Stratum Basale

Integumentary System
Elizabeth A. Mauldin, Jeanine Peters-Kennedy, in Jubb, Kennedy &
Palmer's Pathology of Domestic Animals: Volume 1 (Sixth Edition),
2016
Epidermis
The epidermis consists of a highly organized, continuously renewing
squamous epithelium that is stratified into functionally distinct
layers: stratum basale, stratum spinosum, stratum granulosum,
and stratum corneum. The keratinocytes of the epidermis undergo a
process of differentiation and proliferation that facilitates repair after
external trauma and yields a hydrophobic protective barrier, the
stratum corneum, which is continuously shed into the environment.
The steady state of the epidermis is a balance between cell
proliferation, differentiation, and desquamation. The renewal is
provided by a small population of slow-cycling stem cells (~10% of
cells) in the basal layer that undergo proliferation into transiently
amplifying cells. The amplified cells briefly proliferate then exit the cell
cycle and undergo terminal differentiation. In doing so, the cells march
toward the final product—fully-cornified anucleate keratinocytes
(corneocytes) that are shed into the environment. Within keratinocytes
as well as other epithelial cells, keratin, an intermediate filament,
forms the fibrous cytoskeleton that connects to desmosomes. Type I
(acidic) and type II (basic) keratin subunits assemble into
heterodimers through disulfide bonds. The type of keratin is
differentially expressed in layers of the epidermis as well as body site
(e.g., nonhaired skin of the pawpad and hair follicles). Keratin 5 (K5)
and keratin 14 (K14) form heterodimers in basal layer keratinocytes.
Commitment to differentiation in suprabasal keratinocytes is
associated with induction of keratins 1 (K1) and K10. Keratin 2 (K2) is
expressed in the stratum granulosum (SG).
The epidermis is a prime example of an adult tissue that undergoes
continual and rapid flux. The epidermis maintains homeostasis by
constant proliferation of a single inner (basal) layer of rapidly dividing
progeny of stem cells. As the basal keratinocytes withdraw from the
cell cycle, the transiently amplifying cells commit to terminally
differentiate, detaching from the basement membrane and initiating a
trek toward the skin surface.
•
The stratum basale (basal layer) is the deep germinative layer
of the epidermis and is composed of a single layer of cuboidal to
low columnar cells resting on the basement membrane zone.
The basal cells are attached to the underlying basement
membrane by hemidesmosomes and to adjacent and overlying
keratinocytes by desmosomes. Desmosomes are anchoring
structures that mediate adhesion between cells. They have a
complex structure that includes cadherin proteins of 2 types—
desmocollins and desmogleins. These proteins have different
isoforms, and they are differentially expressed in different layers
of the epidermis. Whereas basal cells express a pair of
desmogleins and desmocollins of simple epithelia, desmosomes
of the spinous layer express more varied isoforms. These
adhesion molecules are the immunologic target in several
blistering autoimmune diseases.
•
The stratum spinosum (prickle cell layer) is characterized
by prominent intercellular bridges that are the desmosomal
attachments between cells. The spinous appearance is due to
shrinkage artifact that occurs during tissue processing. The cells
are polyhedral to slightly flattened and are arranged in 1 or 2
layers in haired skin of dogs and cats and up to 4 layers in large
animals. This layer is much thicker in nonhaired skin and may be
up to 20 cells thick in the footpads and nasal planum.
•
The stratum granulosum is variably apparent on light
microscopy in haired skin and appears only 1-2 cells thick. In
nonhaired skin, this layer is more prominent, averaging 4-8
layers in thickness. The SG is composed of flattened cells with
shrunken nuclei and deeply basophilic keratohyaline granules.
The granules contain a precursor of filaggrin, a histidine-rich
 interfibrillary matrix protein that functions as a biological glue that
aggregates and aligns keratin filaments.
•
The stratum corneum (SC) is composed of >20 overlapping
layers of bland, polyhedral, anucleate cells sandwiched between
layers of lipid. This inconspicuous layer is an active and tough
hydrophobic barrier that regulates water movement into and out
of the skin. Much of the content of the SC is lost during biopsy
sampling, cutting, and processing. The basket-weave pattern is
an artifact resulting from loss of the lipid lamellae during
processing. Thickness varies by species and site, but it is
generally adapted to the degree of surface trauma or friction.
The SC is thickest in nonhaired areas, such as footpads and
nasal planum. Cornification (keratinization) is the process by
which keratinocytes undergo terminal differentiation from the
basal layer to the highly specialized corneocyte. In doing so,
keratinocytes must lose a large amount of water volume (from
70% water in nucleated layers to 15% in stratum corneum).
Minor injuries to the corneal layer from tape stripping or
applications of solvents will result in increased transepidermal
water loss.
Several steps must occur for cornification to proceed normally: (1)
bundling of keratin to establish the corneocyte core, (2) replacement
of the cell membrane with a thick cornified envelope, (3) formation of
lipid lamellar bilayers, and (4) active desquamation. Alterations in any
step can lead to hyperkeratosis, clinical scaling, and decreased barrier
function.
The lipid is derived via lipid-laden organelles, called lamellar
bodies (also called Odland bodies, membrane coating granules,
lamellar granules, keratinosomes), which are synthesized in the upper
stratum spinosum. At the junction of the SG and SC, the lamellar
bodies fuse with the cell membrane and expel their contents into the
intercellular space. Lamellar bodies contain glucosylceramides
(GlcCer), sphingomyelin, glycerophospholipids, and cholesterol
sulfate, along with many modifying enzymes. During this release,
enzymes modify polar “probarrier” lipids into nonpolar “barrier” lipids.
The final product in the lipid bilayers of the SC contains an equimolar
ratio of ceramides, cholesterol, and free fatty acids that together
create a hydrophobic seal.
The protein core of the corneocyte provides much of the structural
integrity of the stratum corneum. Profilaggrin, found in the
keratohyaline granules of the SG, undergoes processing (proteolysis,
dephosphorylation) to the active enzyme filaggrin, which cross-links
the cytoplasmic keratin filaments. Transglutaminases, calcium-
containing enzymes, are located within both the epidermis and hair
follicles. These proteins (in particular, transglutaminase 1) catalyze the
formation of the cornified envelope (CE) by cross-linking small
protein molecules (e.g., involucrin, loricrin, cystatin A) that replace the
cell membrane. The CE surrounds the protein core and provides a
mechanical barrier as well as a scaffold that organizes the
extracellular lipids into lamellar membranes. In the mature SC,
multiple layers of corneocytes are sandwiched between layers of lipid,
producing the so-called “mortar and bricks” analogy.
Corneodesmosomes (desmosomes retained in the SC) are
enzymatically cleaved, and keratin squames (corneocytes) are shed
into the environment.
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Approaches to the Development of Cosmetic Products to
Counter the Effects of Skin Aging
Gopinathan K. Menon, ... Robert Kalafsky, in Skin Aging Handbook,
2009
11.4 The Nucleated Layers of Epidermis
Often termed as the viable epidermis, it spans the three layers of
epidermis underneath the SC, which are called stratum basale (Figure
11.3), stratum spinosum and stratum granulosum. The viable
epidermis is what produces epidermal keratin, NMF and the barrier
lipids, proliferates to heal the wounds (following laser resurfacing,
cosmetic peels, etc.), and replaces the corneocytes that are lost
by desquamation. Cells of this layer also transport
water and glycerol through the aquaporins, receive and
transfer melanin from the melanocytes for photoprotection, house the
antigen presenting langerhans (sentinel) cells, produce anti-microbial
peptides, and secrete a variety of chemokines, growth factors, etc. for
cellular communication within the epidermis as well as with dermal
cells (fibroblasts, mast cells). This layer stimulates production of the
dermal matrix, or when appropriate, its degradation. Being avascular,
transport of nutrients within this layer is conducted by diffusion through
intercellular fluids, once they have passed the selective barrier of
the basement membrane separating epidermis from the
vascular dermis. Sensory nerve fibers do extend into the epidermal
compartment, and secrete trophic neuropeptides that
influence keratinocyte physiology, as well as play some roles in
dysfunctions associated with sensitive skin. Each and every aspect of
this tissue and its functions are potential targets for anti-aging
intervention, and a multitude of approaches have been used to
achieve these results.
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Figure 11.3.
Intrinsic aging leads to a decrease in keratinocyte cell proliferation and
thinning of the epidermis, as seen in histologic comparison between
sun-protected skin from young and aged (30). Other changes in aged
skin include flattening of dermal–epidermal junction (DEJ), loss of
dermal papillae, loss in dermal matrix proteins, and disorganization of
the fibrous network. An association between increased oxidative
stress and intrinsic aging in general has been highlighted (31), and it
is possible that chronologically aged epidermal cells have higher
oxidative stress than epidermal cells of younger individuals. Strategies
to counter oxidative stress or otherwise improve cell proliferation and
subsequent increase in viable epidermal thickness, (measurable with
histology), have been employed. They are achievable with several
actives such as AHAs, BHAs, retinoic acid/retinol, vitamin C, and
several phytochemicals such as pomegranate seed oil (32).
Application of large scale gene expression analysis, such
as sequential analysis of gene expression (SAGE) technology, has
provided valuable insight into the differential expression patterns of
genes in aged skin. Decreased expression of c-fos and IKBA (inhibitor
of NF-kappa B, a well known gene regulator) in aged skin correlates
with reduced sensitivity to mitotic stimuli, and increased expression of
NFkB, respectively (30). However, c-fos and c-jun (components of AP-
1 or Activator Protein 1) can be reactivated in cultured fibroblasts from
old donors (33), an indication that it is biologically possible to
reactivate genes that are down-regulated in aging.
Ingredients with known medicinal or health promoting effects are
tested in cultured human skin cells for their potential to increase or
decrease transcription of such genes, and if devoid of any potential
risks associated with topical use, are selected for further investigations
and, if viable, eventual use in cosmetics. For epidermal cells, actives
that enhance differentiation, synthesis of barrier lipids, anti-oxidant
enzymes, energy production, cellular nutrition, aquaporins, and
cellular communication are currently being identified using gene
expression analysis, and successfully brought to market. On the other
hand, over-activation of AP-1 by UV radiation has been found to
induce over-production of Matrix Metalloproteinases by the epidermis,
causing aging changes via degradation of the dermal matrix (34).
Inhibitors of MMPs, mostly botanically derived, have often been used
as part of an anti-aging strategy. Retinoids, including retinol, prevents
the over stimulation of AP-1 by UV, one of the hallmarks of its anti-
aging effects (34, 35).
Another site of aging within the epidermis is DNA, because of the
damage caused by UV radiation (36, 37). UVB is absorbed by the
double bond in pyrimidine bases in DNA, opening the bond so they
can react with adjacent pyrimidine bases, resulting in a tight four
member ring. These genetic lesions in DNA are corrected quickly by a
cellular process termed “nucleotide excision repair” by DNA repair
enzymes. DNA repair enzymes from algae have been reported to be
effective (36) and several actives and delivery systems targeted to this
endpoint have been tested in vivo showing positive results (38, 39).
Prevention of UV-induced pyramidine dimer formation in epidermis by
green tea polyphenols, in addition to anti-inflammatory and antioxidant
functions of this popular cosmetic ingredient, has also been reported
(40, 41).
UV radiation also leads to lipid peroxidation and generation of reactive
oxygen species, which have been postulated as leading to
mitochondrial damage and aging (42). A multitude of antioxidants,
both enzymatic and non-enzymatic, such as superoxide
dismutase, catalase, glutathione oxidase, ascorbic acid and their
esters, vitamin E, and alpha lipoic acid have also been employed,
often with documented efficacy in in vitro and in vivo test conditions.
Another theory of aging, the telomere shortening hypothesis of aging,
follows the oxidative stress theory. Telomeres, located at the ends of
chromosomes, shorten with subsequent cell divisions, and when the
telomeric DNA reaches a critically short length, it leads to cell cycle
arrest and senescence (43), observed in human cells during the aging
process (44). Introducing telomerase, an enzyme that repairs telomere
damage, into cells, has been shown to extend the life span of human
cells (45). An extract of the fruit of Terminalia chibula, which shows
significant inhibition of oxidative stress as well as the age-dependant
shortening of the telomeric DNA in cultured cells, has potential as an
anti-aging ingredient (46).
One of the most visible signs of photoaging is pigmentary changes,
such as focal hyper-pigmentation or uneven pigmentation of the facial
skin. Among Asians and other darker phototypes (47),
dyspigmentation is a more common denominator of aging
than wrinkles are, until the middle of the fourth decade of life (48).
Skin lighteners are highly popular in Asia and Latin America, and
provide a desirable anti-aging benefit by decreasing the appearance
of uneven pigmentation. Skin lightening strategies have traditionally
utilized hydroquinone, but this active has fallen out of favor due to
safety and regulatory issues in several countries (Japan, European
Union). The classical strategy is to use plant-
derived tyrosinase inhibitors to reduce the activity of tyrosinase, the
crucial enzyme in the biochemical pathway of melanin synthesis.
However, the use of plant derived tyrosinase inhibitors (bearberry
extract, mulberry extract, kojic acid, etc.) alone as skin lightening
agents is no longer considered adequate, due to market trends
and consumer demands for increased efficacy. Hence, a whole slew
of new ingredients, such as cococin, thiodipropionic acid
(49), endothelin antagonists (which block keratinocyte-melanocyte
interaction for increased pigment production and transfer to
epidermis), protease inhibitors from soy (50), peptides, melanocyte
stimulating hormone antagonists, and small interference RNAs that
silence the messenger RNA for tyrosinase (51) have appeared in the
cosmetic field. Again, use of sunscreens as a general anti-aging (skin
lightening in darker phototypes) strategy has gained much ground
around the world. The increasing use of UVA blockers, along with
traditional UVB blockers, by consumers attests to the high level of
consumer awareness of extrinsic aging and the role of UVA radiation
in dermal damage.
As to the changes in immune sentinel cells, the number or activity
of Langerhans cells in the epidermal compartment is known to decline
somewhat in chronological aging (52), and especially so in the photo-
aged skin (53). Products aimed at boosting the skin's immune function
are claimed in a few anti-aging products but, by and large,
the immunocompetence of skin is not a widely addressed facet of anti-
aging cosmetics.
Paracellular Channel in Organ System

Jianghui Hou, in The Paracellular Channel, 2019

7.1.1.1 Epidermal Tight Junction
The epidermis is a multilayered stratified epithelium made of several
cell layers (Fig. 7.1). The innermost basal layer, stratum basale (SB),
consists in undifferentiated keratinocytes, stem cells, melanocytes,
and Merkel cells. On top of this layer resides the spinous layer,
stratum spinosum (SS). The subsequent granular layer, stratum
granulosum (SG), consists of 3–5 cell layers. Tight junctions (TJs) are
found in the second layer of stratum granulosum (SG2) (Yoshida
et al., 2013). The outermost layer, stratum corneum (SC), consists in
corneocytes, that are, dead cells, and intercellular lipids. The primary
role of the epidermis is a tissue barrier against pathogen invasion from
the external environment. While SC was previously considered to be
the only epidermal barrier, it is until recently that the importance of TJ
in epidermal barrier function has been recognized. The expression
profiles of the claudin proteins reflect the complexity of the epidermis
(Table 7.1). Among the claudins analyzed so far, claudin-1, -7, and -
12 are found in all living layers from SB to SG. Because TJ is made
only by the SG2 cells, the claudin expression in other cell layers is
found in the plasma membrane (Brandner, McIntyre, Kief,
Wladykowski, & Moll, 2003; Furuse et al., 2002; Troy, Rahbar,
Arabzadeh, Cheung, & Turksen, 2005). A recent study elegantly
shows how TJs are maintained during cell migration from the SG3 to
the SG2 layer. When an epidermal cell moves up from a lower layer to
SG2, it forms new TJs that are situated beneath the existing TJs in
SG2. This transient twin TJ structure resembles a double-edged
polygon, termed Kelvin’s tetrakaidecahedron. As the newly formed
TJs mature, the existing TJs disappear over time (Fig. 7.2) (Yokouchi
et al., 2016).
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Figure 7.1. Schematic diagram of the epidermis.
The different strata of the skin epidermis are indicated on the left. The granular layer is
composed of three epithelial cell layers (SG1–SG3). TJs are found in the second layer
(SG2). The outer layer of the skin, termed as stratum corneum, was previously
considered to be the only epidermal barrier.
(Reproduced with permission from Tsuruta, D., Green, K.J., Getsios, S., & Jones,
J.C. (2002). The barrier function of skin: how to keep a tight lid on water loss. Trends in
Cell Biology, 12, 355–357)
Table 7.1. Claudin Gene Expression Profiles in the Epidermis

Lower Upper
Genes SB SS SS SG References
Claudin- Furuse et al. (2002); Haftek et al.
+ + + +
1 (2011); Igawa et al. (2011)
Claudin- Telgenhoff, Ramsay, Hilz, Slusarewicz,
− − − +
2 & Shroot (2008)
Claudin-
− − − + Watson et al. (2007)
3
Brandner et al. (2003); Furuse et al.
Claudin-
− − + + (2002); Morita, Tsukita, & Miyachi,
4
(2004)
Claudin- Peltonen, Riehokainen, Pummi, &
− − − +
5 Peltonen (2007)
Claudin-
− − + + Turksen & Troy (2002)
6
 Lower Upper
Genes SB SS SS SG References
Claudin- Brandner, Kief, Wladykowski, Houdek,
+ + + +
7 & Moll, (2006); Kirschner et al. (2009)
Claudin-
− − − + Troy et al. (2005)
11
Claudin-
+ + + + Troy et al. (2005)
12
Claudin-
− − − + Brandner et al. (2003)
17
Claudin-
− − + + Troy et al. (2005)
18
SB, Stratum basale; SG, stratum granulosum; SS, stratum spinosum.

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Figure 7.2. TJ biogenesis in the epidermis.
Subcellular localization of bicellular and tricellular TJ components (ZO-1 and tricellulin)
on single- and double-edged polygons. Yellow arrowheads, edges of the exterior,
exisiting polygon; white arrows, edges of the interior, newly formed polygon; red
arrowheads, vertical edges connecting the vertices of double-edged polygons; yellow
arrows, vertices of single-edged polygons. Bar: 10 μm.
(Reproduced with permission from Yokouchi, M., Atsugi, T., Logtestijn, M.V., Tanaka,
R.J., Kajimura, M., Suematsu, M., Furuse, M., Amagai, M., & Kubo, A. (2016).
Epidermal cell turnover across tight junctions based on Kelvin’s tetrakaidecahedron cell
shape. eLife, 5, e19593)
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Integumentary System
Christine L. Theoret, Ted S. Stashak, in Equine Emergencies (Fourth
Edition), 2014
Epidermis
•
Epidermis is made up of five stratified squamous cell layers (Fig.
19-1).
•
Stratum basale (base layer) has two nucleated cell types:
○
Keratinocytes constantly reproduce and push upward toward the
surface to replace cells that have sloughed off the surface.
○
Melanocytes are responsible for producing the melanin that
gives hair and skin their color.
•
Stratum spinosum (prickle-cell layer): Cells in this layer are
nucleated and become activated to reproduce when the outer
epidermal layers are stripped off.
•
Stratum granulosum (granular cell layer): The cells in this layer
are in the process of dying, with nuclei that are shrinking and
undergoing chromatolysis.
•
Stratum lucidum (clear cell layer): This layer is composed of
nonnucleated keratinized cells and is only present in hairless
areas of the body.
•
Stratum corneum (horny cell layer): This layer is composed of
fully keratinized dead cells that are constantly being shed from
the surface as scales. This layer forms a barrier that protects the
 underlying tissue from irritation, bacterial invasion, and noxious
substances, as well as from fluid and electrolyte losses.

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Figure 19-1. The layers of the epidermis.
(Modified from Stashak TS. In Jennings PB, editor: The practice of large animal
surgery, Philadelphia, 1984, Saunders.)
•
Nourishment is by diffusion of fluids from the capillary beds in the
dermis.
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Toxicologic pathology of the reproductive system
Pralhad Wangikar, ... Subrahmanyam Vangala, in Reproductive and
Developmental Toxicology, 2011
Vagina

During diestrus vaginal mucosa shows three to seven layers of

squamous cells (stratum germinativum). The stratum germinativum
shows an inner layer of stratum basale consisting of a single layer of
columnar cells and outer stratum spinosum multiple layers of
polygonal and plump cells reflecting early mucification. Few infiltrated
leucocytes are seen in the epithelium. The beginning of proestrus is
characterized by formation of stratum granulosum consisting of
flattened epithelial cells which contain keratohyalin granules. There
are numerous mitotic figures seen throughout the vaginal epithelium.
Progressively there is formation of a superficial mucoid layer which
consists of many layers of cuboidal cells with mucin-containing
cytoplasmic vacuoles. There is the formation of an intensely
eosinophilic band of stratum corneum which at the end of the
proestrus shows fully cornified epithelial cells along with superfitial
mucoid layer.
During estrus no mitotic figures are seen and progressive shedding of
the superficial mucoid and cornified layer reduces the height of
epithelium and produces cell debris in the lumen. There is progressive
infiltration of leucocytes at this stage. During metestrus there is
continued desquamation of the remaining cornified epithelium along
with loss of stratum granulosum and upper germinativum. A prominent
polymorphonuclear cell infiltration is present in superficial epithelial
cell layers. Towards the end of metestrus the epithelium reaches its
lowest level.
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Diseases of the Integumentary System
Jerry R. Roberson, ... D.G. Pugh, in Sheep and Goat Medicine
(Second Edition), 2012
The epidermis is composed of five layers—from outermost to
innermost, stratum corneum, stratum lucidum, stratum
granulosum, stratum spinosum, and stratum basale. The stratum
basale produces new cells that continuously move up to replace the
sloughing cells of the stratum corneum. The melanocytes of the
stratum basale and hair follicles are primarily responsible for the color
of the hair coat. All melanins arise from a common metabolic pathway
that is catalyzed by a copper-containing enzyme. One of the signs
of copper deficiency, therefore, is a lighter-than-normal color of the
hair coat. Besides the obvious physical barrier presented by the
epidermis and hair or wool, chemical and microbial barriers to
infection also are recognized: The secretion produced by the sweat
and sebaceous glands has antimicrobial properties. Included within
this secretion are fatty acids, inorganic salts, interferon, transferrin,
complement, and immunoglobulins. Increased hydration of the skin
greatly increases microbial populations. Normal skin flora can inhibit
colonization of other potential pathogens. However, some skin
pathogens also may be components of the normal flora. For example,
dermatophytes and Staphylococcus aureus can be recovered from
clinically normal mammals that do not develop clinical disease.
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Systems Toxicologic Pathology
Kelly L. Diegel, ... Zbigniew W. Wojcinski, in Haschek and
Rousseaux's Handbook of Toxicologic Pathology (Third Edition), 2013
Non-Proliferative Lesions of the Epidermis
Epidermal atrophy is characterized by thinning of all non-cornified
epidermal layers with a corresponding decrease in
nucleated keratinocytes, such that the distinction between stratum
basale, stratum spinosum, and stratum granulosum may no longer be
apparent. Substances that decrease normal keratinocyte proliferation
and metabolic activity, such as topical corticosteroids, are a common
cause of epidermal atrophy.
Epidermal erosion and ulceration is characterized by loss of superficial
epidermal layers (erosion) or complete loss of the epidermis with
disruption of the epidermal basement membrane (ulceration).
Erosions are always due to superficial epidermal trauma, and are
most commonly associated with trauma from scratching. Ulceration is
also often caused by superficial epidermal trauma, but may also be
the result of toxicity or a necrotizing dermatitis. Ulceration due to
toxicity needs to be differentiated from ulcerative dermatitis, which
occurs spontaneously in certain strains of mice and rats, most
commonly in the C57BL/6 mouse.
Epidermal necrosis can be classified as either single cell or full
thickness necrosis. Epidermal necrosis is a hallmark feature
of drug hypersensitivity reactions or drug eruptions, where it can occur
as single cell necrosis, and is termed erythema multiforme, or as full
thickness epidermal necrosis, where it is termed toxic epidermal
necrolysis (TEN). Single cell necrosis of keratinocytes may be further
subdivided into apoptosis, or programmed cell death,
and dyskeratosis, which is the occurrence of terminal keratinization of
individual keratinocytes that has not occurred as part of the orderly
process of epidermal keratinization; apoptosis cannot be differentiated
from dyskeratosis on H&E stained sections. Apoptotic keratinocytes in
UV light-exposed epidermis are often referred to as “sunburn cells.”
Vesicular change refers to intracellular edema of keratinocytes, and is
characterized by increased size and pallor of keratinocytes with
peripheral displacement of the nucleus. In the stratum basale,
synonyms are hydropic degeneration and vacuolar degeneration,
while in the suprabasal epidermis it is often referred to as ballooning
degeneration. If vesicular change is severe, keratinocytes
may rupture and form intraepidermal vesicles.
In contrast to vesicular changes, spongiosis refers to intercellular
edema between epidermal keratinocytes and is characterized by
widened intercellular spaces with accentuation of desmosomes.
Severe epidermal spongiosis may lead to rupture of intercellular
desmosomes and the formation of intraepidermal vesicles. Spongiosis
is a common feature of skin inflammation.
A vesicle is an intra- or sub-epidermal cavity or cleft filled with fluid,
and is also referred to as a bulla. It occurs following loss of cohesion
between epidermal keratinocytes or between epidermis and dermis,
resulting in the formation of a fluid-filled cavity. Vesicles can result
from immune-mediated injury (e.g., acantholysis) or as a result of
epidermal or dermal edema as a consequence of poxvirus infection,
frictional trauma, or burns. Intraepidermal vesicles may develop
secondary to severe spongiosis and/or severe vesicular change with
rupture of keratinocytes, and are also termed reticular degeneration.
Vesicles that are located between the stratum basale and the
underlying mesenchyme are termed clefts.
A pustule, also referred to as a microabscess, is a focal intraepidermal
accumulation of leukocytes, and is commonly found as a feature of
generalized skin inflammation. In contrast, when leukocytes are
diffusely rather than focally infiltrating the epidermis, it is referred to
as exocytosis. Pustules may be further classified according to the
predominant leukocyte population (neutrophilic, eosinophilic, or
lymphocytic). Pustules that are filled with isolated rounded
keratinocytes with a normal nucleus are referred to as acantholytic
pustules. A predominantly neutrophilic pustule in a CD45RBHi SCID
mouse model of psoriasis is illustrated in Figure 55.11.

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FIGURE 55.11. A predominantly neutrophilic pustule within the hyperplastic epidermis
of a CD45RBHi SCID mouse model of psoriasis.
Hyperkeratosis refers to an increase in the thickness of the stratum
corneum, and is classified as either orthokeratotic, composed of
normal anucleate corneocytes, or parakeratotic, composed of
nucleated corneocytes. Hyperkeratosis frequently
accompanies epidermal hyperplasia, and is often associated with
chronic epidermal irritation. When the hyperkeratotic stratum corneum
contains leukocytes or a proteinaceous exudate, it is commonly
referred to as a crust.
A squamous cell cyst is an intradermal cyst lined by a wall composed
of orderly stratified squamous epithelium with a lumen filled by
concentrically arranged lamellar keratin. Squamous cell cysts can
spontaneously occur in mice, particularly in the B6C3F1 strain.
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Vitamins
Annette Zeyner, Patricia A Harris, in Equine Applied and Clinical
Nutrition, 2013
Effects of deficiency and excess
Deficiency
Deficiency of biotin in other species results in poor quality of skin, coat
and hoof or claw horn. Biotin deficiency may slow mitosis in
the stratum basale meaning that the tips of the dermal papillae in the
coronary region become more susceptible to physical damage,
resulting in hemorrhage and bleeding into the horn (Kempson 2005).
In pigs, experimentally induced biotin deficiency caused poor claw
horn (Geyer 2005). As above, poor biotin status in horses may be one
but not the only reason for reduced hoof quality.
Excess
The danger of an excess is not very high because surplus biotin is
excreted in the urine. In rats, subcutaneous injection of extremely high
doses (50 to 100 mg biotin/kg BW) caused fetal resorption (cited
from NRC 2007). Poultry and pigs tolerate at least 10-fold the dietary
biotin requirement without adverse signs (NRC 2007). In horses,
detrimental effects of high biotin doses have not been described.
Currently no recommended upper daily intake limit has been set for
biotin, but as a guide horses should receive no more than
12 mg/100 kg BW/d.
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Parasitic Diseases
Holly N. Burr, ... Neil S. Lipman, in The Laboratory Rabbit, Guinea Pig,
Hamster, and Other Rodents, 2012
Pathology
D. criceti is generally of low to no pathogenicity. Microscopically, D.
criceti mites are found in epidermal pits which extend from the
epidermal surface to the stratum basale (stratum germinativum), rarely
entering into the dermis. All life stages of D. criceti lie within the pits
with their mouth parts facing towards the dermis. They are not found
within normal hair follicles.
D. aurati can distort the normal morphology of hair follicles. Normal-
appearing or dilated hair follicles may contain up to five mites of either
gender along with debris (Nutting, 1961). Hair shafts from infected hair
follicles are variably lost. D. aurati causes little inflammation, but
the stratum corneum may show mild to moderate hyperkeratosis
(Estes et al., 1971).
D. cricetuli also dilate the lumen of hair follicles, as up to six mites may
live within a single follicle (Hurley and Desch, 1994). Mite
opisthosomas have been observed to protrude from hair follicles
(Hurley and Desch, 1994). Histopathology may include
hyperkeratosis, parakeratosis, epidermal hyperplasia with lengthening
of the rete pegs, and some areas of suppurative inflammation
(Hankenson and Van Hoosier Jr., 2007; Hurley et al., 1992).
Pathologic effects are not reported for D. sinocricetuli.
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Proenkephalin-Derived Peptides
Patricia J. McLaughlin, in Handbook of Biologically Active Peptides
(Second Edition), 2013
Peptide Location
The subcellular distribution of methionine enkephalin in epithelium
reveals that this neuropeptide, and its receptor OGFr, colocalize on
the paranuclear cytoplasm and in the nuclei of keratinocytes in
the stratum basale. Immunoelectron microscopic studies with 5- and
10-nm gold particles show that OGF is not always bound to the
 OGFr,32 which in turn is associated with the outer nuclear
envelope (see above for more discussion of OGFr transport).
Because of the ubiquitous nature of the presence of OGF in normal
and neoplastic cells, human and vertebrate, as well as the quickness
of effect observed after addition of OGF, the passage of OGF into
cells was studied with OGF labeled with 5,6-tetramethylrhodamine
(RhoOGF). In a cell line that is devoid of classical opioid receptors,
COS-7 (African green monkey kidney cells), OGF internalization is
temperature dependent. Within 15 min of adding RhoOGF to culture, it
is detected in the cytoplasm of cells incubated at 37 °C, and within the
nucleus after 30 min. No movement is detected at 4 °C. OGF enters
cells by active transport with internalization being dependent on
clathrin-mediated endocytosis.5
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