Robbins Essential Pathology, Inflammation and Repair PDF

CHAPTER 2 Inflammation and Repair 21 Table 2.4...

CHAPTER 2 Inflammation and Repair 21 Table 2.4 Mediators of Inflammation Pharmacologic Mediator Production Role in Inflammation Antagonists Cell-Derived Mediators Histamine Stored as a preformed molecule in granules of mast Dilation of blood vessels, Antihistamines for allergy; cells and basophils; released rapidly upon degran- increased vascular permeability bind to histamine ulation in response to IgE cross-linking (allergy), receptors and compet- trauma, complement products itively inhibit histamine binding Arachidonic acid PLA produc tion is indu c e d in ma n y c ell t y pes by 2 derived complement prod u c ts , c y to k i ne s , o th e r s t i m ul i → releas es arachido n ic a c id fro m membrane phos- pholipids → conv erted to a ctiv e m e dia t or s Prostaglandins Produced in mast cells, leukocytes, endothelial cells, Vasodilation and increased vascular Many nonsteroidal and other cells by cyclooxygenase; activated by permeability (PGD , PGE ); inhibit antiinflammatory drugs 2 2 trauma, complement products, cytokines, microbial (PGI ) or stimulate (TXA ) platelet (NSAIDs) inhibit cycloo- 2 2 products aggregation; pain, fever (PGD , xygenase 2 PGE ) 2 Leukotrienes Produced in mast cells, leukocytes, endothelial cells, Neutrophil chemotaxis (LTB ); smooth Leukotriene receptor 4 and other cells by lipoxygenase; activated by trauma, muscle (e.g., bronchial) contraction antagonists for asthma complement products, cytokines, microbial products (LTC , LTD ), involved in asthma 4 4 Cytokines: see Table 2.5 Platelet-activating Produced in mast cells, leukocytes, endothelial cells, Vasodilation, increased vascular per- factor (PAF) and platelets by action of PLA on membrane meability, constriction of bronchi, 2 phospholipids platelet aggregation (promotes thrombosis) Plasma Protein–Derived Mediators Complement Produced at site of complement activation by sequen- C5a, C3a are chemotactic for leuko- Anti-C5 for diseases proteins (see tial enzymatic (protease) activity cytes (especially neutrophils), dilate caused by excessive Chapter 4) vessels complement activation C3b coats microbes and promotes (in trials) their phagocytosis Pentraxins Synthesized in the liver in response to cytokines Markers of inflammation (acute-phase proteins) C-reactive protein (CRP) CRP: opsonizes microbes for phago- cytosis Serum amyloid protein (SAP) SAP: unknown Kinins Bradykinin: peptide produced in activated endothelial Vasodilation, increased vascular cells by the kinin–kallikrein system permeability, bronchial constriction, pain cysene (C) resdues. Eac group acs preerenay on neurops,    Lpoxns are aso generaed rom aracdonc acd by e poxygen- monocyes, eosnops, or ympocyes. ase paway, bu unke prosagandns and eukorenes, e poxns suppress nlammaon by nbng e recrumen o eukocyes, Plasma Protein–Derived Mediators neurop cemoaxs, and adeson o e endoeum. hes e medaors are pro duc s o pasma proens  a are syn esze d Cytoknes are proens a drec communcaon among eu- n  e ver and o er ssues and ac  vaed a  e se o nlamma- kocyes and oer ces, and are ereore consdered e messenger on. he mos mp or  an o  es e me daors are des cr b ed n  e moecues a reguae mmuny and nlammaon (Tabe 2.5). One oowng (s ee Tabe 2.4). subse o cyoknes consss o e cemoaracan cyoknes, known he compement system consss o severa crcuang proens a as cemoknes, wose uncon s o drec e movemen o eukocyes are acvaed by mcrobes and by anbodes or pasma ecns bound o o e se o nlammaon (cemoaxs). Recognon o mcrobes and mcrobes and oer angenc subsances. Compemen acvaon eads producs o dead ces by e paern recognon recepors o sennes, o sequena enzymac modicaon o e proens, cumnang n macropages, and oer ces, menoned earer, eads o e acvaon e deposon o producs a varousy coa (opsonze) mcrobes and o sgnang paways a nduce e syness and secreon o cyo- oer ces or pagocyoss; recru eukocyes; and yse n-waed knes. Varous cyoknes ave dsnc or overappng roes n acue and mcrobes. Compemen acvaon s descrbed n more dea n Cap- cronc nlammaon, as descrbed aer. Cemoknes are cassied er 4, n e conex o ypersensvy reacons. no our major groups accordng o e arrangemen o e conser ved 22 CHAPTER 2 Inflammation and Repair Table 2.5 Major Cytokines of Acute and Chronic Inflammation Principal Functions and Role in a Cytokine Principal Cell Sources Inflammation Use of Therapeutic Antagonists Cytokines in Acute Inflammation Tumor necrosis Macrophages, dendritic Endothelial cells: activation → expression of Rheumatoid arthritis, inflammatory factor (TNF) cells, T cells adhesion molecules, secretion of chemokines, bowel disease, psoriasis reduced anticoagulant properties (inflammation, coagulation) Neutrophils: activation Hypothalamus: fever Muscle, fat: catabolism (cachexia) Interleukin-1 (IL-1) Macrophages, dendritic Endothelial cells: activation (inflammation, Rheumatoid arthritis, autoinflam- cells, fibroblasts, endothe- coagulation), similar to TNF matory syndromes (rare genetic lial cells, keratinocytes Hypothalamus: fever diseases) Liver: synthesis of acute-phase proteins T cells: Th17 differentiation Interleukin-6 (IL-6) Macrophages, dendritic Liver: synthesis of acute-phase protein Rheumatoid arthritis (juvenile and cells, T cells B cells: proliferation of antibody-producing cells adult) T cells: Th17 differentiation Chemokines (many) Virtually all cell types Recruitment of leukocytes from the circulation into Inflammatory bowel disease tissues (in clinical trials) Maintenance of lymphoid tissue architecture (segregation of T and B cells in secondary lymphoid organs) Cytokines in Chronic Inflammation Interleukin-2 (IL-2) T cells (mainly CD4+ helper T cells: proliferation and differentiation into effector Anti-IL-2 receptor used to prevent T cells) and memory cells; promotes regulatory T-cell acute organ transplant rejection development, survival, and function + Interleukin-4 (IL-4) CD4 T cells (Th2), mast B cells: isotype switching to IgE Asthma, atopic dermatitis cells T cells: Th2 differentiation, proliferation Macrophages: alternative activation Role in allergic inflammation + Interleukin-5 (IL-5) CD4 T cells (Th2) Eosinophils: activation, increased generation Asthma Role in allergic inflammation Interleukin-12 Macrophages, dendritic cells T cells: Th1 differentiation (IL-12) NK cells and T cells: IFN-γ synthesis + Interleukin-17 CD4 T cells (Th17) Epithelial cells, macrophages, and other cell types: Psoriasis; some effect in multiple increased chemokine and cytokine production; sclerosis GM-CSF and G-CSF production → recruitment and activation of neutrophils + Interferon-γ (IFN-γ) T cells (Th1, CD8 T cells), Macrophages: classical activation (increased Hemophagocytic syndromes NK cells microbicidal functions) T cells: Th1 differentiation Interleukin-10 Macrophages, T cells Macrophages, dendritic cells: inhibition (IL-10) (mainly regulatory T cells) Role in termination of inflammation Transforming T cells, macrophages, other T cells: inhibition of proliferation and effector growth factor-β cell types functions; differentiation of Th17 and Treg (TGF-β) Macrophages: inhibition of activation; stimulation of angiogenic factors Fibroblasts: increased collagen synthesis a Specific for the cytokine or its receptor. Pentraxns are pasma proens a ncude C-reacve proen crcuang precursor proens and conrbue o vascuar daon and (CRP) and serum amyod proen (see beow). ey recognze pos- pan a e se o nlammaon. popds expressed on bacera membranes (and apopoc ces) and he our major eaures o nlammaon (nay descrbed n e promoe pagocyoss or acvae e compemen sysem, us causng 1s cenur y AD by e Roman encycopeds Cesus), rubor (redness), e emnaon o ese mcrobes and dead ces. e pasma eves o caor (warm), tumor (sweng), and door (pan), can be expaned ese proens ncrease durng e acue-pase response a accompa- by e acons o parcuar medaors (Tabe 2.6). A it sgn, oss o nes nlammaor y reacons, dscussed aer. Knns are produced rom uncon, was added aer.  CHAPTER 2 Inflammation and Repair 23 B ecause o er essena roe n e nlammaor y process, drugs a nb medaors are par o e pyscan’s armamenarum (see Tabes 2.4 and 2.5). Mos o ese drugs bock e producon or unc- on o ndvdua medaors. An excepon s corcoserods a are wdey used o suppress nlammaon, wc are oug o nb e syness o aracdonc acd–derved medaors (by nbng pospopase A ), as we as e producon o mupe c yoknes. 2 Lympoc yes are aso sensve o corcoserod-nduced apoposs, an efec a s useu n reang varous auommune dsorders as we as ympoc yc magnances. Clinicopathologic Features of Acute Inflammation Acute inammatory reactions show distinct morphologic patterns that are typically associated with different inciting conditions and Fig. 2.4 Serous inflammation. Low-power view of a cross section of a clinical manifestations (Table 2.7) skin blister showing the epidermis separated from the dermis by a focal collection of pale pink-staining or clear serous effusion. Morphology. Speca morpoogc paerns are oten supermposed on e genera eaures o acue nlammaon (vasodaon, eukocye Table 2.6 Role of Mediators in Cardinal Features of recrumen, and edema), dependng on e severy o e reacon, s Acute Inflammation specic cause, and e parcuar ssue and se nvoved. he mpor- ance o recognzng e gross and mcroscopc paerns s a ey Feature Mechanism oten provde vauabe cues abou e underyng cause. Redness (rubor) Vasodilation (caused by histamine, prostaglan-    In serous nammaton (Fg. 2.4), exuded lud s ce poor and  dins) and stasis of blood (erythema in the skin, accumuaes n body caves suc as e peura or percardum congestion in parenchymal organs) (ormng an efuson) or under epea suc as e skn (ormng Warmth (calor) Increased blood flow in the affected organ bsers or vesces). hs reacon s ypca o md njury (e.g., Swelling (tumor) Exudation of fluid due to increased vascular erma burns o skn), necons a damage e adjacen s- permeability (caused by histamine, prostaglan- sue (suc as peurs accompanyng pneumona) or reavey dins); leakage of fibrinogen and formation of nondesrucve necons (suc as vra percards). he lud s fibrin deposits in extravascular tissue (respon- resorbed wen e nlammaon subsdes. sible for induration in chronic inflammatory    Fbrnous nammaton, ke serous nlammaon, occurs on e reactions) surace o organs suc as e ung or ear, bu n s case e vas- Pain (dolor) Action of prostaglandins and kinins on sensory cuar eaks are arge and ence, e exudae conans arge-moec- nerve endings uar-weg pasma proens suc as ibrnogen and coaguaon paway acors, wc become acvaed and conver ibrnogen Table 2.7 Patterns of Acute Inflammation o nsoube ibrn co. Fbrn s deposed on e surace o e organ (Fg. 2.5), and may eer be removed by enzymac yss Type of (caed resouton) or,  exensve, be repaced by scar ssue a Inflammation Morphology Examples of Diseases can cause sgnican uncona mparmen. Repacemen o Serous Accumulation of cell-poor Pleuritis, pericarditis, ibrnous exudae by scar ssue s caed organzaton. fluid exudate mild burns, skin dis-    Puruent (suppuratve) nammaton s caracerzed by eases (pemphigus) desrucve nlammaon eadng o e ormaon o pus, a q- Fibrinous Deposition of fibrin Pericarditis, meningitis, ueied coecon o dead ssues and neurops. I s mos oten pleuritis caused by necons by pyogenc (pus-producng) bacera a Suppurative Necrosis with accumula- Bacterial pneumo- ec a neurop exudae. (purulent) tion of leukocytes and nias, appendicitis,    An abscess s a ocazed coecon o puruen nlammaon formation of pus (con- abscesses (Fg. 2.6) w cenra necross and acue nlammaon oten taining dead leukocytes surrounded by nlammaory ces and scar ssue (  s cronc). and tissue cells) Abscesses may orm n any organ as a resu o seedng by bacera Ulcer Epithelial defect with Gastric ulcer, dia- or odgng o sepc embo. Because ey are poory vascuarzed, underlying acute and betic ulcer, venous ey may ave o be draned surgcay or eang o occur. chronic and arterial ulcers    An ucer (Fg. 2.7) s a ocazed deec n e surace o a ssue, inflammation (typically in lower usuay as a resu o necross and oss o e epeum, as n extremities) e somac or duodenum (oten caused by Hecobacter pyor necon and exacerbaed by gasrc acd), or n e exremes Systemic Manifestations (oten seen n dabecs because o reduced bood suppy, or as bed Acute inammation is usually accompanied by systemic mani sores n edery ndvduas because o proonged mmoby and festations that may cause clinical problems and provide valuable pressure). Mos ucers sow eaures o acue and cronc nlam- diagnostic clues (Table 2.8) maon. Heang o ucers requres reamen o e underyng con- Inlammaon, even   s ocazed, may be assocaed w don. cyokne-nduced sysemc reacons a are coecvey caed e 24 CHAPTER 2 Inflammation and Repair F P A B Fig. 2.5 Fibrinous pericarditis. (A) Deposits of fibrin on the pericardium. (B) A pink meshwork of fibrin (F) overlies the pericardial surface (P) A B Fig. 2.6 Purulent inflammation. (A) Multiple bacterial abscesses (arrows) in the lung in a case of bronchopneu- monia. (B) The abscess contains neutrophils and cellular debris resulting from destruction of alveoli, and is surrounded by congested blood vessels. Alveolar destruction is seen in the lower right corner. Above left shows intensely congested alveolar walls and intra-alveolar exudate. A B Fig. 2.7 The morphology of an ulcer. (A) A chronic duodenal ulcer seen as a defect in the mucosa (arrow). (B) Low-power cross-sectional view of a duodenal ulcer crater with an acute and chronic inflammatory exudate in the base.  CHAPTER 2 Inflammation and Repair 25 Table 2.8 Systemic Manifestations of Inflammation Mechanism Clinical Features Fever Cytokines (IL-1, TNF) stimulate prostaglandin production in In severe cases, increased body temperature can the hypothalamus, act on body temperature control center cause mental disturbances and coma Treated with NSAIDs Leukocytosis Initially, TNF stimulates release of leukocytes from the bone Marker for inflammation; not by itself a cause of marrow. clinical problems Later, colony-stimulating factors (GM-CSF, G-CSF) produced by activated macrophages and T cells act on hemopoietic stem cells in bone marrow and stimulate production of neutrophils and monocytes Increased plasma levels Increased liver synthesis in response to cytokines (IL-6, IL-1, C-reactive protein: marker of inflammation of acute-phase proteins TNF) Fibrinogen: increases erythrocyte sedimentation rate Serum amyloid protein: may lead to amyloidosis in prolonged, chronic inflammation Hypotension, dissem- High levels of TNF and other cytokines → vasodilation, Life-threatening complication of disseminated infec- inated intravascular increased procoagulant activity of endothelium tions and other causes of severe acute inflamma- coagulation, gener- tion (burns, acute pancreatitis) alized edema, organ failure G-CSF, Granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-1, interleukin 1; NSAID, nonsteroidal antiinflammatory drug; TNF, tumor necrosis factor. acue-pase response and are manesed by ever, eukocyoss, and man proens are C-reacve proen (CRP), serum amyod A (SAA) ncreased pasma eves o acue-pase proens. proen, and ibrnogen. CRP and SAA bnd o mcroba ce was and Fever s a c yokne response a aers e body emperaure se may ac as opsonns and ix compemen. Fbrnogen bnds o red ces pon. e pysoogc uncon o ever remans uncear, bu  s a and causes em o orm sacks (roueaux) a sedmen more rapdy vauabe cnca sgn n assessng weer an underyng nlamma- an ndvdua red ces. hs s e bass or measurng e er yrocye or y process s presen. Bacera producs, suc as popoysacca- sedmenaon rae (ESR) as an ndcaor o nlammaon. Anoer rde (caed exogenous pyrogens), smuae eukoc yes o reease pepde wose producon s ncreased n e acue-pase response s c yoknes suc as IL-1 and TNF (caed endogenous pyrogens) a e ron-reguang pepde epcdn. Croncay eevaed pasma con- ncrease e enzymes (c ycooxygenases) a conver  aracdonc cenraons o epcdn reduce e avaaby o ron and are respons- acd no prosagandns. In e ypoaamus, e prosagandns, be or e anema assocaed w cronc nlammaon (see Caper especay PGE , smuae e producon o neuroransmers 9). Acue-pase proens ave beneica efecs durng acue nlam- 2 a rese e emperaure se pon a a ger eve. Nonseroda maon, bu proonged producon o ese proens (especay SAA) an-nlammaor y drugs (NSAIDs), ncudng asprn, reduce ever n saes o cronc nlammaon can, n some cases, cause secondar y by nbng prosagandn syness. Excessve producon o IL-1 amyodoss (see Caper 4). s assocaed w perodc ever syndromes, aso caed auonlam- Severe sysemc acue nlammaon s seen n sepss, caused by ds- maor y syndromes, some o wc are e resu o gan-o-uncon semnaed necons (see Caper 3), and n e systemc nammatory muaons n e Nod-ke recepor amy o proens a sense response syndrome, caused by nonnecous condons suc as severe mcrobes and necroc ces. burns, rauma, and nlammaor y reacons suc as pancreas. he Leukocy toss s an ncrease n crcuang we bood ces a s cassc cnca rad n ese condons s ypoenson, dssemnaed mos oten nduced by c yoknes produced by acvaed eukoc yes. nravascuar coaguaon, generazed edema, and meaboc dsur- Cyoknes smuae e rapd appearance o eukoc yoss (n mnues bances eadng o organ dysuncon, a caused by e massve produc- o ours) by enancng e reease o preormed eukoc yes rom e on o cyoknes, prncpay TNF. margna poo o e bone marrow, and may aso produce a more sus- Outcomes of Acute Inflammation aned eukoc yoss (over days o weeks) by acng on progenor ces n e bone marrow o ncrease eukoc ye producon. hese acv- Mos acue nlammaor y responses ave one o ree oucomes. es ser ve o repace ces a de durng e nlammaor y reacon    R esouton. he response ends because e smu a naed  and o ncrease e numbers o ces a are avaabe o emnae (mcrobes, necroc ces) are emnaed. B ecause mos o e ces e ofendng agen. We bood ce couns are wdey used n e and moecues n nlammaon are sor  ved and need smua- cnc o dagnose nlammaon, wc s presumed o be o nec- on o be acve, once e ofendng agens are no onger presen ous orgn un proved oer wse. In acue nlammaon, e mos e reacon subsdes. Typcay, ere s mnma ssue desruc- promnen ncrease s n bood neurops, wc, n severe cases, on, ence e norma ssue srucure s reaned. can reac numbers approxmang ose n eukemas (e so-caed    Organzaton. Some ypes o acue nlammaon are repaced by eukemod reacon). ibross (scarrng), descrbed n more dea aer. Pasma eves o acute-pase protens rse wen e ver s smu-    Progresson to chronc nammaton may occur  e smuus s aed by cyoknes (many IL-6) o ncrease er syness. he ree perssen and canno be emnaed. In mos nsances, owever, 26 CHAPTER 2 Inflammation and Repair Antigen- + CD4 presenting Th1 cell cell Presents IL-17, antigen to Granuloma TNF T cells Epithelioid cell Cytokines Giant cell γ IFN- (e.g., IL-12, IL-6, IL-23) Leukocyte Monocyte Activated recruitment, macrophage inflammation Fibroblast Activated Lymphocyte macrophage Blood vessel Fig. 2.8 Macrophage–lymphocyte interactions in chronic inflammation. Activated T cells produce cytokines that recruit macrophages (tumor necrosis factor [TNF], interleukin 17 [IL-17], chemokines) and others that activate macrophages (interferon gamma [IFN-γ]). Activated macrophages in turn stimulate T cells by present- ing antigens and via cytokines such as IL-12. Prolonged activation of macrophages may lead to the formation of granulomas. cronc nlammaon s a dsnc reacon a does no necessary Te macropages r y o d es roy or wa o   e o e nd  ng age n by oow an acue pase. pro ducng NO, ys os oma  en zy mes , and c y ok  nes  a re c r u more eu ko c yes. T ympocyes are acvaed by mcroba proen angens, env- CHRONIC INFLAMMATION ronmena cemcas (wc somemes bnd o and mody se pro- Chronic inammation is a prolonged reaction to persistent stimuli ens), and se angens (n auommune dseases). Macropages and in which inammation, tissue injury, and scarring usually coexist. dendrc ces dspay ese angens o T ces and respond o sgnas Cronc nlammaon deveops n e seng o perssen nec- rom e T ces. Subses o acvaed T ces produce many cyoknes ons (e.g., ubercuoss), auommune dseases (e.g., reumaod a conrbue o nlammaon: arrs, mupe sceross), and proonged exposure o oxc agens    IFN-γ acvaes macropages. a may be exogenous (e.g., sca parces) or endogenous (e.g.,    IL-5 acvaes eosnops. coesero cr ysas). In many cases, ere s a srong componen o    IL-17 smuaes e producon o cemoknes a recru neuro- adapve mmuny, especay acvaon o c yokne-producng T ps. ces, wc conrbue o e perssen and promnen acvaon o    TNF acvaes endoea ces and promoes recrumen o euko- oer eukoc yes, especay macropages. he mos  requen causes cyes (as n acue nlammaon). o cronc nlammaon are summarzed n Tabe 2.1 Oer ces n cronc nlammaor y reacons ncude pasma ces. I ere are supermposed epsodes o acue nlammaon, neurops Cellular Reactions of Chronic Inflammation aso may be promnen. Chronic inammatory reactions are dominated by inltration of Chronic inammation is accompanied by tissue injury and repair mononuclear cells. occurring at the same time. Cronc nlammaor y reacons deveop as a consequence o pro- Tssue njur y s caused by e numerous medaors a macro- onged bdrecona neracons beween macropages, T ympo- pages produce n e aemp o emnae e ofendng agen. Wen cyes, and oer mmune ces (Fg. 2.8). e response s srong and proonged, ere s oten consderabe dam- Macropages are  e cen ra  ce s o c ron  c  n   am ma  on. Te y age o oer wse eay ssues a e se o nlammaon. are ac  vae d by c yok  nes pro duc e d by T ce s, mos y IFN-γ, and Repar o njured ssues oten accompanes cronc nlammaon. o er sg na s prov d e d by T c e s. Pers sen  n nae  m mune s  m- Proeraon o bood vesses (angogeness) and ibross are nduced u  a on by To - ke re cepors and o er re c epors may a s o con- by grow acors and c yoknes, noaby vascuar endoea grow  r bue. Tes e macropages ave b e en c a  e d c ass  c a  y ac  v ae d acor (VEGF) and TGF-β, produced by e acvaed macropages. (M1) macropages (n c on r as o a er na vey ac  v ae d [M2] hs process s dscussed aer n e conex o ssue repar. macropages, w c are nvove d n  ssu e rep a r, d s c uss e d  ae r).