Robbins Essential Pathology PDF Chapter 2 - Inflammation and Repair

Summary

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.

Full Transcript

CHAPTER 2 Inflammation and Repair 15...

CHAPTER 2 Inflammation and Repair 15 STIMULUS and or compemen proens, w c re cog nze mcrob es co ae d (microbes, necrotic tissue) (ops onze d) w   an b o des and compemen. 2. Recr utment o eu ko c yes and p as ma proe  ns  no  e  ssues. RECOGNITION BY TISSUE CELLS B e c aus e bo o d p er  us es e ve r y  ssue,  eu ko c y e s and proe ns (”sentinels”) suc as compemen c an be d eve re d o any vas c u  ar z e d se o mcrob a  nvas on. Wen 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 , man y ne u rop  s;  aer, mono c yes and y mpo c y es) and p as ma proe ns are rapd y re cr ue d  rom  e c  rc u  a  on o  e ex ravas c u  ar se Blood vessel w ere  e o endng agen s  o c ae d. Te exo dus o c e s and p asma proens  rom bo o d re qu res co ord  nae d canges n bo o d vess es and  e s e cre   on o me d aors , d es c r b e d n more de a   aer. Exudation of fluid and plasma proteins 3. Remova o e smuus or nlammaon s accompsed many by pagocyc ces, wc nges and desroy mcrobes and dead ces. DILATION; Pagocyoss, descrbed aer, nvoves ree sequena seps: (1) rec- INCREASED ognon and aacmen o e parce o be ngesed by e eukocye; PERMEABILITY (2) engumen, w subsequen ormaon o a pagocyc vacuoe; and (3) desrucon o e ngesed maera. 4. Reg uaton o  e resp ons e s mp or  an or er m na  ng  e re ac -  on w en  as accompse 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  aors and d e a  o eu ko c yes a er  e s mu us s e m nae d. I s  key  a, n conc e r  w   LEUKOCYTE  e n  ammaor y resp ons e, ac  ve re g u  aor y me can 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. Repar eas e damage, and s dscussed a e end o e caper. Features of Acute and Chronic Inflammation The two principal patterns of inammation, acute and chronic, differ in kinetics and many other features LEUKOCYTE Acute nammaton s a rapd, oten se-med, response o nec- TRANSMIGRATION ons and ssue damage I ypcay deveops wn mnues or ours and s o sor duraon (severa ours o a ew days). I s caracer- zed by e exudaon o lud and pasma proens (edema) and e emgraon o eukocyes, predomnany neurops. I e ofend- LEUKOCYTE ACTIVATION AND ng smuus s emnaed, e reacon subsdes and resdua njur y ELIMNINATION OF STIMULUS s repared. Bu  e na response as o cear e smuus, e Fig. 2.1 Sequence of events in inflammation. In most inflamma- reacon progresses o a proraced ype o nlammaon a s caed tory reactions, recognition of an offending agent (the stimulus for cronc nlammaon. inflammation) leads to the production of chemical mediators, which Chronc nammaton may oow acue nlammaon or arse elicit the vascular and cellular reactions that serve to eliminate the de novo (and acue nlammaon may be supermposed on a back- offenders. ground o cronc nlammaon). Cronc nlammaon s o onger duraon and s assocaed w more ssue desrucon, e presence p a ogens), endos omes (or ngese d mcrob es), or  e c yos o o ympoc yes and macropages, e proeraon o bood vesses, (or n race u  ar agens). S ens ors o ce  d amage are pres en n and ibross.  e c yos o o a ce s: e y re cog nze moe c u es  a resu   rom Aoug e dsncon beween acue and cronc nlamma- ce  njur y (e.g., ur c acd, a pro duc  o DNA bre a kdow n). es e on was orgnay based on e duraon o e reacon, we now re cepors b eong o s e vera  moe c u  ar am es, ncudng To - know a ey dfer n severa ways (Tabe 2.1). Acue nlammaon  ke re cepors, NOD- ke re cepors, and o ers. e y are c a  e d s e response o ofendng agens a are ready emnaed, suc p aer n re cog n on re cepors b e c aus e  e y re cog nze and are as many bacera and vra necons and dead ces, and cronc ac  vae d by mcrob a  and de ad ce  pro duc s c a  e d p a ogen- necon s a response o agens a are dcu o eradcae, suc as ass o c ae d and d amage-ass o c ae d moe c u  ar p aer ns (PAMPs some bacera and oer paogens, as we as se and envronmena and DAMPs, resp e c  vey). Engagemen o  e re cepors e ads angens. o  e pro duc  on o me d aors o nl amma on, ncudng c yo- Cells of Inflammation k nes, w os e  unc  ons are des cr b e d  aer. A subs e o c yos oc NOD- ke re cepors ac  vaes a mu  proen compex c a  e d  e The principal cells of inammation are leukocytes (white blood nammas ome, w c s mu  aes  e pro duc  on o  e pron- cells) in the circulation and tissues. l ammaor y and e ver-nducng c yok ne nereu k n-1 (IL-1). he major ces o nlammaon are (1) ssue-resden sennes L eu ko c yes a s o express re cepors or  e Fc p or  on o an b o des a deec paogenc mcrobes, oxns, and producs 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 aso produce many o e medaors o nlammaon, and (2)    Eosnophs are oten seen n aergc reacons and necons pagocyc ces a emnae e noxous subsances. w emnc parases.    he major sentne ces are:    D endrtc ces, so named because o er dendre-ke projec- ACUTE INFLAMMATION ons, recognze mcrobes and dead ces and aso capure and Acute inammation is a rapid tissue response to microbes, toxins, dspay proen angens o T ces, o nae mmune responses. necrotic cells, and antibody deposition.    Mast ces are ocaed adjacen o bood vesses. Acue nlammaon consss o vascuar and ceuar reacons a    Tssue-resdent macropages are presen n a connecve ssues dever eukocyes and pasma proens rom e bood no e ssues, and mos organs. hey are gven speca names n dferen organs were ese ces and proens ge rd o e noxous subsances a (e.g., Kuper ces n e ver, mcroga n e cenra nervous eced e response. sysem, aveoar macrophages n e ung). Durng nlammaon, mos macropages are derved rom bood monocyes, wc Vascular Reactions orgnae rom emaopoec sem ces n e bone marrow. The major changes in blood vessels during acute inammation are Many o e ssue-resden macropages are derved rom ema- dilation and increased permeability. opoec progenors n e yok sac and ea ver eary durng he ex o ces and pasma proens rom e bood no ssues deveopmen and are ong-ved. requres aeraons n bood vesses. he na canges are daon    Phagocytes are ces specazed or eang and kng ofendng agens. and ncreased permeaby o e vesses, oowed by canges a pro- he wo major casses o crcuang pagocyes, neutrophs (poymor- moe e ex o eukocyes. ponucear eukocyes, or PMNs) and monocytes, are recrued rom    Vasodaton s nduced by e acon o severa medaors, noaby e bood no e se o nlammaon. Foowng er enry no samne, on vascuar smoo musce. I irs nvoves e areroes ssues, monocyes maure no macropages. Neurops are more and en eads o e openng o new capar y beds n e area. he abundan eary n e reacon because ey are more numerous n e resu s ncreased bood low, wc s e cause o ea and redness bood and respond more rapdy o cemoacc medaors, bu w (er yema) a e se o nlammaon. me macropages become progressvey domnan because ey are    Increase n vascuar permeabty can occur by wo mecansms: onger ved. Aoug bo ce ypes sare e common uncon o conracon o endoea ces and drec endoea njur y. Con- pagocyoss, ey dfer n e span and specazed acves (Tabe racon o endoea ces w openng o nerendoea spaces 2.2). s e mos common mecansm o vascuar eakage. hs response    Oer ces pay dverse roes n varous nlammaor y reacons: s eced by samne, bradyknn, eukorenes, and oer cem-    Lymphocytes, especay T ymphocytes, are promnen wen e ca medaors a aso cause vasodaon, and occurs rapdy ater ofendng agen ecs an adapve mmune response. hs s exposure o e medaor (wn 15 o 30 mnues). he bood low oten e case w vra necons and auommune and aergc sows, aowng pasma proens a medae os deense o pass reacons. Anbody-producng B ymphocytes and pasma ces roug e vesses no e ssue. Drec endoea njur y s e may aso be promnen n reacons o parcuar smu. 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. mecansm by wc ces and proens escape venues, capares, he ype o eukocye a emgraes no a se o necon or njur y and areroes n cases o severe necrozng njur y (e.g., burns) and depends on e naure o e orgna smuus and e duraon o e exposure o some mcroba oxns. response. Bacera necons end o nay recru neurops, e proen-rc lud a escapes no e ssue (exudate) resus wereas vra necons recru ympocyes, aergc reacons ave n edema a e se o nlammaon. he oss o lud and ncreased ncreased eosnops, and n some cases a mxed nirae. In acue vesse dameer ead o sower bood low, ncreased concenraon o nlammaon, neurops predomnae durng e irs 6 o 24 ours, red ces n sma vesses, and ncreased vscosy o e bood. hese and en undergo apoposs (n 24 o 48 ours), o be repaced by canges resu n e engorgemen o sma vesses w sowy mov- monocyes. ng red ces, a condon ermed stass, wc s seen soogcay as Te 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 vascuar congeston and exernay as ocazed redness (er y tema) 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 nvoved ssue. As sass deveops, bood eukoc yes, prncpay 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 neurops, begn o adere o e vascuar endoeum, 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 sep n er mgraon ou o e vesses.  e o e n d  ng a ge n. E ac sep  nvo ve s s ou b e m e d  a or s an d Lympac vesses aso parcpae n nlammaor y reacons 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- ep o remove e exudae. Vesses dranng ses o acue nlamma-  ea  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 congesed (ympangs), and e dranng  e ave  e v a s c u  au re. Te pr  n c p a  a d  e s  on m o e c u  e s b e  ong o ymp nodes are swoen and ender (ympadens).  wo  am    e s o pro e  ns , s e  e c   ns an d  n e g r  ns , an d  er   g an d s (Fg. 2.2 an d Tab e 2.3). Te seps 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 naton. As  e bo o d  ow sow s ,  eu ko c ye s , Cytokines and other mediators activate endothelial cells at the site b eng  arger  an re d ce s , sow d ow n  e mos and acc umu  ae of inammation 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 bnd o  e end o- thelium and the subsequent migration of cells through the endo-  eum. 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    Endotea actvaton. Two o e cyoknes secreed n response o    Stabe adeson o eukocyes. he acvaed negrns on e eukocyes mcrobes and oer smu, umor necross acor (TNF) and IL-1, bnd gy o er gands, wc are nduced on endoea ces by ac on nearby endoea ces o ncrease e expresson o seec- cyoknes, eadng o e arres and irm aacmen o eukocyes o ns and gands or negrns. Cyoknes aso conver e endoe- e endoeum. a surace rom s norma anromboc sae o a proromboc    L eukoc y te transmg raton. C emok nes and o er me d  aors, sae. Loca romboss may preven dssemnaon o mcrobes and suc as eu ko r enes , comp eme n pro duc  s , and s ome m crob a  oxns. pro duc s, s mu  ae eu ko c y e ce mo axs (d re c e d movemen    Leukocyte rong. Seecn gands on e ps o neurop mcro- a ong a cemc a  g rad  en ). T e  eu ko c y e s mg rae b e  we e n v bnd o seecns on e endoeum. s s a ow-any endo e a  sp aces,  roug   e ve ss e w a  , o  e se o n   am - neracon a s easy dsruped by e lowng bood. hereore, ma on. Ts pro cess o eu ko c y e ex rav as a  on as b een c a  e d e eukocyes bnd, deac, and bnd agan, and us sowy ro dapedes s. aong e endoeum. The noxious substances that triggered inammation are cleared    Integrn actvaton. Cemoknes secreed by senne ces n e s- by phagocytosis followed by intracellular destruction, which pro sue and aso by acvaed endoea ces bnd o and are dspayed ceeds through the following steps (Fig. 2.3) on e surace o e endoeum. hese cemoknes are recog-    Recognton, attacment, and engufment. Acvaed neurops and nzed by recepors on e rong eukocyes, wc dever sgnas macropages bnd mcrobes and oer parces (suc as ragmens a cange e conormaon o negrns on e eukocyes rom a o dead ces, cr ysas, and oregn maera), wrap er pasma ow-any o a g-any sae. membranes around e parces, and nernaze e parces no 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 vesces caed endosomes or pagosomes. Pagocyes use a varey gone and because medaors (see e oowng) and neurops are sor o recepors o bnd o mcrobes, suc as mannose recepors a ved. In addon, as nlammaon deveops, e process se rggers bnd o ermna mannose on mcroba ce wa gycoproens. a varey o sop sgnas a acvey ermnae e reacon, ncudng a e ecency o s process s greay ncreased  e parces are swc n e ype o aracdonc acd meaboe produced, rom pron- opsonzed w ags or wc e pagocyes ave recepors, suc lammaory eukorenes o annlammaory poxns (descrbed aer), as IgG anbodes (wc bnd o IgG-specic Fc recepors on e and e beraon o annlammaory cyoknes, ncudng ransormng pagocyes) and compemen producs C3b and C4b (wc bnd grow acor-β (TGF-β) and IL-10, rom macropages and oer ces. o compemen recepors). Mediators of Inflammation    Kng and destr uc ton. Pagos omes  us e w   y s os omes, and s e vera  enzy mes are ac  vae d n  e con   ne s o  es e ves  ces The reactions of inammation described previously are induced (w ere  e y des roy  e  nge se d sub s anc es w  ou d amag  ng by chemicals, called the mediators of inammation, that are pro-  e pago c ye 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 medaors may be produced by ces resdng a e se o e u es. Tes e g ranu es con an en zy mes  a d es roy ngese d sub- nlammaor y reacon or a are recrued rom e bood and ac- s ances (e.g., e as as e, a s er  ne proe as e  a ce aves  e ma r  x vaed a e se o nlammaon. hey are produced ony n response proen e as n, and many o er proe as es) and o er e nzy mes o moecues a smuae nlammaon, ncudng mcroba prod-  a ac  vae k   ng me can sms ( e. g. , mye op erox  d as e, w   c ucs and subsances reeased rom necroc ces. One medaor can conver s re ac  ve oxy gen sp e c es o more d es r uc  ve  re e r ad - smuae e reease o oer medaors. For nsance, producs o com- c a s, des cr b e d nex). pemen acvaon smuae e reease o samne, and e cyokne    Leukocyte actvaton. Crcuang eukocyes are n a quescen TNF acs on endoea ces o smuae e producon o anoer sae so a ey do no cause njur y o ssues. Ater acvaon cyokne, IL-1, and many cemoknes. hey qucky decay, are nac- by mcroba producs suc as popoysaccardes, cyoknes suc vaed by enzymes, or are oer wse scavenged or nbed. here s as neeron-γ (IFN-γ) and cemoknes, and pagocyc recepors us a sysem o cecks and baances a reguaes medaor acons. suc as mannose recepors or recepors or opsonns, e eukocyes Cell-Derived Mediators acqure e aby o desroy ngesed mcrobes and dead ces.    he major kng mecansms o neurops and macropages hese are produced ocay by e senne ces a recognze pao- ncude reacve oxygen speces (ROS) (see Caper 1), nrc oxde, gens and dead ces, and by recrued eukocyes. he major casses o and ysosoma enzymes. ese medaors are e oowng.    ROS are produced many n neurops by e respraory burs, Hstamne s a sma moecue a daes areroes by acng on a process naed by rapd assemby o e pagocye oxdase smoo musce ces and ncreases e permeaby o capares and enzyme n e membrane o e pagoysosome. hs enzyme ca- venues by causng reracon o endoea ces. I s sored n mas ayzes e generaon o e ROS superoxde, wc can be con- ce granues and reeased rapdy upon mas ce acvaon by pao- vered o ydrogen peroxde or, under e acon o neurop gens and oer sgnas, suc as bndng o aergens o IgE on mas ce myeoperoxdase, o gy reacve ades. A o ese subsances Fc recepors, exposure o e compemen producs C5a and C3a, and damage proens, DNA, and pd membranes and us desroy pysca rauma and ea. mcrobes and ad n e ceanup o debrs rom necroc ces. Prostagandns and eukotrenes are derved rom aracdonc Heay ssues are normay proeced rom ROS-medaed dam- acd. In many ce ypes, nlammaor y smu nduce e enzyme age by e acon o anoxdan enzymes a degrade ROS, suc pospopase A2, wc beraes aracdonc acd rom membrane as superoxde dsmuase, wc degrades superoxde, and caaase, pospopds. Aracdonc acd s en convered by e enzyme wc deoxies ydrogen peroxde, as we as serum proens a cycooxygenase no prosagandns and by poxygenase no euko- scavenge e ree radcas. renes. hese cemcas ave dverse acons on bood vesses and eu-    Ntrc oxde (NO) s made mosy n macropages oowng ran- kocyes, as summarzed n Tabe 2.4. he erapeuc acon o many scrpona acvaon o e enzyme nducbe nrc oxde synase cncay useu annlammaor y drugs depends on er aby o (NOS). NO s convered o ree radcas a ac muc ke ROS. nb e producon or acvy o ese medaors.    Lysosoma enzymes, ncudng easase and oer proeases, gan    Prostagandns are named based on srucura eaures coded by access o e ngesed parces and dges em. a eer (e.g., PGD, PGE, PGF, PGG, and PGH) and a subscrp    E xtraceuar destructon. Some o ese moecues, especay yso- numera (e.g., 1, 2), wc ndcaes e number o doube bonds soma enzymes, are reeased no e exraceuar space, were ey n e compound. he mos mporan prosagandns n nlam- desroy mcrobes and cear dead ssues. Neurops aso exrude maon are PGE , PGD , PGF , PGI (prosacycn), and TXA 2 2 2a 2 2 er nucear conens, ormng a mes o sones and DNA caed (romboxane A ). 2 neurop exraceuar raps (NETs). Mcrobes are rapped n    Leukotrenes are nvoved n vascuar and smoo musce reacons s mes and desroyed by anmcroba subsances a are aso and eukocye recrumen. he syness o eukorenes nvoves reeased no e NETs. mupe seps, e irs o wc generaes eukorene A (LTA ), 4 4 Some coaera damage s an nevabe consequence o proec- wc n urn gves rse o LTB or LTC. LTB s produced by neu- 4 4 4 ve os responses, bu s s usuay se-med. Paoogc esons rops and some macropages, and s a poen cemoacc agen deveop wen e nlammaon s argeed abnormay (e.g., agans and acvaor o neurops, causng aggregaon and adeson o se angens or agans usuay armess envronmena subsances e ces o e venuar endoeum, e generaon o ROS, and suc as poen and oer aergens). e reease o ysosoma enzymes. LTC and s meaboes, LTD 4 4 and LTE , are produced many n mas ces and cause nense vaso- 4 Resolution of Acute Inflammation consrcon, broncospasm (mporan n asma), and ncreased Normay, oowng cearance o e ofendng agen, e acue nlamma- permeaby o venues. In genera, eukorenes are ar more poen ory response sponaneousy subsdes, because e acvang smuus s an samne.

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