Inhibition of geranylgeranyltransferase attenuates neutrophil accumulation and tissue injury in severe acute pancreatitis

[摘要] LeukocyteinfiltrationandacinarcellnecrosisarehallmarksofsevereAP,butthesignalingpathwaysregulatinginflammationandorganinjuryinthepancreasremainelusive.Inthepresentstudy,weinvestigatedtheroleofgeranylgeranyltransferaseinAP.MaleC57BL/6miceweretreatedwithageranylgeranyltransferaseinhibitorGGTI‐2133(20mg/kg)priortoinductionofpancreatitisbyinfusionoftaurocholateintothepancreaticduct.PretreatmentwithGGTI‐2133reducedplasmaamylaselevels,pancreaticneutrophilrecruitment,hemorrhage,andedemaformationintaurocholate‐evokedpancreatitis.Moreover,administrationofGGTI‐2133decreasedthetaurocholate‐inducedincreaseofMPOactivityinthepancreasandlung.TreatmentwithGGTI‐2133markedlyreducedlevelsofCXCL2inthepancreasandIL‐6intheplasmainresponsetotaurocholatechallenge.Notably,geranylgeranyltransferaseinhibitionabolishedneutrophilexpressionofMac‐1inmicewithpancreatitis.Finally,inhibitionofgeranylgeranyltransferasehadnodirecteffectonsecretagogue‐inducedactivationoftrypsinogeninpancreaticacinarcellsinvitro.AsignificantroleofgeranylgeranyltransferasewasconfirmedinanalternatemodelofAPinducedbyL‐argininechallenge.OurfindingsshowthatgeranylgeranyltransferaseregulatesneutrophilaccumulationandtissuedamageviaexpressionofMac‐1onneutrophilsandCXCL2formationinAP.Thus,theseresultsrevealnewsignalingmechanismsinpancreatitisandindicatethattargetinggeranylgeranyltransferasemightbeaneffectivewaytoamelioratesevereAP...

[学科分类] 生理学

[关键词] myeloperoxidase;extravasation;pancreas;inflammation;chemikine;L‐arginine