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1、TheInternationalJournalofBiochemistry&CellBiology39(2007)23242338OverexpressionofMMP9inmacrophagesattenuatespulmonaryfibrosisinducedbybleomycinSandraCabreraa,MiguelGaxiolab,JoseLuisArreola´b,RemediosRam´ıreza,PaulJaraa,JeanineDArmientoc,ThomasRichardsd,MoisesSelman´b,AnniePardoa,
2、∗aFacultaddeCiencias,UniversidadNacionalAut´onomadeM´exico,MexicobInstitutoNacionaldeEnfermedadesRespiratorias,MexicocDepartmentofMedicine,ColumbiaUniversity,NewYork,NY,USAdUniversityofPittsburghMedicalCenter,Pittsburgh,PA,USAReceived18March2007;receivedinrevisedform17June2007;ac
3、cepted23June2007Availableonline12July2007AbstractPulmonaryfibrosisisacommonresponsetoavarietyoflunginjuries,characterizedbyfibroblast/myofibroblastexpansionandabnormalaccumulationofextracellularmatrix.Anincreasedexpressionofmatrixmetalloprotease9(MMP9)inhumanandexperimentallungfibros
4、ishasbeendocumented,butitsroleinthefibroticresponseisunclear.WestudiedtheeffectofMMP9overexpressioninbleomycin-drivenlungfibrosisusingtransgenicmiceexpressinghumanMMP9inalveolarmacrophages(hMMP9-TG).At8weekspost-bleomycin,theextentoffibroticlesionsandOH-prolinecontentweresignificantl
5、ydecreasedintheTGmicecomparedtotheWTmice.ThedecreasedfibrosisinhMMP9-TGmicewasprecededbyasignificantreductionofneutrophilsandlymphocytesinbronchoalveolarlavage(BAL)at1and4weekspost-bleomycin,respectively,aswellasbysignificantlylessTIMP-1thantheWTmice.Fromavarietyofcytokines/chemokin
6、esinvestigated,wefoundthatBALlevelsofinsulin-likegrowthfactorbindingprotein-3(IGFBP3)aswellastheimmunoreactiveproteininthelungsweresignificantlylowerinhMMP9-TGmicecomparedwithWTmicedespitesimilarlevelsofgeneexpression.UsingIGFBP-3substratezymographywefoundthatBALfromTGmiceat1weeka
7、fterbleomycincleavedIGFBP-3.Further,wedemonstratedthatMMP9degradedIGFBP-3intolowermolecularmassfragments.ThesefindingssuggestthatincreasedactivityofMMP9secretedbyalveolarmacrophagesinthelungmicroenvironmentmayhaveanantifibroticeffectandprovideapotentialmechanisminvolvingIGFBP3degra
8、dation.©2007ElsevierLtd.Allrightsreserve
