Robbins Essential Pathology PDF Chapter 2 - Inflammation and Repair
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This chapter from Robbins Essential Pathology details the crucial elements of inflammation and the repair mechanisms within the body. It explores the process of recognition of stimuli, recruitment of leukocytes, removal of the stimulus, and the regulation and repair of damaged tissues.
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CHAPTER 2 Inflammation and Repair 15...
CHAPTER 2 Inflammation and Repair 15 STIMULUS and or compemen proens, w c re cog nze mcrob es co ae d (microbes, necrotic tissue) (ops onze d) w an b o des and compemen. 2. Recr utment o eu ko c yes and p as ma proe ns no e ssues. RECOGNITION BY TISSUE CELLS B e c aus e bo o d p er us es e ve r y ssue, eu ko c y e s and proe ns (”sentinels”) suc as compemen c an be d eve re d o any vas c u ar z e d se o mcrob a nvas on. Wen p a o ge n c m crob es nvad e e PRODUCTION OF MEDIATORS ssues, or ssue ce s d e, eu ko c y es ( rs , man y ne u rop s; aer, mono c yes and y mpo c y es) and p as ma proe ns are rapd y re cr ue d rom e c rc u a on o e ex ravas c u ar se Blood vessel w ere e o endng agen s o c ae d. Te exo dus o c e s and p asma proens rom bo o d re qu res co ord nae d canges n bo o d vess es and e s e cre on o me d aors , d es c r b e d n more de a aer. Exudation of fluid and plasma proteins 3. Remova o e smuus or nlammaon s accompsed many by pagocyc ces, wc nges and desroy mcrobes and dead ces. DILATION; Pagocyoss, descrbed aer, nvoves ree sequena seps: (1) rec- INCREASED ognon and aacmen o e parce o be ngesed by e eukocye; PERMEABILITY (2) engumen, w subsequen ormaon o a pagocyc vacuoe; and (3) desrucon o e ngesed maera. 4. Reg uaton o e resp ons e s mp or an or er m na ng e re ac - on w en as accompse d s pu r p os e. In arge p ar , e r m na - on s b e c aus e o e d e c ay o me d aors and d e a o eu ko c yes a er e s mu us s e m nae d. I s key a, n conc e r w LEUKOCYTE e n ammaor y resp ons e, ac ve re g u aor y me can sms a s o ADHESION TO are r g gere d a s er ve o ur n o e resp ons e. ENDOTHELIUM 5. Repar eas e damage, and s dscussed a e end o e caper. Features of Acute and Chronic Inflammation The two principal patterns of inammation, acute and chronic, differ in kinetics and many other features LEUKOCYTE Acute nammaton s a rapd, oten se-med, response o nec- TRANSMIGRATION ons and ssue damage I ypcay deveops wn mnues or ours and s o sor duraon (severa ours o a ew days). I s caracer- zed by e exudaon o lud and pasma proens (edema) and e emgraon o eukocyes, predomnany neurops. I e ofend- LEUKOCYTE ACTIVATION AND ng smuus s emnaed, e reacon subsdes and resdua njur y ELIMNINATION OF STIMULUS s repared. Bu e na response as o cear e smuus, e Fig. 2.1 Sequence of events in inflammation. In most inflamma- reacon progresses o a proraced ype o nlammaon a s caed tory reactions, recognition of an offending agent (the stimulus for cronc nlammaon. inflammation) leads to the production of chemical mediators, which Chronc nammaton may oow acue nlammaon or arse elicit the vascular and cellular reactions that serve to eliminate the de novo (and acue nlammaon may be supermposed on a back- offenders. ground o cronc nlammaon). Cronc nlammaon s o onger duraon and s assocaed w more ssue desrucon, e presence p a ogens), endos omes (or ngese d mcrob es), or e c yos o o ympoc yes and macropages, e proeraon o bood vesses, (or n race u ar agens). S ens ors o ce d amage are pres en n and ibross. e c yos o o a ce s: e y re cog nze moe c u es a resu rom Aoug e dsncon beween acue and cronc nlamma- ce njur y (e.g., ur c acd, a pro duc o DNA bre a kdow n). es e on was orgnay based on e duraon o e reacon, we now re cepors b eong o s e vera moe c u ar am es, ncudng To - know a ey dfer n severa ways (Tabe 2.1). Acue nlammaon ke re cepors, NOD- ke re cepors, and o ers. e y are c a e d s e response o ofendng agens a are ready emnaed, suc p aer n re cog n on re cepors b e c aus e e y re cog nze and are as many bacera and vra necons and dead ces, and cronc ac vae d by mcrob a and de ad ce pro duc s c a e d p a ogen- necon s a response o agens a are dcu o eradcae, suc as ass o c ae d and d amage-ass o c ae d moe c u ar p aer ns (PAMPs some bacera and oer paogens, as we as se and envronmena and DAMPs, resp e c vey). Engagemen o e re cepors e ads angens. o e pro duc on o me d aors o nl amma on, ncudng c yo- Cells of Inflammation k nes, w os e unc ons are des cr b e d aer. A subs e o c yos oc NOD- ke re cepors ac vaes a mu proen compex c a e d e The principal cells of inammation are leukocytes (white blood nammas ome, w c s mu aes e pro duc on o e pron- cells) in the circulation and tissues. l ammaor y and e ver-nducng c yok ne nereu k n-1 (IL-1). he major ces o nlammaon are (1) ssue-resden sennes L eu ko c yes a s o express re cepors or e Fc p or on o an b o des a deec paogenc mcrobes, oxns, and producs o ce damage, 16 CHAPTER 2 Inflammation and Repair Table 2.1 Acute and Chronic Inflammation Acute Inflammation Chronic Inflammation Onset Rapid: minutes to hours Slower: days Duration Typically brief (days) Prolonged Cellular infiltrate Mainly neutrophils Macrophages (derived from blood monocytes), lymphocytes Tissue injury Usually self-limited May be extensive Scarring Uncommon Prominent Major mediators Histamine, prostaglandins and leukotrienes, Cytokines, other mediators involved in acute inflam- cytokines, complement proteins mation Local and systemic signs Prominent Usually milder Common causes: Infections Pyogenic bacteria (e.g., staphylococci), fungi, some Intracellular bacteria (e.g., Mycobacterium tuberculo- viruses (e.g., influenza). sis), viruses (e.g., hepatitis), fungi Cell death Ischemic necrosis of tissues Not a frequent underlying cause Immune reactions Antibody deposition in tissues (in autoimmune dis- T cell–mediated inflammatory diseases eases), IgE-mediated immediate hypersensitivity Trauma Physical injury, burns, radiation Sometimes, repeated low-dose radiation exposure Environmental toxins Inhaled particles (e.g., silica, beryllium) Others Crystal deposition in tissues (e.g., gout) Examples of human Infections, acute respiratory distress syndrome Rheumatoid arthritis, atherosclerosis, asthma, diseases pulmonary fibrosis and aso produce many o e medaors o nlammaon, and (2) Eosnophs are oten seen n aergc reacons and necons pagocyc ces a emnae e noxous subsances. w emnc parases. he major sentne ces are: D endrtc ces, so named because o er dendre-ke projec- ACUTE INFLAMMATION ons, recognze mcrobes and dead ces and aso capure and Acute inammation is a rapid tissue response to microbes, toxins, dspay proen angens o T ces, o nae mmune responses. necrotic cells, and antibody deposition. Mast ces are ocaed adjacen o bood vesses. Acue nlammaon consss o vascuar and ceuar reacons a Tssue-resdent macropages are presen n a connecve ssues dever eukocyes and pasma proens rom e bood no e ssues, and mos organs. hey are gven speca names n dferen organs were ese ces and proens ge rd o e noxous subsances a (e.g., Kuper ces n e ver, mcroga n e cenra nervous eced e response. sysem, aveoar macrophages n e ung). Durng nlammaon, mos macropages are derved rom bood monocyes, wc Vascular Reactions orgnae rom emaopoec sem ces n e bone marrow. The major changes in blood vessels during acute inammation are Many o e ssue-resden macropages are derved rom ema- dilation and increased permeability. opoec progenors n e yok sac and ea ver eary durng he ex o ces and pasma proens rom e bood no ssues deveopmen and are ong-ved. requres aeraons n bood vesses. he na canges are daon Phagocytes are ces specazed or eang and kng ofendng agens. and ncreased permeaby o e vesses, oowed by canges a pro- he wo major casses o crcuang pagocyes, neutrophs (poymor- moe e ex o eukocyes. ponucear eukocyes, or PMNs) and monocytes, are recrued rom Vasodaton s nduced by e acon o severa medaors, noaby e bood no e se o nlammaon. Foowng er enry no samne, on vascuar smoo musce. I irs nvoves e areroes ssues, monocyes maure no macropages. Neurops are more and en eads o e openng o new capar y beds n e area. he abundan eary n e reacon because ey are more numerous n e resu s ncreased bood low, wc s e cause o ea and redness bood and respond more rapdy o cemoacc medaors, bu w (er yema) a e se o nlammaon. me macropages become progressvey domnan because ey are Increase n vascuar permeabty can occur by wo mecansms: onger ved. Aoug bo ce ypes sare e common uncon o conracon o endoea ces and drec endoea njur y. Con- pagocyoss, ey dfer n e span and specazed acves (Tabe racon o endoea ces w openng o nerendoea spaces 2.2). s e mos common mecansm o vascuar eakage. hs response Oer ces pay dverse roes n varous nlammaor y reacons: s eced by samne, bradyknn, eukorenes, and oer cem- Lymphocytes, especay T ymphocytes, are promnen wen e ca medaors a aso cause vasodaon, and occurs rapdy ater ofendng agen ecs an adapve mmune response. hs s exposure o e medaor (wn 15 o 30 mnues). he bood low oten e case w vra necons and auommune and aergc sows, aowng pasma proens a medae os deense o pass reacons. Anbody-producng B ymphocytes and pasma ces roug e vesses no e ssue. Drec endoea njur y s e may aso be promnen n reacons o parcuar smu. CHAPTER 2 Inflammation and Repair 17 Table 2.2 Phagocytes Neutrophils Macrophages Origin HSCs in bone marrow HSCs in bone marrow (in inflammatory reactions) Many tissue-resident macrophages: stem cells in yolk sac or fetal liver (early in development) Life span in tissues 1–2 days Inflammatory macrophages: days or weeks Tissue-resident macrophages: years Responses to activat- Rapid, short-lived, mostly degranulation and enzymatic More prolonged, slower, often dependent on new ing stimuli activity gene transcription Reactive oxygen Rapidly induced by assembly of phagocyte oxidase Less prominent species (respiratory burst) Nitric oxide Low levels or none Induced following transcriptional activation of iNOS Degranulation Major response; induced by cytoskeletal rearrange- Not prominent ment Cytokine production Low levels or none Major functional activity, requires transcriptional activation of cytokine genes NET formation Rapidly induced, by extrusion of nuclear contents Less Secretion of lyso- Prominent Less somal enzymes This table lists the major differences between neutrophils and macrophages. The reactions summarized above are described in the text. Note that the two cell types share many features, such as phagocytosis, the ability to migrate through blood vessels into tissues, and chemotaxis. The images show a typical blood neutrophil and monocyte (the precursor of tissue macrophages in inflammatory reactions). HSC, Hematopoietic stem cells; iNOS, inducible nitric oxide synthase; NET, neutrophil extracellular trap. mecansm by wc ces and proens escape venues, capares, he ype o eukocye a emgraes no a se o necon or njur y and areroes n cases o severe necrozng njur y (e.g., burns) and depends on e naure o e orgna smuus and e duraon o e exposure o some mcroba oxns. response. Bacera necons end o nay recru neurops, e proen-rc lud a escapes no e ssue (exudate) resus wereas vra necons recru ympocyes, aergc reacons ave n edema a e se o nlammaon. he oss o lud and ncreased ncreased eosnops, and n some cases a mxed nirae. In acue vesse dameer ead o sower bood low, ncreased concenraon o nlammaon, neurops predomnae durng e irs 6 o 24 ours, red ces n sma vesses, and ncreased vscosy o e bood. hese and en undergo apoposs (n 24 o 48 ours), o be repaced by canges resu n e engorgemen o sma vesses w sowy mov- monocyes. ng red ces, a condon ermed stass, wc s seen soogcay as Te pro c e s s o e u ko c y e e m g r a on c an be d v d e d n o vascuar congeston and exernay as ocazed redness (er y tema) o p a s e s , c ons s ng rs o a d e s on o e u ko c y e s o e n d o e u m e nvoved ssue. As sass deveops, bood eukoc yes, prncpay a e s e o n am m a on , en r ans m g r a on o e e u ko c y e s neurops, begn o adere o e vascuar endoeum, e irs rou g e ve s s e wa , an d n a y m ove m e n o e ce s ow ard sep n er mgraon ou o e vesses. e o e n d ng a ge n. E ac sep nvo ve s s ou b e m e d a or s an d Lympac vesses aso parcpae n nlammaor y reacons and a d e s on m o e c u e s , e a e r e x pre s s e d on e u ko c y e s an d endo- ep o remove e exudae. Vesses dranng ses o acue nlamma- ea ce s, a ow ng e u ko c y e s o a c on o e n d o e a ce s an d on are oten engorged and congesed (ympangs), and e dranng e ave e v a s c u au re. Te pr n c p a a d e s on m o e c u e s b e ong o ymp nodes are swoen and ender (ympadens). wo am e s o pro e ns , s e e c ns an d n e g r ns , an d er g an d s (Fg. 2.2 an d Tab e 2.3). Te seps n e u ko c y e re c r u m e n are e o ow ng : Cellular Reactions L eukoc y te marg naton. As e bo o d ow sow s , eu ko c ye s , Cytokines and other mediators activate endothelial cells at the site b eng arger an re d ce s , sow d ow n e mos and acc umu ae of inammation and stimulate the binding of leukocytes to endo- ne ar e vess e wa , a ow ng e e u ko c y es o bnd o e end o- thelium and the subsequent migration of cells through the endo- eum. thelium into the tissue. 18 CHAPTER 2 Inflammation and Repair ROLLING INTEGRIN ACTIVATION BY CHEMOKINES Selectin ligand Leukocyte STABLE ADHESION Integrin (low-affinity state) MIGRATION THROUGH ENDOTHELIUM Integrin (high-affinity state) P-selectin E-selectin PECAM-1 Proteoglycan (CD31) Integrin ligand (ICAM-1) Cytokines (TNF, IL-1) Chemokines Fibrin and fibronectin Macrophage Microbes (extracellular matrix) with microbes Fig. 2.2 Leukocyte migration from blood to tissues. The multistep process of leukocyte migration through blood vessels is shown here for neutrophils. The leukocytes first roll; then become activated and adhere to the endothelium; and then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process: selectins in rolling; chemokines (usually displayed bound to proteo- glycans on endothelium) in activating the neutrophils to increase the avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. ICAM-1, Intercellular adhesion molecule 1; IL-1, interleukin 1; PECAM-1 (CD31), platelet endothelial cell adhesion molecule-1; TNF, tumor necrosis factor. Table 2.3 Selected Adhesion Molecules in Leukocyte Migration Family Adhesion Molecule Major Cell Type Principal Ligands Selectin L-selectin Lymphocytes Sialyl-Lewis X on various glycoproteins expressed on endo- thelium E-selectin Activated endothelium Sialyl-Lewis X on glycoproteins expressed on neutrophils, monocytes, T lymphocytes P-selectin Activated endothelium Sialyl-Lewis X on glycoproteins expressed on neutrophils, monocytes, T lymphocytes Integrin LFA-1 T lymphocytes, neutrophils ICAM-1 expressed on activated endothelium MAC-1 Monocytes, dendritic cells ICAM-1 expressed on activated endothelium VLA-4 T lymphocytes VCAM-1 expressed on activated endothelium α4β7 T lymphocytes, monocytes MAdCAM-1; expressed on endothelium in gut and gut-associ- ated lymphoid tissues Most of the integrins are expressed on many leukocytes; only the cell types that are most dependent on a particular integrin for adhesion are listed. All the selectins, integrins, and their ligands are also named according to the CD nomenclature, but their CD numbers are not shown for simplicity. ICAM, intercellular adhesion molecule; Ig, immunoglobulin; IL-1, interleukin-1; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule. CHAPTER 2 Inflammation and Repair 19 Endotea actvaton. Two o e cyoknes secreed n response o Stabe adeson o eukocyes. he acvaed negrns on e eukocyes mcrobes and oer smu, umor necross acor (TNF) and IL-1, bnd gy o er gands, wc are nduced on endoea ces by ac on nearby endoea ces o ncrease e expresson o seec- cyoknes, eadng o e arres and irm aacmen o eukocyes o ns and gands or negrns. Cyoknes aso conver e endoe- e endoeum. a surace rom s norma anromboc sae o a proromboc L eukoc y te transmg raton. C emok nes and o er me d aors, sae. Loca romboss may preven dssemnaon o mcrobes and suc as eu ko r enes , comp eme n pro duc s , and s ome m crob a oxns. pro duc s, s mu ae eu ko c y e ce mo axs (d re c e d movemen Leukocyte rong. Seecn gands on e ps o neurop mcro- a ong a cemc a g rad en ). T e eu ko c y e s mg rae b e we e n v bnd o seecns on e endoeum. s s a ow-any endo e a sp aces, roug e ve ss e w a , o e se o n am - neracon a s easy dsruped by e lowng bood. hereore, ma on. Ts pro cess o eu ko c y e ex rav as a on as b een c a e d e eukocyes bnd, deac, and bnd agan, and us sowy ro dapedes s. aong e endoeum. The noxious substances that triggered inammation are cleared Integrn actvaton. Cemoknes secreed by senne ces n e s- by phagocytosis followed by intracellular destruction, which pro sue and aso by acvaed endoea ces bnd o and are dspayed ceeds through the following steps (Fig. 2.3) on e surace o e endoeum. hese cemoknes are recog- Recognton, attacment, and engufment. Acvaed neurops and nzed by recepors on e rong eukocyes, wc dever sgnas macropages bnd mcrobes and oer parces (suc as ragmens a cange e conormaon o negrns on e eukocyes rom a o dead ces, cr ysas, and oregn maera), wrap er pasma ow-any o a g-any sae. membranes around e parces, and nernaze e parces no 1. RECOGNITION AND ATTACHMENT A Microbes bind to phagocyte receptors Lysosome with enzymes Fusion of phagosome with Microbe ingested Phagocytic lysosome in phagosome receptor Degradation of microbes by lysosomal enzymes 2. ENGULFMENT in phagolysosome Phagocyte membrane Phagolysosome zips up around Phagosome with microbe 3. KILLING AND DEGRADATION ingested microbe Cytoplasmic Primary oxidase granule MPO MPO + Cl O NADPH 2 Active oxidase + NADP iNOS O OCl 2 H O Arginine 2 2 ++ Fe Membrane NO oxidase OH ROS Membrane Phagocyte oxidase O 2 B PHAGOCYTIC VACUOLE C Fig. 2.3 Phagocytosis and intracellular destruction of microbes. (A) Phagocytosis of a particle (e.g., a bacte- rium) involves binding to receptors on the leukocyte membrane, engulfment, and fusion of the phagocytic vacuoles with lysosomes. This is followed by destruction of ingested particles within the phagolysosomes by lysosomal enzymes and by reactive oxygen and nitrogen species. (B) In activated phagocytes, cytoplasmic components of the phagocyte oxidase enzyme assemble in the membrane of the phagosome to form the –. active enzyme, which catalyzes the conversion of oxygen into superoxide (O ) and H O. Myeloperoxidase, 2 2 2. present in the granules of neutrophils, converts H O to hypochlorite (OCl ). In the presence of metals such 2 2. ++ as Fe , H O can also be converted to highly reactive hydroxyl radicals (OH ). (C) Microbicidal reactive oxy- 2 2 gen species (ROS) and nitric oxide (NO) kill ingested microbes. During phagocytosis, granule contents may be released into extracellular tissues (not shown). iNOS, Inducible NO synthase; MPO, myeloperoxidase; NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species. 20 CHAPTER 2 Inflammation and Repair vesces caed endosomes or pagosomes. Pagocyes use a varey gone and because medaors (see e oowng) and neurops are sor o recepors o bnd o mcrobes, suc as mannose recepors a ved. In addon, as nlammaon deveops, e process se rggers bnd o ermna mannose on mcroba ce wa gycoproens. a varey o sop sgnas a acvey ermnae e reacon, ncudng a e ecency o s process s greay ncreased e parces are swc n e ype o aracdonc acd meaboe produced, rom pron- opsonzed w ags or wc e pagocyes ave recepors, suc lammaory eukorenes o annlammaory poxns (descrbed aer), as IgG anbodes (wc bnd o IgG-specic Fc recepors on e and e beraon o annlammaory cyoknes, ncudng ransormng pagocyes) and compemen producs C3b and C4b (wc bnd grow acor-β (TGF-β) and IL-10, rom macropages and oer ces. o compemen recepors). Mediators of Inflammation Kng and destr uc ton. Pagos omes us e w y s os omes, and s e vera enzy mes are ac vae d n e con ne s o es e ves ces The reactions of inammation described previously are induced (w ere e y des roy e nge se d sub s anc es w ou d amag ng by chemicals, called the mediators of inammation, that are pro- e pago c ye s e ). Neu rop s ave wo yp e s o g ranu es , duced or activated at the site of the reaction (Table 2.4). c a e d azurop (or pr mar y) and sp e c c (or s e c ond ar y ) g ran - hese medaors may be produced by ces resdng a e se o e u es. Tes e g ranu es con an en zy mes a d es roy ngese d sub- nlammaor y reacon or a are recrued rom e bood and ac- s ances (e.g., e as as e, a s er ne proe as e a ce aves e ma r x vaed a e se o nlammaon. hey are produced ony n response proen e as n, and many o er proe as es) and o er e nzy mes o moecues a smuae nlammaon, ncudng mcroba prod- a ac vae k ng me can sms ( e. g. , mye op erox d as e, w c ucs and subsances reeased rom necroc ces. One medaor can conver s re ac ve oxy gen sp e c es o more d es r uc ve re e r ad - smuae e reease o oer medaors. For nsance, producs o com- c a s, des cr b e d nex). pemen acvaon smuae e reease o samne, and e cyokne Leukocyte actvaton. Crcuang eukocyes are n a quescen TNF acs on endoea ces o smuae e producon o anoer sae so a ey do no cause njur y o ssues. Ater acvaon cyokne, IL-1, and many cemoknes. hey qucky decay, are nac- by mcroba producs suc as popoysaccardes, cyoknes suc vaed by enzymes, or are oer wse scavenged or nbed. here s as neeron-γ (IFN-γ) and cemoknes, and pagocyc recepors us a sysem o cecks and baances a reguaes medaor acons. suc as mannose recepors or recepors or opsonns, e eukocyes Cell-Derived Mediators acqure e aby o desroy ngesed mcrobes and dead ces. he major kng mecansms o neurops and macropages hese are produced ocay by e senne ces a recognze pao- ncude reacve oxygen speces (ROS) (see Caper 1), nrc oxde, gens and dead ces, and by recrued eukocyes. he major casses o and ysosoma enzymes. ese medaors are e oowng. ROS are produced many n neurops by e respraory burs, Hstamne s a sma moecue a daes areroes by acng on a process naed by rapd assemby o e pagocye oxdase smoo musce ces and ncreases e permeaby o capares and enzyme n e membrane o e pagoysosome. hs enzyme ca- venues by causng reracon o endoea ces. I s sored n mas ayzes e generaon o e ROS superoxde, wc can be con- ce granues and reeased rapdy upon mas ce acvaon by pao- vered o ydrogen peroxde or, under e acon o neurop gens and oer sgnas, suc as bndng o aergens o IgE on mas ce myeoperoxdase, o gy reacve ades. A o ese subsances Fc recepors, exposure o e compemen producs C5a and C3a, and damage proens, DNA, and pd membranes and us desroy pysca rauma and ea. mcrobes and ad n e ceanup o debrs rom necroc ces. Prostagandns and eukotrenes are derved rom aracdonc Heay ssues are normay proeced rom ROS-medaed dam- acd. In many ce ypes, nlammaor y smu nduce e enzyme age by e acon o anoxdan enzymes a degrade ROS, suc pospopase A2, wc beraes aracdonc acd rom membrane as superoxde dsmuase, wc degrades superoxde, and caaase, pospopds. Aracdonc acd s en convered by e enzyme wc deoxies ydrogen peroxde, as we as serum proens a cycooxygenase no prosagandns and by poxygenase no euko- scavenge e ree radcas. renes. hese cemcas ave dverse acons on bood vesses and eu- Ntrc oxde (NO) s made mosy n macropages oowng ran- kocyes, as summarzed n Tabe 2.4. he erapeuc acon o many scrpona acvaon o e enzyme nducbe nrc oxde synase cncay useu annlammaor y drugs depends on er aby o (NOS). NO s convered o ree radcas a ac muc ke ROS. nb e producon or acvy o ese medaors. Lysosoma enzymes, ncudng easase and oer proeases, gan Prostagandns are named based on srucura eaures coded by access o e ngesed parces and dges em. a eer (e.g., PGD, PGE, PGF, PGG, and PGH) and a subscrp E xtraceuar destructon. Some o ese moecues, especay yso- numera (e.g., 1, 2), wc ndcaes e number o doube bonds soma enzymes, are reeased no e exraceuar space, were ey n e compound. he mos mporan prosagandns n nlam- desroy mcrobes and cear dead ssues. Neurops aso exrude maon are PGE , PGD , PGF , PGI (prosacycn), and TXA 2 2 2a 2 2 er nucear conens, ormng a mes o sones and DNA caed (romboxane A ). 2 neurop exraceuar raps (NETs). Mcrobes are rapped n Leukotrenes are nvoved n vascuar and smoo musce reacons s mes and desroyed by anmcroba subsances a are aso and eukocye recrumen. he syness o eukorenes nvoves reeased no e NETs. mupe seps, e irs o wc generaes eukorene A (LTA ), 4 4 Some coaera damage s an nevabe consequence o proec- wc n urn gves rse o LTB or LTC. LTB s produced by neu- 4 4 4 ve os responses, bu s s usuay se-med. Paoogc esons rops and some macropages, and s a poen cemoacc agen deveop wen e nlammaon s argeed abnormay (e.g., agans and acvaor o neurops, causng aggregaon and adeson o se angens or agans usuay armess envronmena subsances e ces o e venuar endoeum, e generaon o ROS, and suc as poen and oer aergens). e reease o ysosoma enzymes. LTC and s meaboes, LTD 4 4 and LTE , are produced many n mas ces and cause nense vaso- 4 Resolution of Acute Inflammation consrcon, broncospasm (mporan n asma), and ncreased Normay, oowng cearance o e ofendng agen, e acue nlamma- permeaby o venues. In genera, eukorenes are ar more poen ory response sponaneousy subsdes, because e acvang smuus s an samne.
