炎症介质与抗炎药物

炎症介质与抗炎药物Inflammation(炎症）Theclassicalsignsofinflammationareredness,swelling,heat,pain,andlossoffunction.

SkinabscessPneumoniaTheProcessofInflammation1.Initiationoftheeventbyaforeignsubstanceorphysicalinjury2.Recruitmentandchemoattractionofinflammatorycells,andactivationofthesecells3.Releaseinflammatorymediatorscapableofdamagingorkillinganinvadingmicrobeortumor.Insomeinstances,theinflammatoryresponseisinitiatedbyanotherwiseharmlessforeignmaterial(e.g.,pollen).Inflammationcanalsoresultfromanautoimmuneresponsetothehost’sowntissue,asoccursinrheumatoidarthritis.Whydoweneedanti-inflammatorydrugs?Inmostcases,theinflammatoryresponseeventuallysubsides,butifsuchaself-limitingregulationdoesnotoccur,theinflammatoryresponsewillrequirepharmacologicalintervention.Theneedforanti-inflammatorydrugsariseswhentheinflammatoryresponseisinappropriate,aberrant,sustained,orcausesdestructionoftissue.Hosttissuemayundergoinjury,sincemanyoftheinflammatorymediatorsarenotspecificforaparticulartissuetarget.THEINFLAMMATORYPROCESSThephasesofinflammatoryresponsesRapidphase:secondstominutes,consistingofvasodilation,increasedbloodflow,edema,andpain.Chronicphase:overmonthstoyears;dramaticallyincreasedproductionofinflammatorymediators.AsthmaSecondarychronicphaseofinflammation:afteryearsofoxidativedamagehasdegradedbloodvesselsandtissues.Suchchronicinflammationappearstoplayaroleinmanydiseasestates,suchasarteriosclerosisandcancer.动脉硬化InflammatoryMediatorsEicosanoids类花生酸Theeicosanoids,derivedfroma20-carbonunsaturatedfattyacid,arachidonicacid(eicosatetraenoicacid),areobtainedfrommembranephospholipidsandsynthesizeddenovoatthetimeofcellularstimulation.ArachidonateMetabolismPathways

Phospholipids

ArachidonicAcid

COX-2COX-1Oldanti-inflammatorydrugtarget

ProstaglandinH2

PGI2

PGF2α

PGE2PGD2TXA2

PhospholipaseA2PGESPGES:prostaglandinEsynthase,anewanti-inflammatorydrugtargetPGDH15-keto-PGE2Cyclooxygenase(COX)Twoisoforms:COX-1：Constitutiveor“housekeeping”isoformthatisresponsibleforthebasalproductionofprostaglandins,prostacyclins,andthromboxanes.COX-2：Induciblebycytokinesandotherinflammatorystimuliandisbelievedtopredominateduringchronicinflammation.ThefinalproductoftheCOXpathwayistissuespecific.Forexample,plateletsproducethromboxaneA2(TxA2);vascularendothelialcellsproduceprostacyclin(PGI2);mastcellsproduceprostaglandinD2(PGD2);COX-2selectiveinhibitorssuperiortonon-selectiveinhibitors?15-ProstaglandinDehydrogenaseCOX-2and15-PGDHapricoxibNONSTEROIDALANTIINFLAMMATORY

DRUGS(NSAIDs)Thenonsteroidalanti-inflammatorydrugs(NSAIDs)haveavarietyofclinicalusesasantipyretics,analgesics,andanti-inflammatoryagents.Unliketheopioidanalgesics,theydonotcauseneurologicaldepressionordependence.NSAIDsreducepainandinflammationassociatedwithrheumatoiddiseasesbutdonotdelayorreversethedisease’sprogress.MechanismofAction

Theanti-inflammatoryactionsoftheNSAIDsaremostlikelyexplainedbytheirinhibitionofprostaglandinsynthesisbyCOX-2.TheCOX-2isoformisthepredominantCOXinvolvedintheproductionofprostaglandinsduringinflammatoryprocesses.ProstaglandinsoftheEandFseriesevokesomeofthelocalandsystemicmanifestationsofinflammation,suchasvasodilation,hyperemia,increasedvascularpermeability,swelling,pain,andincreasedleukocytemigration.AdverseEffectsofNSAIDs

AnumberofthetoxicitiescommonlycausedbytheNSAIDsresultfromtheinhibitionofprostaglandinsynthesis.TheabilityofNSAIDstoincreasegastricacidsecretionandinhibitbloodclottingcanleadtoGItoxicity.BiologicalOxidantsThebiologicallyderivedoxidantsarepotentbacterialkillersbutarealsoamajorcontributingfactorintissueinjurythatresultsfromtheinflammatoryresponse.Theseoxidantsincludethesuperoxideanion(•O2-),hydrogenperoxide(H2O2),nitricoxide(NO),peroxynitrite(OONO),hypochlorousacid(HOClTheseoxidants,largelygeneratedbyphagocyticcellssuchasneutrophilsandmacrophages,inducetissueinjurybeyondthatproducedbydigestiveenzymesandeicosanoids.Inhibitionofproductionoftheseoxidantsorinactivationofthesesubstancesbyantioxidantsisanimportantstrategyforthetreatmentofinflammatorydisorders.CytokinesTNF-andIL-1areproducedprimarilybycellsofthemonocyte–macrophagelineage.Theyworkinconcerttostimulateinflammatoryresponsessuchaspain,fever,andtherecruitmentoflymphocytes.Inaddition,theyinduceproductionofmanyotherinflammatorymediatorsandcontributetothetissuedamageseeninchronicinflammation.ApproximatelyonemillionindividualsworldwideareeitherundergoingtreatmentorhavebeentreatedwithTNFinhibitorsavailableinthepharmaceuticalmarket,encompassingindicationsthatincluderheumatoidarthritis,psoriaticarthritis牛皮癣性关节炎,psoriasis银屑病andinflammatoryboweldiseases炎症性肠病糖皮质激素（Glucocorticoid），又名“肾上腺皮质激素”，是由肾上腺皮质分泌的一类甾体激素