, which discha rge sweat glands Wltl1 un ranc 1e s
of the eye their secretions directly onto the skin, the eyelid contains g The lacrimal gland produces tears that moisten the cornea and
in as a simple spiral d otmd serous tubu -
four other major types of glands (see Fig. 23 .16): / 1 glan s, camp . pass to the nasolacrimal duct
Accessory acrzma distended lumina . They are
The vitreous body is loosely attached to the surroundi.ng loalveolar glands that hfa.ve .f 1 pper eyelids (glands
Tarsal glands (Meibomian glands}, long sebaceo us I sur ace o t1e u b the lacrimal glands and to 1~sser
stnictures, i11cluding the inner limiting membrane of the
glands embedded in the tarsal plates that appear as ver-
located on t le mner +.
of Wolfring) a nd in the ,ormx o
. f the lacrimal sac Tears are produced y I . I glands The lacnmal
I sory K nma c I
retina. The main portion of the vitreous body is a homo- degree by tle acces c cti va on the upper at-
gland_is located ~el: eatlil t~e3~I;;.u;be lac rimal gland con-
tical yellow streaks in the tissue deep to the conjunctiva. (glands of Kmuse) .
geneous gel conta ining approximately 99% water (the vir-
About 25 tarsal glands are present in the upper eyelid,
era! stde of the Ol bit (F g. I b l f tubuloacinar serous
and 20 are present in the lower eyelid. The sebaceous se-
All glands of the h.uman. ey
elid are innervated by neu-
m and their secretion sists of several separate o ~ es. o I' 1ed wit11 columnar
rons Of tile autonomtc ner ve syste ' glands. The acini have large umma II
8 l0 C HAPTER 2 3 Eye
Modified drawing of human eye, meridional mu scle (see Plate I 02), which brings about adjustments of
D perspective by E. Sobotta.
The innermost layer is the retina (R), which consists of
several layers of cells. Among these are receptor cells (rods
and cones), ne uro ns (e.g., bipolar and gang lion cells), sup-
the lens to focus li ght. The ciliary body also contains
processes to which the zonular fibers are attached. These
fibe rs function as suspe nsory ligaments of the le ns ( L). The
iris (I) is the most anterior compone nt of the uvea and con-
1-
porti ng cells, a nd a pigment epithelium (see Plate I 0 I). The tains a central opening, the pupil.
receptor components of the reti na are situated in the poste- The outermost layer of the eyeball, the fibrous layer, FC-
rior three fifths of the eyeball. At the anterior boundary of consists of the sclera (S) and the cornea (C). Both of these
the receptor layer, the ora serrata (OS), the retina becomes contain collagenous fibe rs as the ir main structural element;
reduced in thkkness, and nonreceptor components of the however, the cornea is transparent, a nd the sclera is o paque.
retina continue forward to cover the posterio r o r inner sur- The extrinsic muscles of the eye insert into the sclera and
face of the ciliary body (CB) and the iris (I). This anterio r effect movements of the eyeball. These are not included in
no nreceptor extension of the inner layer is highl y pi g- the preparation except fo r two small pieces of a muscle in- '.
me nted, and the pigment (melanin) is ev ident as the black sertion (a.Jmws) in tbe lower le ft and top center of the il-
inne r border of these structures. lustration. Posterio rly, the sclera is pierced by the emerging
The uvea, the mi dd le layer of the eyeball , consists o f the optic ner ve (ON). A deep depression in the neural retina lat-
c horoid, the ciliary body, and the iris. The choro id is a vas- eral to the optic nerve (above the ON in thi s fig ure) is the
c ula r layer; it is re latively thin and diffic ult to distinguish in fovea central is ( FC), the thinnest and most sensitive portion
the accompa nying figure except by location. On thi s basis, of the neural retina.
the choroid (Ch) is identified as being j ust ex te rnal to the The lens is considered in Plate 103. Just posteti or to the
pig mented layer of the retina. It is also hi ghl y pigmented; lens is the large cavity of the eye, the vitreous cavity (V),
the choroidal pigment is evident as a discrete layer in sev- whi ch is fi lled with a thick j ell y-like material, the vitreous
eral parts of the section. humor or body. Anterio r to the lens are two additional,
Anteri or to the ora senata, the uvea is thi ckened; here, it fluid-fi lled c hambers of the eye, the anterior (AC) and pos-
is called the ciliary body (CB). T his contai ns the c iliary terior chambers (PC), separated by the iris.
Ch
KEY
AC, anterior chamber I, iris R, retina
C, cornea L, lens S, sclera
CB, ciliary body ON, optic nerve V, vitreous cavity
Ch, choroid OS, ora serrata arrows, muscle insertions
FC, fo vea centralis PC, posterior chamber
812
CHAPTER 23 Eyt 8 15
Figure 1, eye, human, H&E x 65. below). T hey traverse the sclera through a num ber of open-
Figure 2, eye, human, H&E x325. 7. In ner plexifo rm layer (I PL), contam mg processes
KEY
BV, blood vessels JPL, inner plexiform layer O NL , outer nuclear layer (nuclei of rod and
C h, choroid LC, lamina cribrosa cone cells)
ELM, external limiting membrane LV, lam ina vitrea OPL, outer plexiform layer
G C , layer o r gangl ion cells NFL , nerve fiber layer PEp, pig ment epithelium
lLM, internal lim iting membrane O D, optic disc R&C, layer of rods and cones
I NL, inner nuclear layer (nuclei of bi polar, O N, optic nerve arrows, openings in sclera (lamina cribrosa)
horizontal, amacrine, and MUller's cell s)
814
CHA PTE R 23 Eyr 8I7
s
B
Figure 1, eye, human, H&E x45; inset x75. Just lateral to the junction of the cornea a nd sclera is the
A portion of the anterior segment of the eye, shown in
thi s figure , includes parts of the cornea (C), sclera (S), iris
(/), ciliary body (CB), anterio r chamber (AC), posterior
chamber (PC), lens (L ), and zonul ar fibers (ZF).
canal of Schl emm (CS; see also Fig. 2). T his canal takes a
circular route about the perimeter of the cornea. It commu-
nicates with the anterior chamber thro ugh a loose trabecu-
lar meshwork of tissue, the s paces of Fontana. The canal of
\
~ cs
AC
The relationship of the cornea to the sclera is illustrated Schlemm also communicates w ith episcleral veins. By
to advantage he re. The junction between the two (arrows) means of its communicati o ns, the canal of Schlemm pro-
is marked by a change in staini ng, wi th the substance of the vides a route for the flu id in the anterior and posterior
cornea appearing lighter than that of the sclera. Tbe corneal c hambers to reach the bloodstream.
epithelium (CEp) is continuous with the conjunc ti val ep- The inset shows the tip of the iris. Note the heavy pig- PC
ithelium (CjEp) that covers the sclera. Note that the epithe- mentation on the posterior surface of the iris, which is cov-
li llln thickens considerably at the corneoscleral j unction ered by the same double- layered epithelium as the cili ary '"' .
and resembles that of the oral mucosa. The conjuncti val ep- body and ci liary processes. I n the cil iary epithel ium, the
-zF
ithelium is separated from the dense fib ro us compo nent of
the sclera by a loose vascular connective tiss ue. Together,
thi s connective ti ssue and the epithelium constitute the con-
juncti va (Cj). The epithe lial-connecti ve ti ssue junction of
outer layer is pigmented and the inner layer is nonpig-
mented. In the iris, both layers of the irid ial epitheli um
(/Ep) are heavil y pigmen ted . A portion of the iridial con-
strictor muscle (M ) is seen beneath the epithe lium .
----
the conjunctiva is irregular; in contrast, the undersurface of
the corne al epi thelium presents an even profile .
Figure 2, eye, human, H&E x90; inset x 350. basement membrane of the pigmented cil iary epithelial
KEY
A, artery CM, cili ary muscle M, iridial constrictor muscle
AC, anterior chamber CP, ciliary processes npE, nonpigmented layer of ci liary epithe-
C, cornea CS, canal of Schlemm lium
CA, ci rcular artery CV, ci rcul ar vein PC, posterior chamber
en, ciliary body I, iris PE, pigmented layer of ci liary epithel ium
CEI>, corneal epi thelium IEp, iridial epithelium S, sclera
Ch, choroid L, lens V, vein
CiEp, ciliary epithelium LV, lamina vitrea VL, vascul ar layer (of ciliary body)
Cj, conjunctiva ZF, zonular fibers
CjEp, conjuncti val epithelium arrows, junction between cornea and sclera ZF- 2
816
C HAP TE R 2 3 Eye 8I9
Figure 1, sclera, human, H&E x 130. lar con nective ti ssue. Together, this epithelium and under- -~
=- c
This low-magnification micrograph shows the full thick- lying connective tissue represents the conjunctiva (Cj). The
ness of the sclera just lateral to the corneoscleral junction or white opaque appearance of the sclera is due to the irregu-
limbus. To the left of the arrow is sclera; to the rig ht is a lar dense arrangement of the collagen fibe rs that make up
small amount of corneal tissue. The conjunctival epithelium the stroma (S). The canal of Schlemm (CS) is seen at the
(C}Ep) is irregular in thickness and rests on a loose vascu- left close to the inner surface of the sclera.
Figures 2 and 3, sclera, human, H&E x360. cornea l epithelium, is just perceptible but disappears beneath
Figure 2 is a higher-magnification micrograph showing the conj unctival epithelium. Figure 3 shows at higher magni- D ~En_
- -- --- -\-- . l i-
the transition from the corneal epithelium (CEp) to the in eg- fication of the canal of Schlemm ( CS) than does Figure I.
ular and thicker conjunctival epithelium (CjEp) covering the That the space shown here is not an rutifact is evidenced by
sclera. Note that Bowman 's m embrane (B), lying under the the endothelial lining cells (En) that face the lumen. AC AC 4
Figure 4, cornea, human, H&E x 175. artifacts). Nucle i (N) of the keratocytes of the stroma lie
This low-magnification m icrograph shows the fu ll between lamellae. The corneal epithelium rests on a thick-
thickness of the cornea (C) and can be compared with the ened anterior basement membrane called Bowman's mem-
sclera shown in Figure l. The corneal e pi the]jum (CEp) brane (8). The posterior surface of the cornea is lined by a I
presents a uniform thickness and the underlying stroma (S)
has a more homogeneous appearance than the stroma of
the sclera (the w hite spaces seen here and in Fig ure 1 are
simple squamous epithelium called the corneal endothe-
lium (CEn); its thick poste rior basement membrane is
called Descemet' s m embrane (D ).
B
B_
}s 5
Figures 5 and 6, cornea, human, H&E x 360.
-__/s _ce~r
has a homogeneous appearance, a reflectio n of the dense
Figure 5 is a higher magnifi cation showi ng the corneal packing of its collagen fibril s. The fl attened nucle i belong
epithelium (CEp) with its squamous s urface cells, the very to the keratocytes. Figure 6 shows the posterior su rface of
' .\ - ... (l)
-- -
thick ho mogeneous-appearing Bowman's membrane (B), the cornea. Note the thick homogeneous Descemet's me m-
and the underlying strom a (S). Note that the stromal tissue brane (D) and the underlyi ng corneal e ndothelium (CEn). c.s.. . \ /1.~ 6
\.
KEY
AC, anterior chamber
B, B owman's membrane
CEp, corneal epithelium
Cj, conjunctiva
En, endothelial lining cells
LC, lens capsu le
BV, blood vessel s CjEp, conjunctival epithelium LF, lens fibers
C, cornea CS, canal of Schlemm N, nuclei
CEn, corneal endothel ium D, Descemet's membrane S, stroma
7
818
24 temporal bone
auditory
Ear les
\...- vestibulocochlear
~\ nerve
BOXES
BOX 24.1. Clinical Correlations: Vertigo 829 FIGURE 24.1
BOX 2 4.2. Clinical Correlations: Hearing Loss-Vestibular Dysfunction 832 Three divisions of the ear. The th ree divisions of the ear are repre- the Internal ear containing the bony labyrinth (semicircula r canals,
sented by different colors and consist of the external ea r (a uricle and vestibule, a nd cochlea) (blue) and the membranous labyrinth (not
external acoustic meatus) {/les/7 tone), the middle ear (tympanic cavity, visible).
auditory ossicles, tympanic mem brane, and auditory tube) (pink), and
I
- fl uid (i t has a high I('' concentratio n and low Na + con-
centration ).
Perilymphatic space, lying between the wa ll of the bo ny
laby rinth a nd the wall of the membra no us la byrinth.
T he perilymph is simila r in co mposition to extracellula r
flu id (it has a low K ' concentration an d a high Na + con-
centration).
Cortilymphatic space, lying withi n the orga n of Co rti. It
is a true inte rcellular space. T he cells surrounding the
tympanic sp ace loosely resem ble an absorptive e pithelium. The
cavity
cortilymphatic space is fi lled with cortilymph, which h as
a co mpositio n simila r to t hat of extrace llu lar fl uid.
FIGURE 24.6
The three spaces of th e bony labyrinth , as ill ustrated in
Photograph of a cast of the bony labyrinth of the internal ear. The
Figure 24.6, are
cochlear portion of the bony labyrinth appears blue-green; the
external Semicircular canals vestibule and semicircular canals appear orange-red. (Courtesy of Dr.
acoustic Merle Lawrence.)
meatus Vestibule
Cochlea
The vestibule is the central space that contains the utricle and
saccule of the membranous labyrinth
lows infections in t he midd le ea r to spread into th ese cells, The semicircular canals are tubes within the temporal bone
The auditory tube connects the middle ear to the nasopharynx
ca using mastoiditis. Befo re the develo pment o f antibiotics, that lie at right angles to each other
T he a uditory (Eustachi an) tube is a narrow flattened repeated episodes of otitis medi a a nd mastoiditis usua ll y
channel approximately 3.5 e m long. T his t ube is lined wi th led to deafness. T hree sem icirc u lar cana ls, each form ing a bou t three
cilia ted pseudostratified column a r epithel iu m, about o ne quarters of a ci rcle, extend fro m t he wa ll of th e vestibul e
fifth o f w hich is co mposed of goblet cells. It ven ts the mid- a nd return to it. The semicirc ul a r ca n als a re ide ntified as
dle ear, equa lizing t he pressure of th e m idd le ear w ith at- Q INTERNAL EAR ante ri o r, p osterior, an d late ra l a nd lie w ithin t he tempo-
ral bone a t app roximately right a ngles to eac h other.
mosphe ric press ure. The wa lls of th e tube a re n o rma lly
p ressed together but separate d uring yawning a nd swa l- The internal ear consists of two labyrinthine compartments, T hey occ upy three p la nes in space, sagitta l, fronta l, a nd
lowi ng. lt is co mmon fo r infec tions to spread from the one contained within the other hor izon tal. The e nd of each semicirc ular ca nal closest to
phary nx to the midd le ear via the a uditory tube (ca using the vestibu le is expa nded to fo rm th e ampulla (Fig.
otitis media). A small mass of lymp hatic tissue, the tubal The bony labyrinth is a complex system o f intercon- 24. 7 a). T he three cana ls open into the vestib ul e t hrough
tonsil, is often fou nd at t he pharyngeal o rifice o f t he a udi- nected cavities a nd ca na ls in the petro us part o f t he tem - five orifices; th e a nte rior a nd poste ri or semi circu lar
pora l bone. The memb1'auous labyrinth lies within t he can als jo in a t o ne end to fo rm th e common bony limb
tory tube.
bony laby rin th a nd consists of a complex system of small (Fig. 24. 7a).
The mastoid air cells extend from the middle ear into the sacs an d tubules that also for m a co'ntin uo us sp ace e n-
closed w ith in a wa ll of epi theli um a nd connective tissue. The cochlea is a cone-shaped helix connected to the vestibule
t emporal bone
There ar e three fl uid-filled spaces in the interna l ear :
A system of a ir cells projects in to the mastoid portio n o f The lu men of t he coc hlea, like that of t he semicirc ul a r
the temporal bone from the middle ea r. The epithelia l lin- Endolymphatic spaces, con tained w it hin the membra- FIGURE 24.5 canals, is continuous w it h that o f the vest ibule. It co n-
ing of th ese air cells is continuo us w ith th a t o f the t ym- no us la by rinth. T h e endolymph of the membran o us Photograph of the three articulated human auditory ossicles. The nects to the vestibu le on the side opposite the semicircu-
la byrinth is similar in co mposition to int1'a cellu lar til ree ossicles are tile rna Ileus, tile incus, and the stapes. x 30. la r canals. Between its base a nd t he apex, th e cochl ea
panic cavity a nd rests on p eri osteum. T his continui ty a l-
B~6 CHA PTE R 24 Enr CHAPTER 24 Enr 827
elliptical recess makes abo ut 2 % turns a rou nd a central core of spongy
for utricle
bone ca lled the modiolus. A sensory ga ng lion, the spiral
ganglion, lies in the m odiolus. One open ing of the canal,
the ro und w indow o n its infe rior surface near the base, is
covered by a thin m e m bra ne (the secondary tympanic
anterior ) semi-
. membrane).
posterior circular
lateral canals The membranous labyrinth contains the endolymph and is
suspended within the bony labyrinth
efferent nerve
HAIR CELLS
FIGURE 24.9 FIGURE 24.10
Diagram of two types of sensory hair cells in the sensory areas of Diagram of the crista ampullaris within a semicircular duct. The cel-
the membranous labyrinth. The type I hair cell has a flask-shaped lular organization of the crista ampullaris of a semicircular duct is
structure with a rounded base. The base is enclosed in a chalice-like sl1own in the large diagram and the enlarged rectangle. The crista am-
afferent nerve ending that has several synaptic boutons for efferent pullaris is composed of both type I and type II sensory hair cells and
nerve endings. Note the apical surface specializations of this cell, supporting cells. The stereocilia and kinoclllum of each hair are ern-
which include a klnociliurn and several stereocilia. The apical cyto- bedded in the cupula that projects toward the nonsensory wall of the
plasm contains residual basal bodies. The type II hair cell is cylindri- ampulla.
cal and possesses several nerve terminals at its base for both afferent
and efferent nerve fibers. The apical surface specializations are iden-
tical with those of the type I cell.
son is standing, th e macula of th e utricle is in a horizon-
ta l p la ne, and t he macula of the sacc ul e is in a vertical
fixed to the wa ll of the duct a nd the end o lymph. Ben ding p lane.
o f th e stereocilia in the na rrow space between the hair ca lls The gelatino us polysaccharide mate ria l th at overlies the
a nd the cupula generates nerve impu lses in the associa ted maculae is called the otolithic membrane (Fig. 24. 11 ). Its
nerve endings. outer surface contains 3- to 5-JLm c rysta lline bodies of ca l-
cium ca rbona te a nd a protei n (Fig . 24.12). Otoliths are
The maculae of the saccule and utricle are sensors of gravity heavier t ha n the endolymph. T he o uter surface of the
and linear acceleration o to lithic memb ra ne lies opposite th e su r face in w hich the
stereocilia o f th e ha ir cells a re embedded. The otolithic
The maculae of t he saccul e a nd t he utricle a re inn e r- membrane moves o n the macula in a man ne r a nalogo us to
FIGURE 24.11
vated senso ry t hic kenings of th e ep ithelium th at face the tha t by which the cupu la moves on t he crista . Stereocilia of
Diagram of a macula within the utricle. A more detailed diagram of
e ndolym ph of the saccule and utricle (see Fig. 24. ?c). A s the ha ir cells a re be nt by gravity in the statio na ry individ- the cellular organization of the macula of the utricle is shown in the
in t he cristae, each macula consists of type r and t ype II ual w hen the otoli th ic membra ne a nd its otoliths pull on enlarged rectangle. Supporting cells can be seen lying between the two FIGURE 24.12
ha ir ce lls, supporting cells, and ne rve endin gs associa ted t he stereocilia . T hey are also bent during lin ear movement principa l types of sensory hair cells (types I and II). The stereoci lia and Scanning electron micrograph of human otoconia. Each otoconium
w it h th e hair cells . The macu lae of t he utricle and saccul e w hen t he indiv id ual is moving in a straigh t line a nd t he kinociiium of each sensory hair cell are embedded in the otolithic has a long cylindrical body with a three-headed facet on each end.
are o riented at ri g ht a ngles to o ne a noth er. W hen a per- o to lithic membrane drags on the ste reocilia because of in - membrane on which otoconia lie. xs,ooo.
830 CHAPTER 24 Ear C HAPTER 24 Ear 83 I
mesothelial cell
perilymph of scala vestibuli
cochlear
duct
scala vestibuli
vestibulocochlear
nerve
.
endolymph of scala media epithelial cell
FIGURE 24.1 5
Transmission electron micrograph of the vestibular (Reissner's) lial cell, which faces the scala media and is bathed by endolymph.
membrane. Two cell types can be observed: a mesothelial cell, which X 8,400.
faces the scala vestibuli and is bathed by perilymph, and an epithe
scala tympani
FIGURE 24.18
Hair cells are attached through the p halangea l ce.Us to
Scanning electron micrograph of the spiral organ of Corti. This elec-
tron micrograph illustrates the configuration of stereocilia on the api-
the basilar membrane, which vibrates d uring sound recep-
Several types of disorders can affect the auditory and vestibu lar gitis, chronic otitis media), acoustic trauma (i.e., prolonged expo- tion. T he stereocilia of these hair cells ar e in turn atta ched
cal surfaces of the inner row and three outer rows of the cochlear sen-
system, resulting in deafness, dizziness (vertigo), or both. Auditory sure to excessive noise), and adm inistration of certain classes of to the tectoria l membrane, wh ich also vibrates. However,
sory hair cells. x 3,250.
disorders are classified as either conductive or sensorineural In na- antibiotics and diuretics. the tectorial membrane and the basilar mem brane are
ture. Conductive hearing loss results when sound waves are me- Another example of sensorineural hearing loss often occurs as
cells rest o n the t ym panic li p of t he spiral la mina; the o u ter hin ged at d iffe rent points. T hus, a shearing effect occurs
chanically Impeded from reaching the auditory sensory receptors a result of aging. A loss of the sensory hair cells or associated nerve
pillar cells rest o n the basilar membrane. Between t hem, between the basila r membrane (and the cells attached to it)
within the internal ear. This type of hearing loss principally in- fibers begins in the basal turn of the cochlea and progresses api~
they fo rm a triangular t un nel , the imter spiral tunnel (see and the tector ial membrane when sound vibrations im-
volves the external ear or structures of the middle ear. One exam- cally over time. The characteristic impairment is a high-frequency
ple of a conductive hearing loss is otosclerosis, a disease charac- Fig. 24.17) . pinge o n the internal ea r.
hearing loss termed presbycusis (see presbyopia, page 808).
terized by the growth of new spongy bone within the bony In selected patients the use of a cochlear implant can partially
Because they are inserted into the tectorial membrane, the
labyrinth near the ova l window. This spongy bone growth can restore some hearing function. The cochlear implant is an elec- The tectorial membrane extends from the spiral limbus over stereocilia of t he hair cells are the o nly structures that con-
cause the fixation of the base of the stapes (ankylosis) in the oval tronic dev ice consisting of an external microphone, amplifier, and the cells of the spiral organ of Corti nect the basilar membrane and its complex epithelial layer
window, decreasing the efficiency of sound conduction to the in- speech processor linked to a receiver implanted under the skin of to the tectorial membrane. T he shearing effect between the
ternal ear. the mastoid region. The receiver Is connected to the multielec- The tecto ria l membra ne is attac hed medially to the basilar membrane and the tectorial membrane distorts the
Sensorineural hearing impairment may also occur after injury trode intracochlear implant Inserted along the wall of the cochlear mo dio lus. Its lateral free edge projects over and attaches stereocilia and thus the apical portion of the hair cells. This
to the auditory sensory hair cells within the internal ear or to the canal. After considerable training and tuning of the speech proces- to t he o rga n o f Corti by 'the stereocilia of the hair cells . distortion generates membrane potentials that are conveyed
cochlea r division of cranial nerve VIII. Such hearing losses may be sor, the patient's hearing can be partially restored to various de- Tt is described as a keratin-like laye r conta ining fibrils to the brai n via the cochlear ne1've (cochlea~' division of the
congenital or acquired. Causes of acquired sensorineural hearing grees ranging from recognition of critical sounds to the ability to
embedded in a dense amor phous ground substance. vestibulocochlear nerve, crmtial nerve VIII).
loss include infections of the membranous labyrinth (e.g., menin- converse.
-
CHAPTER 2 4 E" r 83 5
oval w indow
IP :i.
.
.....
.! ' ~
;,
~
, .j
:}
tympanic cav ity
FIGURE 24.21
Schem atic diagram illustrating the dynamics of the three divisions placement of the basilar membrane on which rest the auditory sen-
of the ear. The cochlear duct is shown here as if straightened. Sou nd sory hair cells. Such displacement leads to stimulation of the hair cells
waves are collected and transmitted from the external ear to the mid- and a discharge of neural impulses from them . (Modified from
dle ear, w here they are converted Into mechanical vibrations. The Karmody CS. Textbook of Otolaryngology. Philadelphia: Lea & Febiger,
mechanical vibrations are then converted at the oval window into 1983.)
flu id vibrations within the internal ear. Fluid vibrations cause dis-
a
FIGURE 24.19
Electron micrograph of an inner and outer hair cell. a. Observe the round the outer hair cells basally. Their apical projections form the Innervation of the Internal Ear meatus (see Fig . 24.22). Neurons of the cochlear nerve
rounded base and constricted neck of the inner hair cell. Nerve end- apical cuticular plate (ACP). Note that the lateral domains in the mid- fibers are a lso b ipolar, and their cell bodies are loca ted in
ings (NE) from afferent nerve fibers (AF) to the inner hair cells are seen dle third of the outer hair cells are not surrounded by supporting cells. The vestibular nerve innervates the sensory receptors the spiral ganglio1t within the modiolus. D endritic
basally. JP, inner pillar cell; /PH, Inner phalangeal cell. x 6 ,3 00. b. Af- x 6,300. (From Kimura RS. Sensory and accessory epithelia of the
associated with the vestibular labyrinth processes of the afferen t cochlear nerve fibers exit the modi-
ferent {AF) and efferent (EF) nerve fiber endings on the base of an cochlea. In: Friedmann I, Ballantyne J, eds. Ultrastructural Atlas of t/1e In-
o.lus thro ugh foramina nervosa and enter the spira l organ.
outer sensory hair cell are evident. Outer phalangeal cells (OPH) sur- ner Ear. London: Butterworths, 1984.)
The vestibu locochlear nerve (crania l nerve VIII) is di- The axons of the cochlear nerve enter t he brainstem and
vided in to a vestibular nerve, which innerva tes the sensory terminate in the cochlear nuclei of the medulla . Nerve fibers
recep tor s associated with the vestibu lar labyr inth, and a from these n uclei pass to the geniculate nucleus of the thal-
cochlear nerve, which innervates the sensory recepto rs as- a mus and then to the auditory cortex of t he temporal lobe.
sociated wi th the cochlear labyrinth (Fig. 24.22 ). The Efferent fibers conveying impulses from the brain pass
vestibular nerve innervates the cristae ampullaris of the pa rallel to the ascending afferent nerve fibers of the
three semici rcular d ucts, the macula of the utricle, a nd the vestibulocochlear nerve (cochlear efferents of Rasm ussen).
macula of the saccule. Effe rent nerve fibers from the brainstem pass tlu-ough t he
T he cell bod ies of the bipolar neurons of the vestibulm- vestibular nerve. They synapse either on afferent endings
nerve a re loca ted in the vestibular gangliott (of Scm-pa) in of the inner hair cell o r on the basal aspect of an outer hair
th e interna l acoustic meatus. Dendritic processes of the cell. Efferent fibers are thought to effect control of a udi-
vestibu lar nerve fibers synapse at the base of the vestibula r tory and vestibular inpu t to the central nervous system,
facet for o uter hair cell
sensor y hai r cells, either as a chalice around a type l hai r preswnably by enhancing some afferent signals while sup-
cell o r as a bouton associated with a t ype ll hair cell. The pressing other signals.
axons of the vestibu lar n erve fibers enter the brainstem and
outer phalangeal cell terminate in the vestibular nuclei . Some second a ry neu-
Blood Vessels of the Membranous Labyrinth
rona l fi bers travel to the cerebellum and to the nuclei of
cr a ni al nerves III, IV, and VI, which innervate the muscles
of th e eye. Arterial blood is supplied to t h e membranous labyrinth by the
labyrinthine artery; venous blood drainage is to the venous
The cochlear nerve innervates the sensory receptors dural sinuses
b of the spiral organ of Corti
T he blood supply to the external ear, middle ear, and
FIGURE 24.20 Nerve fibers of the cochlear nerve division enter the bony bony labyri nth of th e internal ear is derived from vessels
Structure of the outer phalangeal cell. a. This scanning electron mi- cal cuticular plate that supports the outer sensory hair cells. x 2,400. coch lea th rough the modiolus from the internal acoustic associated with the external carotid arteries. The arterial
crograph illustrates the architecture of the outer phalangeal (Deiters') b. Schematic drawing showing the relationship of an outer pha-
cells. Each phalangeal cell cups the basal surface of an outer sensory langeal cell to an outer sensory hair cell.
hair cell and extends its pha langeal process apically to form an api-
836 C HAPTER 24 Ear
- - - - inferior part of
vestibular nerve
B
Figure 1, ear, guinea pig, H&E x 20. marked by the white arrow. At the upper right are cross sec-
In this secti o n thro ugh the inner ear, bone surro unds the tions of the membranous labyrinth passi ng through compo- ---OL
I
entire inner ear cavity. Because of its labyrinthine charac- nents of the semicircular duct system ( DS).
ter, sections of the inner ear appear as a number of separate The cochlea is a spiral structure havi ng the genera l
chambers and ducts. These, however, are all interconnected shape of a cone. The specimen illustrated here makes 3~
(except that the perilymphatic and endolymphatic spaces turns (in huma ns, there are 2% turns). The section goes
re main separate). The largest chamber is the vestibule (V). tluough the central ax is of the cochlea. This consists of a
The left side of this chamber (black arrow) leads in to the bo ny stem called the modiolus (M ). It contains the begin-
cochlea (C). Jus t below the black arrow a nd to the ri ght is ni ng of the cochlear nerve (CN) a nd the spiral gangli on
the oval li game nt (OL) surrounding the base of the stapes (SG). Because of the plane of section and the spiral
(S). Both structures have been c ut obliquely and are not arrangement of the cochlear tunnel, the tunnel is cut cross-
seen in their entirety. The facial nerve ( FN) is in an osseous wise in seven places (note 3 1/ 2 turns) . A more detail ed ex-
tunnel to the left of the oval ligament. The communication amination of the cochlea and the o rgan of Corti is provi9ed
of the vestibule with one of the semicircular canal s is in Plate 105.
B
Figure 2, ear, guinea pig, H&E x 225. they can, however, be di stinguis hed o n the basis of locatio n
A hig her mag nifi cati on of one of the sem icircul ar canals (see inset), as the hair cells (H C) are situated in a more s u-
and of the cri sta ampull aris (CA) within the canal seen in perfic ial location th an the sustentacular cells (SC). A gelat-
the lower ri g ht of Fig ure I is provided here. The receptor inous mass, the cupula (Cu), surmounts the epithe lium of
for moveme nt, the crista ampullaris (note its relatio nships the cri sta am pullaris. Each receptor cell send s a hair-like
in Fig. I), is present in each of the se mic ircu lar canals. The projection deep into the s ubstance of the cupul a.
epithelial ( EP) surface of the c rista cons ists of two ce ll
types, suste ntacular (supporting) cells and ha ir (recepto r)
cells. (Two types of hair cells a re dis tingui shed with the
The epithelium rests on a loose, cellular connecti ve tis-
sue (CT) that a lso contains the nerve fibers associated with
the receptor cells. The nerve fibers are difficult to identify
-.I
.
. ..._.... .
---~ .t .
electro n microscope.) lt is difficult to identify the hair and because they are not o rgani zed into a di screte bundle.
sustentacular cells on the basis of spec ific characte ri stics;
l
if
KEY
C, coch lea EP, epithelium SC, sustentacular cell
CA, crista ampullari s FN, facial nerve SG, spi ral ganglion
CN, cochlear nerve HC, hair cell V, vestibule
CT, connective tissue M, modiolus black arrow, entry to cochlea
Cu, cupula OL, oval ligament white arrow, entry to semici rcular canal
DS, duct system (of membranous labyri nth) S, stapes
838
CHAPTER 2 4 Ear 84 I
B
Figure 1, ear, guinea pig, H&E x65; inset x380. with endolymph. It is thought that the endolym ph is formed
A section through one of the turns of the cochlea is by the portion of the spiral ligament that faces the cochlear
shown here. The most important fu nctional compone nt of duc t, the stria vascularis (StV). T his is highly vascularized
the cochlea is the organ of Corti, enclosed by the rectang le and contains specialized "secretory" cells.
and shown at hi gher magnification in Figure 2. Other struc- A shelf of bone, the osseous spiral lamina (OSL), ex-
tures are included in thi s fig ure. The spiral li gament (SL) is tends fro m th e mod iolus to the basil ar me mbrane. Branches
a thickening of the periosteum on the oute r part o f the tun- of the coch lear ne rve (CN) travel along the spi ra l lamina to
nel. Two membranes, the basilar membrane (BM) a nd the the modiolus, where the main trunk of the ne rve is formed.
vestibu lar membrane (VM), join with the spiral ligament The components o f the coc hl ear nerve are bipolar neurons
and di vide the cochlear tunnel into three parallel canals, whose cell bod ies consti tu te the s piral ganglion (SG ). These
namely, the scala vestibuli (SV), the scala tympani (ST), and cell bodies are shown at hig her magnification in the inset
the cochl ear duct (CD). Both the scala vestibuli and the (upper right). The s piral lam ina su pports an elevatio n of
scala tympani are perilymphatic spaces; these communicate cells, the limbus spiral is ( LS). T he surface of the limbus is
at the apex of the cochlea. The cochlear duct, on the other composed of columnar cells.
hand, is the space of the me mbranous labyrinth and is fi lled
Figure 2, ear, guinea pig, H&E x180; inset x 380. here but can be seen in the inset), where they form a retic-
location (see inset) and because their nuclei are well fro m other groups by spaces that form spiral tunnels. T hese //
aligned. Because the hai r cells rest o n the phalangeal cells, tunnels a re named the inner tunnel (IT), the outer tunnel
it can be concluded that the upper three nucle i belo ng to (OT). and the internal spi ral tunnel (1ST). Beyond the sup-
/ "' CD
oute r hair cell s, whereas the lowe r three nuclei be lo ng to porting cells are two addi tio nal gro ups of cells, the cells of
oute r phalangea l cells. Claud ius (CC) and the cells of Bottcher (CB).
The supporti ng cells extend from the basi lar membrane
(BM) to the surface of the organ of Corti (thi s is not ev ident
HC&OP
KEY
BM, basilar membrane IP&H C, inner phalangeal and hair cel ls RM, reticu lar membrane
CB, cells of Btittcher IPC, inner pillar cell s SG, spi ral gangli on
CC, cells of C laudius IST, internal spiral tunne l SL, spiral ligament
CD, cochlear duct IT, inner tunnel ST, scala tympani
CH, cells of Hensen LS, limbus spiralis StV, stria vascularis
CN, cochlear nerve OPC, outer pill ar cell s SV, scala vestibu li
HC&OI', hair and outer phalangeal cell s O SL, osseous spiral lamina TM, tectorial membrane
IBC, inner border cells OT, outer tunnel VM, vestibular membrane
840
INDEX
In t his index, page numbers in italics designate figures; page numbers followed by b designate boxes; page numbers followed by fJ designate plates;
page numbers followed by t designate tables; and page numbers fo llowed by n designate .footnotes. Cross-references indicated by see o r see also des-
ignate re lated ropics o r rnore detailed lists of su btopics.
Anricoagulams, 332 Astrocytes, 299-300, 300 Basal cells, 57 L, 572- 573 of eye, 791 , 799, 807 Bone fo rmation, 193-200 Brush border, in kidney, 90
Anridiuretic hormone (A Dl-1, vasopressin), fibrou s, 299, 301 Basa l lamina, 104-109. 105, 106, 107, 108 of kidney, 624- 625, 625 clinica l correlation: nutr itional factors, Brush cells, 570, 572, 576, S79
622/;, 65 .1-652, 6.52t protOplasmic, 299, 300 terminology, I 07/; of liver, 53.5-536, 536 J 99b Bulbo urethral (Cowper's) glands, 629, 709,
Anrigen(s), 357 Atherosclerosis, 337, 337b Basement membrane, 704, 104-109, 105, of m<lmmmy gland, 763 endochondral bone growth, 194-198, 711
prostate-specific (PSA), 709 Atherosclerotic plaque, 346/; 109. See also Basa l la mina of ovary, 740-742 195, 208- 2l1p Bundle (interwoven) bone, 185
Rhesus (Rh), 2J 9/; Atresia, of ova rian follicles, 729, 739-740, glomeru la r; 609 of pancreas, 559 zonc(s) of epiphysea l plate . Bundle of His, 346
sperm-specific, 700b 766-767p of splen ic vessels, 109 of pen is, 71 I calcified cartilage, 196, 210- 21 1{1 Bundles, of muscle fiber. See Fascicle(s)
Anrigen-dependent acrivarion, of lympho- Atrial natriuretic factor, 262 terminology, I07/; of placenta, 753- 754, 754 hypertrophy, 196, 210-21 1/J Bursa of Fabricius, 361 b
cytes, 359 Atriovemricular (A-V) bundle (bu nd le of trachea l, 104, 577-578, 578 of respiratory system, 590 proli feration, 196, 210-21 1p Bursa-equivalent organ (bone marrow and
Antigen-presenring cells, 144, 366-368, 367, H is), 346 Basic dyes, 61, 6-7 of testis, 686 reserve carti lage, 195, 21 0-2 ll p GALT), 358- 359, 361/J
3 68. 369, 370 Atrioventricular (A-V) node, 345-346 Basket, nuclear (nuclear cage), 66, 66 of uterus, 745, 745-746 resorption, 196, 210-2llp
of epidermis (Lnngerhans' cells), 408, Atrophy, of skeletal muscle, 259 Basophilic erythroblast, 236 Blood vessels, genera l features, 32 7, ossification (
408-410,410 Attachment phase, of skeleta l muscle con- Basophi ls, 146, I 4 6, 224-225, 225. 226. 327-328 , 328t. See also Arteries; endochondral, 194-198, 195, 208-211/J C cells (para foll icular cells), 656, 657
Antwm, of ovarian follicle, 732 traction, 254, 254-255 244-245p Arterioles; Ca pillaries; Veins inrramembranous, 193, 193-194, C protein, 254
Aorta, 350-351{1 Attachment plaq ue, of desmosome, 100, mature, 238 Blood-aqueous barriet; 798 212-213{1 ca~-
Aortic body, 347 I '10-1 11 Bcl-2 protei ns, 73, 74 Blood-br:1in barrier, 283, 304-306, osteona l (Haversian ) system, 183-184, in fertilization, 738- 739
Aperrure, o f bone marrow sinuses, Attenuation reflex, 823 Beds, na il, 420 3 J3, 313 184. 198- 200, /99, 200, 200 ovarian foll icles and, 732
240-24 1 Auditory (Eustachian) tube, 821, 822, 824 Bending phase, of skeleta l muscle contrac- Blood-ocular ba rrier, 798 Bone growth, hormonal regulation, 201 b parathyroid hormone and, 661
Apical foramen, of tooth, 4 51 Auerbach's (myenteric) plexus, 4 77, 478, tion, 255, 255 Blood-testis barrier, 700, 700b Bone marrow, 183, 240- 241, 241 in skeletal muscle contraction, 256,
Apocrine glands, of eyelids (glands of Mol l), 491,500,507 Benign prostatic hyperplasia (BPH), 708, Blood-thymus barrier, 38 1-382, 382 nonactive, 24 J 256- 257
809,809 Auricle (pinna ) of ear, 82 J, 82 1 709/; Body (bodies) red, 182, 24 1 Ca 2 - channels
Apocrine mamma ry secre tion, 761 Autonom ic nervous system (ANS), 30 7-3 11 Bertin, co lumns of (renal columns), 605, abacus, 450, 451 sinusoidal system of, 240-24 'I, 241 ligand-gated, 268
Apocrine secretion, .I I I classifica rion, 306 605-606 aortic, 347 with GALT (bursa-equivalent organ), voltage-gated , 256, 290
Apocrine sweat gl:mds, 419, 419/;, 4 19-420, defined, 283 Bile apoptotic, 74, 75 358-359,361/? Cah -ca lmodulin complex, 266, 267-268
426-429p orga nization, 308, 308-3 10, 309 composition of, 535t Balbiani, 729, 730 yellow, 182 Ca 2 - ca lmodulin/myosin light chain kinase
Aponeuroses, 130 parasympathetic division, 283, 308, 309, ga llb ladder and, 548 Ba rr, 62, 63, 221 Bone remodeling un it, 198, 199 system, 267-268
orrhogonal a rray, of collagen fibers, 310 hepa tic prod uction o f, 535 basa l, 92, 94 Bone resorption, 190- 191, 192 Cad hcrin-catenin complex, 99
130-13 1 regula tory functions, 283-284 Bile ca nal icu li, 545, 547 Cali-Exner, 733, 733 Bone spicules, 188- 189, 192 Cadherin zipper, 101, 102
Apoprosis, 72, 73-75, 74, 75, 358 sum marization of distributio n, 308, 309, Bile ducts, 535, 547, 547 carotid, 34 7 Bone tissue, J 86-192 Cage, nuclear (nuclear basket), 66, 66
blcbbing, of membrane, 73- 74 3 10-3 1 I Bile salts, 548 Cha rcot-Bottcher, 698 bone-lining cells, 187, 187- J 88 Calcification, of cartilage, 171, 171,197
of granulosa cel ls, 739-740 sympa thetic division, 308, 309, 3 10, Bilia ry tree, 543, 545-548, 546- 548, 547 c ilia ry, 789, 789, 790, 796, 797, classification of, 181, 182 Calcified cartilage, zone of epiph yseal plare,
Apoprotic bodies, 74, 75 3 16-3 17p Bilirubin, 23 7 797- 798 osteoblasts, 188, 188-190 196, 197, 210- 211p
Appendix (appendices) Autoradiography, 9- 11, 10 Biologic minera lization, o f bone, 200-20 I crystalloid, 223 osteoclasts, 190- 193, 192 Calcitonin (thyrocalcitonin), 657t, 658
o mental, .503 Aurosomes, 62 Bipola r neurons, 284, 285, 286 dense (cytoplasmic densities), 266- 267, osteocytes, 190, 191 Calcium . See Ca"
vermiform, 373- 374 Axoaxonic synapses, 288 Birbeck granu les, 409 267 osteoprogenitor cells, J 86- '188 Call-Exner bodies, 733 , 733
Appositiona l growth, 170, 193 Axodendritic synapses, 288, 290 Birefringence, 250 H erring, 65 1 Bony callus, 201, 202 Callus
Aquaporin proteins (AQPs), 6 1S, 619&, Axon(s), 8 1, 287-288 Bizzozero, node of, of kera tinocytes, 402 ketone, 534 Bony labyri nth, 825, 825 bony, 201, 202
622b myelinated, 296 Bladder, urina ry. See Urina t)' bladder lamella r, 406, 583, 584, 585, 586 Border carrilaginous, 20 .1, 202
Aqueous humor, 790, 793 , 794, 795, 798 unmyelinated, 295, 298 Blastema, of preca rtilage (protochondral tis- pineal. See Pinea l gland brush, in kidney, 90 Calmodu lin, 266-268
Araclmoid, 312, 312-3 L3 Axon hillock, 287-21!8 sue), 170 of stomach, 480, 481 ruffled, of osteoclast, 190, I 92 Calyx (calyces), renal, 604, 606, 606
Arachnoid tra becu lae, 3 12, 3 12 Axonal transport systems, 293 BlastoC)'StS, 748, 748-749 o f ute rus, 743 striated, in smal l intestine, 90, 492, 493 Canal
Areolar tissue. See Loose connective tissue Axosomatic synapses, 288 Blood, 2 14-245, 242-245p. See also specific vitreous, 790 , 808 Bouton terminal (end bul b), 289 a limenta ry, 435-436
Argentaffin cells, 486-4!! 7 Azuroph ilic granu les, 222, 223, 244-245/J COI11/JOIIC IIIS Weibei-Palade, 331 Boutons e n passant, 269, 289 o f Hering, 54.3, 545
Argyrophil cel ls, 4 86-4!!7 clinical correla tions Body wal l, a utonom ic distribution to, 308, Bowman's capsule, 607, 609-610, 6 I 0, 611, hya loid (Cloq uet's), 808
Argyrophilicity, '134 , 73 7 B ABO and Rh blood group systems, 2 19/J 309,3 JI-312 614,614 inguinal, 685
Arrector pil i muscles, 404, 414 B cells, pancreatic, 555 hemoglobin disorders, 220b Bone, 180-2 L3 Bowman 's (olfactory) glands, 572, 573 pilosebaceous, 4 13
Arteria lis, 345 B lymphocytes (B cells), 146, 226 , 358 eqrhrocyres (reel cells), 217. 2 17-221, Bone(s). See also Bone for mation; Bone tis- Bowman's membrane, 793, 793, 795 resorption, of bone, 198, 799
Arteries, 327,327. 327-337, 328-337 memory, 363, 364 218,219, 2J9b, 220, 220/J. sue; a11d specific 1ypes Bra in o f Schlemm, 795, 796, 797
Arterioles, 327, 327, 335- 337, 336, origin of name, 36 I/; 242-245p biologic mineralization, 200-201 cerebellar tissue, 322- 323p semicircular, 825, 825
354-355p Balbiani bodies, 729, 730 examination technique for (blood smea r), blood supply to, 184- 185, 185 cerebrum, 320-3 12p Cana licu lar system, intracellular, 484
Anerioveno us a nastomoses (shunts), 340 Band 3 protein, of erythrocyte membrane, 2 16,2 16-2 17 classification of, 18 1- 182, I 82 Brain natriu retic factor, 262 Cana liculi
Artery (arte ries), 328-337. See also Blood 2 17 formarion of blood cells (hemopoiesis), clinical correlatio n: articular cartilage and Brain sand (corpora arenacea), 653-654, bile, 545, 547
supply Band 4 proteins, o f erythrocyte membrane, 23 1-240, 2321, 23.3. See also He- joint diseases, 183/J 654 lacrima l, 810,810
aona, 350-3S i p 2 17, 2 19 mopoiesis compact, 184, 184, 206-207p Breasts. See 1\tlammary gla nds Cancer, prostate, 708b
arterioles, 335-337, 336 Band (smb) cells, 238 fu nned c le ments of, 2 1St endochond ral ossification , 194- 198 Brighr-field microscope, 12 Candidate hormo nes, 488t, 4891>, 498
cl inical correlations Baro receprors, cardiac, 347 leukocytes (whi te cells), 221-229 flat, 18 1,182 Bronchia l advenriti3, 580 Ca p, acrosomal, 693
atherosclerosis, 337b Ba rr bodies, 62, 63 , 22 1 basophils, 224-225, 225, 226 genera l structure, 182-186. See also Bone Bronchia l cartilage layer, 580 Ca p phase, of spermatogenesis, 693
hypertension, 336/J Barrier cosinophils, 224, 225 cavities; Periosteum Bronchia l circulation, 5 90 Capacitation, 696, 704, 737- 738
elastic, 328, 328/, 328-334, 334 air- blood, 585, S86. 587 lymphocytes, 225-228, 22 7. See also ground, 204-205p Bronchia l mucosa, 580 Capil laries, 338-340
genera l features, 327, 327- 328, 328/ blood- aqueous, 798 Immune S)~tcm; Lymphatics intramembranous ossi ficat ion, 193-J 94 Bronchia l muscularis, 580 continuous, 338, 339
hepatic, 536 blood- bra in, 283, 304-306, 3 13, 3 I 3 monocyres, 228. 228-229 immature, 185, 185- 186, 186 Bronchia l submucosa, 580 discontinuous (sinusoidal), 340
hypophyseal, 645, 646 bl ood-ocula r~ 798 neurrophils, 22 I, 22 1- 224, 223 immature vs. mature, 185 Bronchiolar ca rtilage plates, 58 1-582 fenestrated, 339, 339- 340
muscula r, 334, 334-335, 335, 352- 353/J blood- testis, 700, 700& overview, 214-2 15 irregular, 181, 182 Bronchiole(s), 598- 601./J fenes trated sinusoidal, 661
rena l, 624, 625 epidermal warer, 406, 40fi-407 plasma , 2 l5-2 17 long, 18 1, 182, 185 function, 581, 581- 582 func tional aspects, 340
sm~ ll , 335-337 mucosal , 435, 475, 484 platelets, 229, 229-23 L, 230 ma trix vesicles, 200- 20 I structure, 5 80-5 81, 58 I glomerula r, 609, 6 I I , 6 I 2
smooth muscle of, 280-28 1/1 nonthrornhogen ic o f a rterial endothel ium, Blood cel ls, fo nn;Hi on o.f, 2.3 1-240, 2321, ma tun: (la mellar), 183- 185, 18-f term in al, 58 L, 58 I, 600-60 I /1 lymphatic, 347
um bilica l, 753, 754 332 233 . See also Hemopoiesis m:Hure spongy, 184 Bronchioles. 580, 580-583, 581 si nusoida I. See Sin usoids
Arthritis, J 82 pe rivitelli ne, 739 131ood filtrat ion, by spleen, 385-38 7 mem brane (intra membranous), 194 Bronchus (bronchi), 579-580, 580 C3pillary epi thel ium, 38 1- 382, 382
gouty (gout), 182 physiologic gastric mucosal, 484 Blood smear tech nique, 2 I 6. 216- 2 17 overview, 180- 181 Bronchus-associated lymphatic tissue Ca pi lla r)' sphincter, 340, 340
rheumatoid , 182 placenta l, 752-753, 753 Blood supply ph ysiologic fu nctions, 1 81, 20 1 (BALT), 374, 578 Capsule
Artifacts, of rourine fi xation, 455, 455 selective permeability, of elastic arteries, of ad renal glands, 661- 662, 664, 665 short, 181, 182 Brown adipose tissue, 160-J 6 1, I 6 1 Bowman's, 607, 609- 610, 610, 61 I, 614,
Arylsulfatase, 223, 244 331-332 of bone, 184-1 85, 185 spongy, 206-207/J Bruch's membrane, 798- 799 6 14
Aspartate, 29 1 Ba rs, terminal, 96, 96-97 of chorionic villi, 752 Bone cavities, 183 Brunner's (submucosal ) glands, 499-500, of hy:1linc ground substance (territo rial
Astral microtubules, 69 Basa l bodies, 58- 59, 92, 94 of ear, 835-836, 836 Bone cells, 186-192. See also Bone tissue 500 matrix), 166, 166
84o furb /llrt<X 84 7
Capsule (continued) of adrenal medulla, 662-665, 664, 665b M, of small intestine, 498, 509b Cell body Chemical synapses, 289. See also Neuro- eye
inrem al and externa l o f m uscle fibers, 260, a dven titial, 240-2.4 1, 241. See also Peri- mast, 224-225 of neurons (perikaryon), 81, 286-287, tra nsm itters gla ucoma, 799b
260 cytes mastoid :1ir, 824 287,288 Chemotaxis, 222 retinal d etachment, 80 1b
lens, 807-808 am ine precursor uptake a nd decarbo xyla- matrix, of hair fo llicle, 413 response to in jury, 314, 314 Ch iasmata, 71, 72 fema le rep roductive system
of lymph node, 374 tion (APUD), 489b Merkel's, 410-411 , 411 of sensory neurons, 303-304, 306-307 Ch ief cells, Pap smear, 757b
renal, 604, 694 anterior horn (ventral motor neurons), 306 of mononuclear phagocytotic system, 144t Cell cycle, 68-72, 69 of gastric gland, 484, 485, placenta ar birth, 755b
splenic, 382, 384 of a nterior pitui tary, 648t mucous, 575-576, 578 meiosis, 62, 69- 73, 70 of parathyroid (p rincipal), 659-660, 660 polycystic ovarian disease, 735b
Tenon's, 795 antigen-presenting, 144, 366-368, 367, mucous neck, 484 mitosis, 68-69, 70, 71 Cho leca lciferol. See Vitamin D immune system, acqu ired immu-
Carboh)drate digestion, 502- 503b 368, 408,408-410,410 M iiller's, 800, 804 Cell death, 72-75 Cholecystokinin (CCK), 4 88t, 555 nodefi ciency syndrome (AlDS),
Cardia, gastric, 480, 481 argentaffin, 486-487 multipoten tiallymphoid stem (CFU-Ls), disorders as compared with cell di vision, Cholesterol, 534, 548, 668b 367b
Cardiac glands, o f stomach, 487 argyrophil , 486-487 378 72, 73 C holinergic nem o tra nsmitters, 269b integumental")' system
Ca rdiac muscle, 262, 262-265, 276- 277p, B. See B lymphocytes (B cells) myoepi thelia l, 4 '18, 455-456, 458 programmed. See Apo ptosis Cho linergic vs. adrenergic receptors, 29 1 sk in repair, 42 1
278-279p band (stab), 238 myoid, 271 Cell di vision, disorders as compared w ith cell C hondroclasts, l7l swearing and disease, 4 19b
injury a nd repair, 265 basal, of respiratory mucosa, 571, o f nasal epithelium, 570-571 dea th, 72, 73 Chond rocytes, '164, 166-'167, 167 kid neys
Purki nje fibers, 278-279p 572-573, 576 narural killer (NK), 226, 22 8, 35 8, 365 Cell loss, disorders o f, 72, 73 Chondroitin sulfa te, 165 hormona l regulation of duct func tion,
structure, 262- 265, 263, 264 blood. See also specific cell types; Blood; nerve. See also Neurons a11d specific types Cell populations, ty pes of, 68 Chordae tendineae, 345 622b
Cardiovascular system, 326- 355. See also H emopo iesis rypes of, 8 1-84 Cell renewal, 68 Chorionic cavity, 749, 750 hypertension and renin-a ngiotensin-
Arterio le; Artery; Blood supply; bone, 186- 192 neurilemmal. See Schwa nn cells epithelial tissue, 116- 117 Cho rionic villi, 751-752, 752 aldosterone S)'Stem, 616b
Capillary; Vein brush, 570, 572, 576, 579 neuroglial, 8 I Cell replication, zone o f (small intestine), 501 Cho roid, 789, 789, 79 1, 798-799 urinalysis, 614b
arteries caveolated tu ft , 504 nucleus, 60-68 Cell-cell adhesion, epithelial, 96-104. See Choroid fiss ures, 791 liver, lipoproteins, 545b
aorra, 350-35 l p cell cycle, 68-72 olfactory, 57 1 also Epithelium, lateral doma in; Choroi d plexus, 301 male reproductive system
muscular, 352-353p centroacinar, 552, 553 o f o ral cavity Ju nction(s) Chromaffi n cells, 486-487, 662-665, 664, erection and erectile dysfunction,
arterioles, 354-355p CFU-GM, 192 basal, 440 Cell-med ia ted immune response, 357-358, 665b 712b
arteriovenous anastomoses (shunts), 340 C FU-M, 192 neu roepithelia l, 439-440 361 Chro matids, 62, 69 factors a ffecting spermatogenesis,
capilla ries, 338-340 chief, supporting, 440 Cell-to-extracellula r matrix adhesion, Chromatin, 60-62 694b
clinical correlations o f gastric gland, 484, 485, o rganelles o f 104-1 11 chromosomes, 61, 62 sperm-specific antigens and im mune re-
atherosclerosis, 337b of parathyroid, (pr incipal), 659-660, 660 membranou