Inflammation and Repair PDF
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This chapter from Robbins Essential Pathology covers the clinicopathologic features of chronic inflammation, discussing its role in various diseases like pulmonary fibrosis, atherosclerosis, liver cirrhosis, and autoimmune diseases. It details morphological aspects, systemic manifestations, and tissue repair processes. The chapter also delves into angiogenesis and factors affecting tissue repair.
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CHAPTER 2 Inflammation and Repair 27...
CHAPTER 2 Inflammation and Repair 27 * A B Fig. 2.9 Chronic inflammation. (A) Chronic inflammation in the lung, showing all three characteristic histo- logic features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows). (B) Typical tuberculous granuloma showing an area of central necrosis surrounded by mul- tiple Langhans-type giant cells, epithelioid cells, and lymphocytes. ubercuoss. In severe and proonged cases, g eves o TNF may Clinicopathologic Features of Chronic Inflammation nerere w appee and ncrease e caabosm o pds, resung Chronic inammation underlies many important diseases. n weg oss (caed cacexa wen severe). Inrequeny, cronc Some o e mos vexng dseases o umans, suc as pumonar y nlammaon s aso assocaed w deposon o amyod proen n ibross, aeroscleroc coronar y arer y dsease, lver crross, end- ssues, because e precursor serum amyod proen s an acue-pase sage renal dsease, and varous auommune and allergc dseases, are proen wose producon ncreases durng nlammaon. In some caused a leas n par by cronc nlammaon. Despe mpressve cases o cronc nlammaon, suc as cronc vra epas, obvous advances n mmunoerapy or some o ese dseases, ey reman pysca sgns are absen, and e dagnoss requres aboraor y assess- mporan cnca caenges and major causes o morbdy and mor- men and ssue bopsy. ay. hese dsorders are dscussed n capers on e dferen organ sysems. TISSUE REPAIR Morphology. Mos cronc nlammaor y dseases sow mononu- After the offending agent is eliminated and inammation subsides, cear ce (ympoc ye and macropage) niraon w ibross damaged tissue is repaired by two processes, regeneration and and ssue njur y (Fg. 2.9A). Under some crcumsances, suc as scarring. necon w uberce bac, e reacon may deveop a parcu- he erms repar, eang, and resouton are oten used ner- ar morpoog y reerred o as granuomaous nlammaon. Gran- cangeaby, aoug eang generay reers o skn wounds and uomas are crcumscrbed coecons o acvaed macropages resouon reers o resoraon o norma ssue arcecure w- w abundan c yopasm, caed epteod ces because ey ou scarrng. Under dferen condons o ssue njur y, e repar ave a laened, epeum-ke sape Acvaed macropages s many by regeneraon or scarrng (descrbed beow and sown aso may use o orm munuceae gant ces (Fg. 2.9B). Gran- n Fg. 2.10). B o processes are rggered by c yoknes and grow uoma ormaon s a cassc exampe o a speca ype o cronc acors a are produced many by macropages. In some suaons, nlammaon n wc macropages are srongy acvaed eer e macropages a nae repar beong o e aernavey ac- by T ces or by recognon o perssen oregn bodes. Granuo- vaed (M2) subse, wc produces varous annlammaor y c yo- mas are seen n ony a ew condons, and recognzng er pres- knes (o ermnae nlammaon) and grow acors (o promoe ence as mporan erapeuc mpcaons. Were ubercuoss repar). One secreed c yokne a can bo suppress nlammaon s endemc, may be e mos requen cause o granuomaous and smuae ibross (scarrng) s TGF-β nlammaon. In e wesern word, granuomas are more oten Regeneraon s e proeraon o resdua ces o resore e dam- seen n Cron dsease, a ype o nlammaor y bowe dsease, n aged ssue. I occurs wen e njured ssue s capabe o proeraon sarcodoss, a rare bu proean dsease o unknown eoog y, and or conans sem ces a can dferenae no uncona ces, and n some unga dseases suc as sopasmoss. wen e connecve ssue sroma s suceny nac o provde a scafod or e arcecura resoraon. Regeneraon s mos oten seen n epea o e skn, nesnes, and ver, wc ave a g Systemic Manifestations proerave capacy and conan abundan ssue sem ces. her he sysemc reacons o cronc nlammaon are smar o bu yp- proeraon s smuaed by grow acors secreed by macropages cay ess severe an ose o acue nlammaon. Fever s common; and oer ces. By conras, cardac musce and neurons are ncapabe n ac, recurren ever and ng sweas are a cassc manesaon o o proeraon and regeneraon. 28 CHAPTER 2 Inflammation and Repair Platelet Eschar Fibroblast Epithelial cells Macrophage Granulation Collagen scar tissue Neutrophil New blood vessels Capillary A B C Fig. 2.10 Tissue repair. Following mild injury, which damages the epithelium but not the underlying tissue, resolution occurs by regeneration, but after more severe injury with damage to the connective tissue, repair is by scar formation. Steps in repair by scar formation are shown, specifically during wound healing in the skin. (A) Inflammation and clot formation. (B) Formation of granulation tissue by vessel growth and proliferating fibroblasts. (C) Remodeling to produce the fibrous scar. Fbrous scar s ormed e ssue s unabe o regenerae or Vasodaton n response o nrc oxde (NO) and ncreased perme- e srucura ramework s rreversby damaged. Aoug a scar aby nduced by vascuar endoea grow acor (VEGF) acks e uncons o e eay ssue, provdes adequae sruc- Separaton o percytes rom e abumna surace and breakdown ura negry o manan some ssue uncon. Grow acors o e basemen membrane o aow ormaon o a vesse sprou suc as TGF-β and ibroblas grow acor (FGF) are produced by Mgraton o endothea ces oward e area o ssue njur y acvaed macropages and oer cells, and ac on ibroblass n e Proeraton o endothea ces jus bend e eadng ron (p) o connecve ssue o smulae er proleraon and collagen syn- mgrang ces ess. C oncomanly, VEGF, also produced by macropages, leads Remodeng no capar y ubes o e ormaon o new blood vessels a provde nuron o e R ecr utment o per e ndothea ce s (p er c yes or sma c ap - prolerang ibroblass (see below). Durng e nal 3 o 5 days o ar es and smo o mus ce ce s or arger vess es ) o or m e repar, e area o njur y s illed w newly ormed capllares, mac- maure vess e ropages, and ibroblass embedded n loose exracellular marx, Suppresson o endothea proeraton and deposon o e base- called granuaton tssue. e amoun o granuaon ssue depends men membrane on e sze o e ssue deec and nensy o nlammaon. Grad- uay, coagen s ad down by e ibrobass o orm e scar, wc Clinicopathologic Features of Tissue Repair over me s modied by enzymes n e exraceuar marx roug The appearance of repaired tissue varies according to the nature a process caed remodeng. hs process nvoves e cross-nkng and extent of injury. o coagen ibers o srengen e ssue and subsequen resapng Wen e njur y s md, acue, and n a ssue capabe o proera- and para resorpon by marx meaoproeases. Remodeng eads on, s repared by ce regeneraon, so e edges are cosed. Exam- o srucuray srong and we-compaced coagen. C oagen depos- pes ncude regeneraon o e ver and e epeum o e skn ed n a perpera se (mb, skn) s usuay caed a scar, bu wen and gu. No scar ssue s ormed. occurs n a parencyma organ n abnormay arge amouns (ver, Heang by irst ntenton occurs n a cean, unneced surgca nc- ung), s reerred o as ibross. he undamena underyng pro- son o e skn a s cosed w surgca suures. he wound s n- cesses n a ese reacons are essenay e same. ay seaed by a bood co, oowed by e arrva o neurops and macropages and e ormaon o a sma amoun o granuaon s- Angiogenesis sue a s repaced by a n scar. Concomany, e surace epea Ang ogeness s e pro cess o ne w bo o d vess e d e veopmen rom ces regenerae and brdge e ncsona gap. exs ng vess es. I s no on y cr c a n e a ng a ses o njur y bu Heang by second ntenton occurs n more severe and deep nju- a s o n e de veopmen o co aera c rc u a ons a se s o s cem a res o e skn, wen e edges canno be cosed. he sequence o and n a ow ng umors o nc re as e n sz e b e yond e c ons ra n s evens s denca o e one descrbed prevousy, w e excep- o er or g na bo o d suppy. Ang ogenes s nvoves sprou ng o on a e amoun o granuaon ssue s muc arger and per- ne w vess es rom exs ng ones and conss s o e o ow ng seps sss or a onger perod, and, ence, more coagen s ad down and (Fg. 2.11): e ibrous scar s cker. By abou 4 o 6 weeks, e skn wound CHAPTER 2 Inflammation and Repair 29 Quiescent Vasodilation vessel (VEGF) Leading (“tip”) cell (VEGF) Angiogenic factors Pericyte Pericyte detachment (angiopoietin) Basement membrane Basement membrane Endothelium degradation (MMPs) Pericyte A recruitment ECM Elongation of vascular stalk Formation of new vessel B Fig. 2.12 Tissue repair. (A) Granulation tissue showing numerous blood vessels, edema, and a loose extracellular matrix containing occasional inflammatory cells. Collagen is stained blue by the trichrome stain; Fig. 2.11 Angiogenesis. In tissue r e p a i r, angiogenesis occurs mainly minimal mature collagen can be seen at this point. (B) Trichrome stain by the sprouting of new vessels. The steps in the process, and the of mature scar, showing dense collagen, with only scattered vascular major signals involved, are illustrated. The newly formed vessel channels. joins up with other vessels (not shown) to form the new vascular bed. ECM, extracellular matrix; MMP, matrix metalloproteinases; VEGF, vascular endothelial growth f a c t o r. conracs because o e acon o myoibroblass n e connecve cyokne producon by macropages. Dabec skn ucers do no ssue, srnkng e area o njur y (Fg. 2.12). ea normay and conan exensve granuaon ssue. Compromsed bood suppy, wc can cause ucers n e ower Repair can be impaired by numerous factors. exremes. ese ncude: In conras o ese suaons o deecve repar, ere are cond- Mecanca factors suc as excessve movemen or pressure ons n wc e repar process becomes excessve. hs can gve rse Infecton, wc proongs e nlammaon and causes progressve o yperropc scars oowng njur y, wc usuay regress sowy, ssue njur y and scar ssue a grows beyond e margns o e njur y and as Dabetes, a dsease n wc eang s rearded because o e o regress, caed keod (Suppemena eFg. 2.1). Excessve scarrng underyng meaboc abnormay and vascuar narrowng, eadng n organs resus n uncona compromse and s e bass o serous o a reduced bood suppy. Furermore, dabecs are suscepbe o dsorders suc as pumonar y ibross (Caper 10) and crross o necons because o decreased neurop uncon and mpared e ver (Caper 13). CHAPTER 2 Inflammation and Repair 29.e1 Supplemental eFig. 2.1 Keloid. Excess collagen deposition in the skin forming a raised scar known as keloid. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 219.) 3 Hemodynamic Disorders, Thromboembolism, and Shock O U T L I N E Hyperemia, Congestion, and Edema, 30 Embolism, 36 Edema, 30 Pulmonary Thromboembolism, 37 Hemostasis and Hemorrhage, 31 Systemic Thromboembolism, 37 Platelets, 32 Nonthrombotic Emboli, 37 Coagulation Cascade, 33 Infarction, 37 Coagulation Control, 34 Shock, 38 Thrombosis, 35 Septic Shock, 39 e ea o ssues depends on adequae bood crcuaon, wc Edema devers oxygen and nurens and removes carbon doxde and me- In nor ma ssues, end o e a junc ons n c ap ar es are p e r me abe aboc wase producs. Bood as wo major consuens: ceuar ee- o waer and s a s and o e r s ma mo e c u e s , bu no o proe ns. mens made n e marrow (we ces, red ces, and paees) and Hg n ravas c u ar yd ros a c pre ssure ends o pus waer and a lud pase (pasma), conssng o waer, norganc sas, organc s a s no e ssues , bu s s ne ary b a anc e d by o s mo c pressure, meaboes, and numerous proens, mos o wc are made by e w c s generae d by p as ma proe ns and pu s w aer b ack no e ver. Imporan pasma proens ncude abumn, e mos abundan vess es (Fg. 3.1). Te sma amoun o u d a do es acc umu ae n proen n pasma; mmunogobuns and componens o e compe- nor ma ssues s a ken up by y mpa c ve ss es and re ur ne d o e men sysem (dscussed n Caper 4); and coaguaon acors, wc crc u a on roug e ora c c du c . upon acvaon caayze a seres o reacons a cause e bood o co. Edema and efusons may occur w ncreased ydrosac pres- Dsorders a dsurb norma lud baances beween e bood and sure, decreased osmoc pressure, or ympac obsrucon. Common ssues or a compromse e negry or paency o bood vesses causes are sed n Tabe 3.1. Noe a some acors cause lud accu- are ver y common, and may cause dysuncon or necross o afeced muaons roug severa drec or ndrec efecs. ssues. In s caper, we w rs dscuss dsorders o lud baance, Inammaton (dscussed n Caper 2) promoes edema by ncreas- ncudng e accumuaon o excessve lud wn ssues or body ng bo bood low and vascuar permeaby o proens. he pro- caves and e oss o bood, and en urn o dsorders o nade- en-rc lud o nlammaon s reerred o as an exudate, wereas quae or excessve cong, ncudng paoogc nravascuar cong proen-poor nonnlammaor y edema lud s reerred o as a tran- (romboss) and e seddng o cos no e crcuaon (embosm), sudate. and er downsream consequences. We w ns by dscussng Cardac aure, wc akes wo orms: sock, a dsorder w severa dferen causes a ave n common a Rght-sded cardac aure causes passve venous congeson n sysemc aure o ssue peruson. e sysemc crcuaon, rasng e ydrosac pressure n e mcrocrcuaon, wc n urn causes egress o proen-poor HYPEREMIA, CONGESTION, AND EDEMA lud n e nersum, resung n subcuaneous edema. L et-sded cardac aure s a common cause o pumonar y Swelling of tissues may stem from increased blood volume due to edema and peura efuson and aso dmnses e bood sup- hyeperemia or congestion, or from increased uid within the inter py o e kdney, wc responds by ncreasng renn produc- stitium, a condition called edema. on. Renn acvaes angoensn, ereby ncreasng ar eroar Hyperema s dened by ncreased low o arera bood no a s- smoo musce one and smuang e producon o ado- sue, generay due o areroar daon. I s a norma adapaon o serone by e adrena corex, wc promoes reabsorpon ceran envronmena caenges (e.g., ncreased workoad n exercs- o sodum and waer by e kdney. he reenon o sodum ng skeea musce, or cod n exposed skn). By conras, congeson s and waer ncreases e ydrosac pressure, oten worsenng an abnorma process caused by decreased venous oulow rom a ssue. edema rougou e body. Congesed ssues ave poor bood dever y and are prone o dysunc- on and even necross. Edema reers o an abnorma accumuaon o Morphology. Edema s easy recognzed. Tssues (parcuary e lud n ssues. hroug smar mecansms as ose a cause edema subcuaneous ssue, ungs, and bran) are swoen and eavy. Sub- (descrbed n e oowng), abnorma lud accumuaons caed efu- cuaneous edema s accenuaed n dependen pars o e body (e.g., sons may aso gaer n body caves suc as e peura, percarda, e sacrum n recumben paens and e ee oowng proonged and peronea spaces. 30 CHAPTER 3 Hemodynamic Disorders, Thromboembolism, and Shock 31 he erms sed descrbe beeds accordng o er sze and sng or sandng). Pumonar y edema s marked by eavy ungs, appearance: wc reease roy, bood-nged lud wen cu. Bran edema, Hematoma descrbes a beed no ssues and may range rom skn generazed, eads o e narrowng o suc because o compresson bruses o aa nracerebra emorrages (Fg. 3.3). o e swoen g yr agans e sku. Anasarca (generazed edema) Petecae are pnpon, 1- o 2-mm beeds no e skn, mucous s seen n cronc ear aure. By conras, e edema a accom- membranes, or serosa suraces (see Fg. 3.3), usuay seen n panes rena aure somemes preerenay afecs oose ssues paens w nadequae paee uncon. (e.g., e eyeds). Varous orms o ear aure are assocaed w congeson as we as edema. In paens w severe rg-sded ear aure, congeson produces necross o e epac obues Table 3.1 Causes of Edema and Effusions (centrlobular necross). he gross appearance s known as numeg ver (Fg. 3.2). In et-sded ear aure, pumonar y congeson Increased Hydrostatic Pressure produces bood-engorged capares, nersa edema, and e Impaired Venous Return presence o emosdern-aden nraaveoar macropages (heart alure cells), e aer semmng rom sma beeds. Congestive heart failure Constrictive pericarditis Liver cirrhosis (ascites) Venous obstruction or compression (e.g., by a mass) Clncal Features. he cnca efecs o lud accumuaons var y Venous thrombosis wdey dependng on er sze and ocaon. Subcuaneous edema Lower extremity inactivity with prolonged dependency may sgna an mporan underyng dsorder (e.g., ear or kdney Sodium retention (e.g., renal failure, left-sided heart failure) aure) and severe may nerere w wound eang and cear- Sodium Retention ance o necons. Pumonar y edema mpars gas excange (poen- ay exacerbang underyng condons suc as ear aure) and Renal failure aso ncreases e rsk o necons. Bran edema may be aa snce Left-sided heart failure e bran canno expand wn e encosed sku. Increases n CNS Arteriolar Dilation pressure may compromse e bood suppy o e bran or cause er- Inflammation naon roug e oramen magnum, njurng meduar y ceners a conro respraon (see Caper 17). Reduced Osmotic Pressure Protein-losing glomerulopathies (nephrotic syndrome) HEMOSTASIS AND HEMORRHAGE Liver failure Malnutrition Hemorrhage is caused by injuries that disrupt blood vessels, Protein-losing gastroenteropathy allowing blood to extravasate into tissues or outside of the body. It Lymphatic Obstruction represents failure of hemostasis. Inflammatory he negry o bood vesses may be dsruped by rauma or dsor- Neoplastic ders a desroy vesse was (e.g., vascus, eroson by cancers). Ds- Postsurgical orders a mpar bood cong exacerbae beedng endences, even Postirradiation n e absence o obvous rauma. LYMPHATICS To thoracic duct and eventually to left subclavian vein Obstruction Increased interstitial Hydrostatic pressure fluid pressure Malnutrition Liver failure Heart failure Nephrotic syndrome Renal failure Inflammation Sepsis Plasma colloid osmotic pressure Arterial end CAPILLARY BED Venous end Fig. 3.1 Factors influencing fiuid movement across capillary walls. Capillary hydrostatic and osmotic forces are normally balanced, so there is little net movement of fluid into the interstitium. What little fluid accumu- lates is cleared by lymphatic drainage. Edema may result when hydrostatic pressures rise (as in renal failure or heart failure), osmotic pressures fall (as in malnutrition, liver failure, or nephrotic syndrome), vascular per- meability increases (as with inflammation or sepsis), or lymphatic vessels are obstructed.
