Coordinated induction of cyclooxygenase‐2/prostaglandin E2 and hepatocyte growth factor by apoptotic cells prevents lung fibrosis

[摘要] ApoptoticcellinstillationafterbleomycininducespersistentHGFproductionandprotectsfrompulmonaryfibrosis,buttheunderlyingmechanismremainsunclear.Weinvestigatedimmediateandprolongedeffectsofinvivoinstillationofapoptoticcellsintobleomycin‐stimulatedmouselungs(2daysold)onCOX‐2expressioninlungtissueandalveolarmacrophagesandPGE2productioninBALF.Furthermore,functionalinteractionbetweenthesemoleculesandHGF,followingapoptoticcellinstillationinableomycin‐inducedlungfibrosismodel,wasassessed.ApoptoticcellinstillationresultsinenhancedimmediateandprolongedexpressionofCOX‐2andPGE2whencomparedwiththosefrombleomycin‐only‐treatedmice.CoadministrationoftheCOX‐2‐selectiveinhibitorNS398ortheselectivePGE2REP2inhibitorAH6809inhibitedtheincreaseinHGFproduction.InhibitionofHGFsignalingusingPHA‐665752inhibitedincreasesinCOX‐2andPGE2.Long‐terminhibitionofCOX‐2,PGE2,orHGFreversedthereductionofTGF‐β,apoptoticandMPOactivities,proteinlevels,andhydroxyprolinecontents.Up‐regulationofCOX‐2/PGE2andHGFthroughapositive‐feedbackloopmaybeanimportantmechanismwherebyapoptoticcellinstillationexertsthenetresultsofanti‐inflammatory,antiapoptotic,andantifibroticaction...

[学科分类] 生理学

[关键词] TGF‐βalveolar macrophages;pulmonary fibrosis;bleomycin;mice