C HAPTER 2 Inflammation I. INT RODUCT ION Infla mmati o n is a vascular resp ons e to injur y. A .

Processes
y y

Exu dation of fl uid fro m v ess els Attraction of leu ko cytes to th e inj ur y. L eukoc yt es eng ul f and d estro y bacteria, tissue debris, an d other particulat e mat erial.

y y y

Acti vatio n of chemical mediat ors Prot eol yti c d egr ad ation of extra cell ular d eb ri s R estoration of injur ed tissue to its nor mal struct ur e and fun cti on. This is limited b y th e ext ent o f tissue destr uction a nd b y t he r eg en erati ve capa cit y of the sp eci fi c tissue.

B . C ardinal signs
y y

Rubor (red ness caused b y dilation of v essels) Dolo r (pain d ue t o incr eas ed press ur e ex ert ed b y the accumulatio n o f int erstitial fluid an d to medi ators su ch as b ra d yki ni n)

y y y

Calor (heat caus ed b y i n cr eas ed blood flo w) T umor (swelling due to an extra vascular accumulation o f flui d) Functio la esa (loss of fun cti o n)

C . C au ses
y y y y y y

Infectio n Trau ma Ph ysi cal inju r y fr om t her mal extremes or fr om i onizi n g ra diation C hemical injur y I mmun ol ogi c inj ur y Tissue d eat h. In flammat or y chang es occu r in viab l e tissue adjacent to necr otic ar eas.

II. ACUT E INFL AMM AT ION A . A dh esion mo lecules

y

General considerations

Adh esion mol ecul es p lay an i mp ortant r ol e in acut e infla mmati on.

The y ar e di vi d ed into thr ee famili es: sel ectins, immu nogl ob ulin- famil y ad hesion p r ot eins, an d integrins.

Selectins
o

Thes e mol ecul es are in duced b y t he cyt okin es int erl euki n-1 (IL-1) a nd tumor necr osis factor (TNF).

L -selectins are expr essed o n neutr ophils and bind to endothelial muci n-like mol ecules su ch as Gl yC am-1.

E - an d P-selectins are expr ess ed o n endot hel ial cells and bind to oligosa cchari des such as sial yl -L ewis X on the sur face o f leuko cyt es. P -selectins, stor ed in end oth elial W eib el-Palad e bo di es and platel et alp ha gra nul es, relo cat e to the plasma memb ra ne aft er stimulation b y medi ators su ch as hista min e and thr ombin.

Immunog lobu lin-family adhesion proteins

o

Int er cellular adh esio n mol ecules 1 and 2 (IC AM-1 and IC AM2) are exp ressed o n end othelial cells and bin d to integri n mol ecules on leu koc yt es.

Vascular cell ad hesi on mol ecul es (VC AMs) similarl y are expr ess ed on en dothelial cells and b ind to int egri n mol ecul es on leu ko cytes.

Integ rins. Exampl es in cl u de leu koc yt e LFA- 1, MAC-1, and VLA-4, whi ch b ind to en dothelial i mmu no glob ulin - famil y adh esi on prot ei ns.

B . Vasoa ctive chang es

y

Thes e cha ng es begi n wit h a b rief p eriod of vasoconstricti on, foll owed shortl y b y dilation o f art eriol es, cap illaries, and post cap illar y venul es.

The r esultant mar ked incr ease in bloo d flow t o the affect ed area is cli ni call y ma ni fest b y r ed ness and incr eas ed wa r mt h of the a ffect ed area.

C . Increased ca pilla ry permeability

y

This results in lea ka ge of p rot ein aceo us flui d, whi ch caus es edema.

C aus es includ e endothelial cha ng es that va r y fr om contr a ctio n of endothelial cells in postcap illar y v en ul es, wit h wi d eni ng o f int er en doth elial gaps, to major endot helial damag e in volvi ng art eriol es, capillari es, an d v enul es.

D. Typ es o f inflamma tory cells

y

Neu trop hils are the most promi nent in flamm ator y cells in foci of acute infl a mmation durin g th e first 24 ho urs. I mp ortant ca us es o f neutrophilia (incr eased n eutr op hils in the p eriph eral bloo d) incl ud e bacterial in fections a nd oth er caus es o f acut e infla mmati on, such as infar cti o n. Th e earl y rel eas e o f neutrop hils into the perip heral b lood in a cut e infl a mmation is fr om the b o ne ma rr ow post mit otic r es erv e po ol. Ther e is oft en an incr ease in th e p rop ort ion of less mat ur e cells such as ba nd neutrophils (Figur e 2-1).

Aft er 2 3 da ys, neutrop hils ar e rep laced mai nl y b y monocytesma crop hag es, whi ch ar e cap abl e of eng ul fing larger particl es, ar e lon ger-lived, and ar e capabl e of di vidi n g and proli ferati ng withi n th e infla med tissue. I mp ortant caus es o f monocyt osis (i.e. , incr eased nu mb er o f mo noc yt es in the p eriph eral blood) incl ud e tub er culosis, bru cell osis, typ hus, and sal monella infection.

L ymphocy tes are the most promi nent in flam mator y cells in man y viral infecti o ns an d, alon g with mon ocyt es -macr oph ag es and p las ma cells, are the most promi nent cells in chro ni c infla mmati on. L ymphocy tosis (i.e. , an increased nu mb er o f l ymp ho cyt es in th e perip h er al bloo d) is most oft en ca us ed b y vira l infecti ons su ch as influ en za, mu mp s, rub ella, and infectio us mo no nucl eosis and certain bacterial in fections such as whooping co ug h a nd tub er cul osis.

E osinophils are the pr edo min ant inflam mat or y cells in aller gic r ea ctio ns a nd p ar asitic infestations. The most imp ortant ca us es o f eosinoph ilia incl ud e allergi es such as asthma, hay fev er, and hi ves and also parasitic infections. Oth er causes include p ol ya rt eritis no dosa an d Hod gki n l ymp ho ma.

M ast cells and ba sophils are sources o f histami ne. I mp ortant caus es of ba sophilia includ e chr oni c m yel og en ous l euk emi a and ot h er m yel opr oli fer ativ e diseases.

E . C ellular respo nse o f leuk ocytes

y

E mig ra tion is the passage of infla mmat or y l euk ocyt es b et ween th e endothelial cells into the adjacent int erstitial tissue. B efor e emig ration, cir culati ng l eukoc yt es fr o m t h e central b lood fl ow move towar d the endothelial sur fa ce.
o

M argin ation occurs as leu ko cytes localiz e to the out er mar gi n of th e b lood flow adjacent to th e v as cular endotheli um.

o o

Pav emen tin g occurs as leuko cytes line the en doth elial sur face. Rolling (or tumbling) is mediat ed b y t he action of endothelial sel ecti ns loos el y bi n di ng to leuk ocyt es, p rodu ci n g a chara ct eristic "r olling" mov ement of th e l euk oc yt es alon g the endothelial sur fa ce.

Adhesion occurs as leuko cytes ad here to the end oth elial sur face a nd is medi ated b y the i nt era ctio n o f int egri ns on leuko cyt es bindi ng to immuno gl ob ulin- famil y adh esion prot ei ns on endotheli um.

T ra nsmig ration is the mo vement o f l eu koc yt es acr oss th e endotheli um an d is mediat ed b y platel et en dot helial cell adhesi on mol ecul e-1 (PE CAM-1) on b oth l euk oc yt es and endotheli um.

Chemota xis
o

This is the pr o cess b y which l euko cyt es are at tra cted to a nd move t owar d a n injur y.

C hemotaxis and ot h er for ms of cellular mi gration ar e meas ur ed in an in vitr o syst em (Bo yd en chamb er techniq ue) that assesses the migratio n o f cells fro m a n upp er chamb er thr ough a mi cr op or ous memb ran e t o a lower ch amb er fil led wit h a chemo attracta nt.

This p ro cess is mediat ed b y diffusib l e chemi cal agents (Table 2 -1); movemen t of l eu ko cyt es occurs alon g a ch emi cal gra di ent.

Chemota ctic fact o rs for neutrophils, produced at the site of injur y, in clud e:
 

Prod ucts fr o m b act eria C ompl ement comp o nents, esp eciall y C 5a

Ar achido ni c aci d metab olites, esp ecially l eukotriene B 4 (LTB 4 ), hydr ox yei cosat etra en oi c aci d (HETE), and kallikr ei n

Pha gocytosis
o

Definition. Phag ocyt osis is the ing estion of p articulat e mat erial ( e.g., tissue debris, living or d ea d b act eria, other for ei gn cells) b y p hag oc yti c cells. Neu trop hils and monocytes-ma crop hag es are the most i mp ortant phag oc yti c cells.

Anatomic cha nges



Phag ocyt osis is chara cterized morp hol ogi cally b y i nt er nalization of t he atta ch ed op so niz ed particl e b y ps eu dop odial ext ensions fr om th e sur face o f the l eu koc yt e, whi ch encl os e th e for ei gn p arti cle, fo r mi n g an int er nalized v esi cl e, the pha gosome.

Phag os omes fus e with cyt op lasmi c l ysos omes and form pha golysosomes.

Phag ol ys osome for mation is associat ed with leuk ocyti c degr anulati on.

Opsonization


This p ro cess fa cilitates p ha goc yt osis. It is the coatin g of p arti culat e mat erial b y s ub stances r efer r ed to as op so ni ns, whi ch i mmobilize th e p arti cl es on the sur fa ce of th e p ha goc yt e.

The most imp orta nt ops oni ns ar e immunoglo bulin G (IgG) sub types and C3b, a co mp l ement co mp onent.

Fragments ops onized b y I gG are bo un d to pha go cyti c cells b y cell-sur face r ecepto rs for th e F c p ortion of th e IgG mol ecul e.

Fragments ops onized b y C 3b bind to cell ular r ecept ors for C 3b .

Intra cellular microbia l killing is mediat ed withi n p ha go cytic cells b y ox ygen - dep end ent and ox yg en-ind ep en dent mecha nis ms.
o

Oxyg en -dependent microbial killing is the most i mportant intra cell ular mi cr ob icidal pro cess.

Phag ocyt osis initiates acti vit y of th e h ex os e monop h osphat e sh unt, causi ng an oxi dati v e b urst an d supp l yi ng el ectr ons to an NADPH oxidase i n th e phag osomal memb ra ne.

One of the pro ducts of th e N ADPH oxid as e r ea ctio n is sup er oxide ani on (O 2 - ), whi ch is furt her co nv ert ed to h ydr og en peroxi d e (H 2 O 2 ) b y dis mutatio n. H 2 O 2 ma y b e furt her co nv ert ed to th e acti vated h yd r ox yl radi cal (OH).

In th e p r es en ce of th e l euko cyt e enz yme m yel op er oxidas e an d a halide i on su ch as chl ori de, H 2 O 2 oxidiz es mi cr obial p rot ei ns an d disr upts cell walls. This entir e process is referr ed t o as the my eloperoxidase-ha lide sy stem of bacterial killing.

Oxyg en -independent microbial killing



This p ro cess is much less effe ctiv e than ox yg endep endent mi crobial killing.

This p ro cess is mediat ed b y p rot ei ns, such as l ys oz yme, lact oferrin, maj or basic pr ot ein o f eosi nop hils, and cationi c p rot ei ns, such as b act eri cidal permeab ilityincr easing p rot ei n and d efensi ns. table 2-1 Chemotactic Factors

Factor Formylated peptides C5a HETE, LTB4 Kallikrein

Description Bacterial products of Escherichia coli

Chemotactic For Neutrophils

Activated complement component Leukotrienes

Neutrophils Neutrophils

Product of factor XIIa-mediated conversion of prekallikrein Plasma protein

Neutrophils

Fibrinogen

Neutrophils

PAF

AGEPC; from basophils, mast cells, and other cells From platelets, monocytes-macrophages, smooth muscle cells, and endothelial cells From platelets, neutrophils, macrophages, lymphocytes, and fibroblasts Extracellular matrix protein

Eosinophils

PDGF

Neutrophils and macrophages

TGF-

Macrophages and fibroblasts

Fibronectin

Fibroblasts and endothelial cells

PAF, platelet-activating factor; PDGF, platelet-derived growth factor; AGEPC, acetyl-glyceryl-ether phosphorycholine; transforming growth factor- .

F . E xogenous and end ogenou s mediato rs o f acute in fla mma tio n Thes e mediat ors in fl uence chemo taxis, vasomoto r p heno mena, vascular per meabilit y, p ai n, an d other asp ects of th e in flammat or y pr ocess (Tabl e 22 ).
y

E xogen ous media tors are most oft en of mi crobial origi n ( e.g., for m yl at ed peptides of Esch erich ia coli, whi ch ar e chemo tacti c for n eutrop hils).

E ndogenou s med iators are of h ost origi n.

o

Vasoa ctive amines



Hista mine mediat es th e in cr eas e in cap illar y per meabilit y asso ci at ed with the contra cti on of endothelial cells in postcap illar y v en ul es that o ccurs with mil d injuri es.


Histami ne is lib erated fro m ba sophils, ma st cells, and pla telets.

(b) B asop hils and mast cells. Histami ne is liberat ed b y d eg ra nulatio n trigg er ed b y the follo wi n g stimuli:


B indi ng of speci fi c antig en to b as op hil and mast cell memb r ane -b o un d IgE ( co mp l ement is not involved)

B indi ng of co mp l ement fr ag ments C 3a and C 5a, an aphy latoxins, to sp eci fic cell sur face r ecept ors o n b asop hils an d mast cells (sp eci fi c a ntig en an d I gE antib odies are not invol ved)

  

Ph ysi cal stimuli su ch as heat an d cold C yt o kine IL -1 Fact ors fr om neutr op hils , mon ocyt es, and platelets

Platelets. Histami ne is lib erat ed fro m platel ets b y plat el et ag gr egation a nd the r el eas e rea cti on, whi ch can be trigger ed b y en dot h elial injur y an d thr o mb osis or b y plat el et-acti vating fact or (PAF).


PAF is derived fr om t he gr a nul es o f basop hils and mast cells an d fr om endothelial cells, macrop hag es, neutr op hils, and eosi nop hils. PAF is acet yl -gl ycer yl -et her p hosp hor yl ch oline, also kno wn as AGEPC .

PAF activat es an d aggr egat es platel ets, with th e r el ease of hista mine an d ser oto nin; ca us es vas oa cti v e a nd bro nchospastic effects; and activat es ara chi do ni c aci d metab olism.

Serot onin (5 -hydroxy tryp tamin e)

 

This sub stance acts similarl y to hista mi n e. It is derived fr om plat elets. It is lib erated fr om platelets, along with histamin e, d uri ng the r el ease r ea cti o n.

Ara chid onic acid metab olites. Phosp holipase A 2 stimulat es the r el ease of a rachi do ni c aci d fr om membr ane phosp holipids. The metab olism of ar achid oni c aci d proceeds alo ng two pathwa ys:


T he cy clooxy genase (cyclic end opero xide) pathwa y is catal yz ed b y t wo en z ymi c iso for ms, referr ed to as cyclo ox ygenas e-1 (C OX-1) and cycl oox ygena se-2 (C OX-2).

This p athwa y is inhibit ed b y asp iri n and oth er a nti -infla mmat or y dru gs.

It yi el ds thr o mb oxa nes an d prosta glandi ns: thr o mb oxa ne A 2 (TxA 2 ) in p latel ets, p rostac ycli n (PGI 2 ) in end ot helial cells, and oth er prosta glandi ns in ot her tissues.


Platelet T xA 2 is a p owerful vas oconstri ctor an d platel et aggrega nt. E ndothelia l PGI 2 is a p owerful vas odilator a nd inhib itor of p latel et aggr egation.

T he lipoxyg ena se pa th way yiel ds h ydr op er o x yei cosat etra enoi c aci d (HPET E ) and its deri vatives, 12 -HPE TE in platel ets, and 5-H PE TE and 15 -HPE T E in leuk oc yt es.


5 -HPE T E in turn gives ris e to HE T E , a chemo tacti c fa ct or fo r neutr op hils.

5 -HPE T E also giv es rise to leukotrien es:

 

LTB 4 , a ch emota cti c fact or for n eutr op hils LTC 4 , LTD 4 , and LTE 4 , potent vas oconstri ctors, b roncho co nstri ctors, and medi ators of in cr eas ed capillar y per meabilit y, whi ch ar e so meti mes jointl y r eferred to as the slow-reacting sub sta nce of a naphylaxis

5 -HPE T E also indirectl y gi v es rise to lipoxins. LXA 4 and LXB 4 inhibit p ol ymorp hon ucl ear neutr op hils and eosinop hils and also acti vat e mono cyt es a nd ma cr op ha ges. It is proposed th at thes e lip oxi ns ar e involved in res olvin g infla mmati on a nd ar e pot ential anti -infla mma tor y medi ators that may ha ve therap euti c val ue.

Cytok ines. Thes e soluble proteins are s ecr et ed b y s ev er al t yp es o f cells. They ca n a ct as effecto r molec ul es that influ en ce the b eha vi or o f other cells.

C yt o kines ar e mediators of i mmu nologi c r esp o ns e (e.g., int er fer on- [p rodu ced b y T cells and nat ural killer cells] activat es mono cyt es).

The c yt oki nes IL -1 and T NF are s ecr et ed b y mono cyt esmacr op hag es an d ot her cells and ha ve sever al effects on infla mmati on.

IL-1 and TNF induce acute phase resp onses, such as



Sy stemic effects of in flammati on, incl uding fev er and l eukoc yt osis

Hepa tic synth esis of a cut e p hase p rot ei ns, such as C -rea ctiv e prot ei n, ser u m a m yl oi d associ ated prot ei n, co mp l ement co mp on ents, fib rin og en, prot hr ombi n,
1 -antitr yp si n, 2 -macr ogl ob ulin,

ferritin, an d cer uloplasmi n

  

Sy nthesis of a dhesion molecules Neu trop hil degranula tion

IL-1 and TNF red uce t h e thr omb or esistant p rop erti es of endotheli um, thus p romoti ng thr omb osis.

K inin system. The kini n s yst em is initiated b y activat ed Hag eman fact or ( fact or XIIa). Factor XIIa also activat es the intrinsi c pathwa y of coagulati on a nd th e p lasmi no gen (fibri nol yti c) syst em. Acti vati on of this s yst em i n tur n activat es th e compl ement cascad e. Th us, fact or XIIa link s th e kinin, coag ulation , plasminog en, and complement sy stems.


This s yst em con verts prekallikr ei n to kallikr ein (a chemo tacti c fact or).

It results in the cl eavag e, b y kallikr ein, o f highmol ecular- wei g ht kini no gen to brady kinin, whi ch is a peptid e t hat is nin e a mino aci ds in length that mediat es vas cular p er meabilit y, art eri olar dilation, an d p ain.

Complemen t sy stem. The compl ement s yst em consists of a gr o up o f pla sma proteins that particip ate in immune l ysis of cells an d p lay a signi fi ca nt rol e in in flammati on.


C3a and C5 a (anap h ylato xi ns) mediat e degran ulation o f basop hils and mast cells with the r el ease of histami n e. C 5a is ch emota cti c, mediat es th e r el ease o f histami ne fr om plat el et- dens e gran ul es, indu ces expr ess ion o f

leuko cyt e a dh esi on mol ecul es, and acti vat es th e lipox ygenas e pathwa y of arachi do ni c acid metabolism.
 

C3b is an op so nin. C5b -9, the membra ne atta ck compl ex, is a l yt ic a gent for b act eria an d ot h er cells.

Nitric oxide ( for merl y k no wn as endot helium -derived r elaxin g factor)

 

This is produced b y en doth elial cells. It stimulat es r elaxatio n o f smoot h mus cl e, thu s p laying a rol e in co ntr ollin g vas cular tone.

It inhibits platel et ag gr egation, contributin g to endothelial thro mb or esistance.

G. Outco me of a cute infla mmatio n

y

Resolu tion o f tissue structure and fu nction oft en o ccurs if the injuri ous agent is eli minat ed.

T issue destruction a nd persisten t a cu te infla mma tion

o

Abscess. This is a cavit y filled with pus (neut rop hils, mono cyt es, and liq uefi ed cellular debris).


It is oft en wall ed o ff b y fib rous tissu e and is r elativ el y ina ccessible to th e cir culatio n.

It results from tissu e d estr uction b y l ysos omal products and ot her degrad ativ e enz ym es.

It is usuall y caused b y b act erial infections, often b y stap hyl o co cci.

Ulcer
 

This is the loss of s ur face ep ithelium. This can b e ca us ed b y acut e i nfla mmation o f ep ithelial sur faces ( e.g., p ep tic ul cer, ulcers of the s kin).

Fistula. This is an abnor mal co mmun i cation bet ween t wo or gans or b et ween an or gan and a surfa ce.

Scar. This is the final res ult o f tissue d estr uction, with r esulta nt distortion of stru ctu r e a nd, in some cases, alter ed fun cti on.

Conv ersion to chronic inflammation

This cha nge is mar ked b y t he r eplacement o f n eutr op hils and mono cyt es with l ymp hoc yt es, plasma cells, and macrop hag es.

It oft en in cl ud es p roli feration o f fibr ob lasts and new vess els, with r esultant scarri n g and distortion of ar chi tect ur e.

H. Hered itary d efects that imp air the acute in fla mma to ry response
y

Deficiency o f complement components

o

This d efect manifests clinicall y as in cr eas ed sus ceptib ility to infecti on.

o y

Notabl e defici enci es incl ud e C 2, C3, and C 5 .

Defects in neutrophils
o

Chronic granu loma tous disea se of childh oo d



This diseas e is most commo nl y an X -linked disord er chara ct erized b y de ficient activity of on e o f the enz ymes inv olved in NADP H oxidase activity and th e oxidative burst. Autoso mal recessive variants also occu r.

Th e dis ease is mar ked b y p hagoc yti c cells tha t ingest but do not kill certain mi cr oor ganis ms.

Catala se-positiv e orga nisms are ing est ed but not killed. T hese or ga nis ms (e. g., Sta ph ylococcus aureus) can destr oy H 2 O 2 generat ed b y b act erial metab olis m. B eca us e enz yme- defi ci ent n eut rop hils can not prod uce H 2 O 2 and b acterial H 2 O 2 is destr o yed b y ba ct erial catalas e, H 2 O 2 is not availabl e as a substrate for m yel op er oxidas e. Thus, the m yel op ero xi das e- halide s yst em of b act erial killing fails.

Catala se-nega tiv e org anisms are ing est ed and kill ed. Thes e o r ganis ms ( e.g., strepto co cci) pr od uce suffi ci ent H 2 O 2 to p er mit ox yg en- dep end ent mi cr obi ci dal mecha nis ms to proceed. In effect, the sub strat e for m yel op er oxidas e is p roduced b y t h e b act eria, an d th e bacteria in a sens e kill themsel ves.

M yelop eroxidase d eficiency



This d efect is rar el y asso ci at ed with r ecurr ent bact erial infecti ons but oft en has little clini cal conseq u en ce.

In some i nstan ces, this defect has b een asso ci ated with a mar ked incr eas e in susceptibilit y to in fections with C an dida alb ica ns.

Chdiak -Higashi syndrome



This autoso mal r ecessive disorder is ch ara ct eriz ed b y neutr op enia, albinism, cranial and perip heral n eur op at h y, a nd a tendenc y t o devel op r ep eat ed infecti ons.

It is mar ked b y t he pr esence of ab normal whit e b loo d cells, whi ch are cha ra cterized as follows:


Function ally, b y ab no rmal mi cr ot ub ul e for matio n, a ffectin g mov em ent, with impaired chemotaxis and migr ation

M orph olog ica lly, b y lar g e c yt oplasmi c gran ules (r ep res enting ab n or mal l ysoso mes ) in gra nul ocyt es, l ymp hoc yt es, an d mon ocyt es and b y lar g e ab n or mal mela noso mes in mela noc yt es, all ca us ed b y i mp air ed memb ra ne fusion o f l ys oso mes

L eu kocyte adh esion d eficiency (L AD) ty pes 1 and 2



L AD ty pe 1 deficiency is associat ed with r ecurrent bacterial in fections a nd is ca us ed b y d efi ci en cy of int egrins.

2-

L AD ty pe 2 deficiency is also asso ciat ed with r ecurr ent bacterial in fections a nd r es ults fr om mutati o n s in the gene that co des fo r fucos yltransferas e, req uir ed for the s ynth esis of sial yl-L ewis X on neutrop hils.

III. CHRONIC INFL AM M AT ION A . Gen eral consid eratio ns

y

C hro ni c infl ammatio n can occur when th e in citing injur y is persistent or r ecurr ent or wh en the i nfla mmat or y r eacti on is insu ffi ci ent to compl etel y deg rad e th e a gent ( e.g., b act eria, tissue debris, for ei gn bo di es) that in cit es the inflammat or y r ea cti o n.

It oft en o ccurs de no vo, with out a pr ecedi ng a cut e in flam mator y r ea ctio n.

It occu rs in two maj or patter ns: chr oni c n ons peci fi c infl a mmation a nd gra nul omatous inflammati o n.

B . Chronic no nspecific inflamma tion (Figur e 2 -2 )

y

A cellula r rea ction with a prep on der an ce o f mononuclear (round) cells (macroph ag es, l ymph oc yt es, and plasma cells), oft en with a prolifera tion of fibrob lasts a nd new vessels. Sca rring and distortion o f tissue architecture is ch ara ct er istic.

This t yp e of infla mmatio n is mediat ed b y t he int eracti on of mono cyt es -macr oph ag es with l ymp hoc yt es.

Monoc yt es ar e r ecruited fr om t he cir culation b y various chemo tacti c fa ct ors.

C yt o kines deri ved fr om mo no cytes- macrop hag es activat e l ymp h oc yt es. T he a ctivated lympho cyt es, in tur n, ar e th e sour ce of additio nal cyt okin es th at acti vat e mo noc ytes- macr op hag es.

B lymp h oc yt e activati on b y ma crop ha ge-pr esent ed a ntig en res ults in the for mati o n of a ntib od y-pr o duci ng plasma cells.

table 2-2 Vasoactive Mediators Activity Vasoconstriction Mediator TxA2 LTC4, LTD4, LTE4 PAF Vasodilation PGI2 PGD2, PGE2, PGF2 Bradykinin PAF

Nitric oxide Increased vascular permeability Histamine Serotonin PGD2, PGE2, PGF2 LTC4, LTD4, LTE4 Bradykinin PAF

LTC4, leukotriene C4; LTD4, leukotriene D4; LTE4, leukotriene E4; TxA2, thromboxane A2; PAF, platelet-activating facto prostacyclin (prostaglandin I2); PGD2 , prostaglandin D2 ; PGE2, prostaglandin E2 ; PGF2 , prostaglandin F2 . C . Gra nulo ma tous infla mmatio n (Figur es 2 -3 an d 2 -4 )
y

This t yp e of infla mmatio n is chara ct erized b y granulomas, whi ch ar e no dular coll ections of sp ecialized macr op hag es r eferr ed to as epithelioid cells. Granul omas are us uall y surro und ed b y a ri m of l ymp h oc yt es.

Acti vatio n of ma cr op ha ges b y int era ctions with T l ymp h oc yt es is inv ol v ed. Poorl y di g estible antigen is presented b y macr op ha ges to C D4+ l ymp ho cytes. Int eraction with the antigen-sp eci fi c T- cell r ecept or o f thes e cells trigg ers the r el eas e of cyt okines ( esp eciall y int er fer on- ), whi ch medi at e th e trans for mati on of mon oc yt es and macr op hag es to epith eli oid cells and giant cel ls.

Caseous necrosis is oft en chara ct eristic ( esp eciall y i n tub ercul osis), r esultin g fr om the killing o f myco ba ct eria -lad en macrop hages b y T l ymp h oc yt es and possibl y b y cyt oki n es or s ensitized macr op hag es. Noncaseating pulmonary g ra nulomatous disea se is caused most oft en by sa rcoidosis.

The pr es ence of mu ltinucleated giant cells derived fr om macr op hag es is also char act eristic. The L anghan s g iant cell

has nucl ei arr an ged in a h ors esho e-shap ed patter n ab out the perip h er y o f t he cell an d is particularl y ch aract eristic of, but not speci fi c fo r, the gran ul o mat ous in flammat ion of tub er cul osis. The foreig n body g iant cell has scatter ed nu cl ei.
y

Gran ul omatous infla mmati on is the charact eri stic form of infla mmati on asso ciat ed with a numb er of di vers e eti ologi c a gents, includi ng:
o

Infecti ous ag en ts
 

Mycoba cteriu m tubercu losis and M. lepra e Blastomyces derma titidis, Histo pla sma ca psulatu m, C occid ioides immitis, and ma n y ot her fungi

  o o

Trep on ema p allid um The ba ct eri um of cat -s crat ch disease

Foreign bodies Unknown etiol og y, incl uding sar coi dosis

IV. TISS UE RE PAIR A . R estora tion o f normal stru cture. This occurs when t h e con necti v e tissue infr astruct ur e remai ns relativ el y inta ct. It requir es that the sur vi ving a ffect ed parench ymal cells ha ve the capa cit y to regenerat e.
y

L abile cells
o

Thes e cells divi de activel y thr oug ho ut life to r ep lace lost cells.

o o

The y are cap abl e of r egeneration aft er injur y. The y in cl u de cells of the epider mis and g astroint estinal mucos a, cells lining th e s urfa ce of t h e g enito uri nar y tr a ct, and hemat opoi eti c cells o f the bon e marr o w.

Stab le cells
o

C haract eristicall y, th es e cells und er g o few di visio ns but ar e capabl e of di vision wh en acti vat ed; that is, the y can regenerat e fr om G 0 cells when needed.

o o

The y ar e also cap ab l e o f regener atio n follo wi n g injur y. The y in cl u de hep atoc yt es, r enal tub ular cells, p arench ymal cells of man y glan ds, and n umer o us mes en ch ymal cells ( e.g.,

smo ot h muscl e, cartila ge, conn ective tissu e, end otheli um, ost eoblasts).
y

Permanent cells
o

Thes e cells have b een consi der ed to b e in cap a ble of divisio n and r egeneration (a vi ew chall enged b y r ecen t prov ocativ e n ew evi d ence in vol ving stem cells).

o o

The y in cl u de neur ons and myocar dial cells. The y ar e repla ced b y s ca r tissue (t ypi call y fib rosis; gliosis in the central ner vous syst em) aft er irreversible injur y a nd cell loss.

B . C ellular prolifera tion. This p ro cess is mediat ed b y an assemblage of gro wt h fact ors.
y

Platelet -deriv ed g rowth factor (PDGF ) is a comp et ence fac tor that pro mot es the pr oliferati v e r esp onse of fibr obl asts and s mooth mus cl e cells on concurr ent stimulation b y prog ression facto rs (e. g., oth er gr o wt h factors). Indir ectl y in this ma nn er, PDGF p romot es th e s ynth esis of collagen.
o o

PDGF is synth esiz ed b y p lat el ets and several other cells. PDGF pro mot es the chemo tacti c mi grati on o f fibr ob lasts and smo ot h muscl e cells.

o o

PDGF is ch emota cti c for mon ocyt es. PDGF reacts wit h sp eci fi c cell -s ur face r ecept ors. Generall y, gr o wt h factor r ecept ors are transme mb ra ne pr ot eins that r espo nd to ligand int eraction b y con for mation al cha ng es that ind uce t yr osine kinas e a ctivit y in their intr acell ular d omains.

E pidermal g rowth fac tor (EGF) is a p rogr ession fact or that pro mot es the gr o wth of endot helial cells and fib r oblasts, as well as epithelial cells.

Fibrobla st g rowth facto rs (FGFs) pro mot e th e s yn t hesis of extracellular matrix pr ot ein (in cl u di ng fibr on ecti n) b y fibrob lasts, endothelial cells, mon ocyt es, and ot her cells. Fibronectin is a gl ycop r ot ein with the following char a ct eristics:
o o

It is ch emota cti c for fibr oblasts an d end ot helial cells. It promot es an gi ogenesis (new vess el for mation).

It links other extracellular matrix comp o nents (e.g., collag en, prot eo gl ycans) and ma cro mol ecul es (e.g. , fib r in, h ep ari n) to cell -s ur face int egri ns. Integrins mediat e int era ctions bet ween cells an d extra cell ular matrix.

T ra nsforming growth fac t ors (T GFs)

o o

T GFT GF-

fun cti o ns similarl y to EGF. is a growth inh ibitor for man y cell t ypes a nd ma y ai d

in mod ulating the rep air process; it is also a chemot acti c fa cto r for macr op hag es a nd fib r oblasts.
y

M acropha ge-deriv ed gro wth factors (IL -1 and T NF) pro mot e th e pr oli ferati on of fib roblasts, smoot h muscl e cells, and endot helial cells.

C . The rep air process

y

Remov al of d ebris begi ns in the earl y sta ges o f inflammati o n and is initiated b y liqu efacti on an d r emo val of dead cell ular mat erial and oth er d eb ris.

Formati on o f gran ulation tissue

o

Gran ulation tissue is highl y v as cular, n ewl y formed conn ecti ve tissue consisting of capillaries and fibrobla sts; it fills defects created b y liq uefacti on o f cell ular deb ris.

Gran ulation tissue is not r elat ed to gra nul o ma s or gra nul omat ous inflammati on.

Scarring
o

Colla gen is prod uced b y fib r oblasts. As the amo unt of collag en in gr anulati o n tissue prog ressiv el y i ncr eases, the tissue b ecomes gra duall y l ess vascular an d less cellular.

Prog r essive contracti on of the woun d also occu rs, oft en r esultin g in a d efo rmit y o f the origi nal struct ur e.

D. F actors that d ela y or impede rep air

y y y y

R etentio n o f debris I mpair ed cir culation Persistent infecti o n Metab olic disor ders, such as diab et es mellitu s (associat ed with bot h sus ceptib ility to in fecti on an d i mpaired cir cul ation)

Dietar y d efi cienc y o f as corbi c aci d or pr ot ein, which ar e r eq uir ed for collagen for matio n.