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1、TheInternationalJournalofBiochemistry&CellBiology39(2007)23242338OverexpressionofMMP9inmacrophagesattenuatespulmonary?brosisinducedbybleomycinSandraCabreraa,MiguelGaxiolab,JoseLuisArreola′b,RemediosRam′?reza,PaulJaraa,JeanineDArmientoc,ThomasRichardsd,MoisesSelman′b,AnniePardoa,
2、?aFacultaddeCiencias,UniversidadNacionalAut′onomadeM′exico,MexicobInstitutoNacionaldeEnfermedadesRespiratorias,MexicocDepartmentofMedicine,ColumbiaUniversity,NewYork,NY,USAdUniversityofPittsburghMedicalCenter,Pittsburgh,PA,USAReceived18March2007;receivedinrevisedform17June2007;ac
3、cepted23June2007Availableonline12July2007AbstractPulmonary?brosisisacommonresponsetoavarietyoflunginjuries,characterizedby?broblast/myo?broblastexpansionandabnormalaccumulationofextracellularmatrix.Anincreasedexpressionofmatrixmetalloprotease9(MMP9)inhumanandexperimentallung?bros
4、ishasbeendocumented,butitsroleinthe?broticresponseisunclear.WestudiedtheeffectofMMP9overexpressioninbleomycin-drivenlung?brosisusingtransgenicmiceexpressinghumanMMP9inalveolarmacrophages(hMMP9-TG).At8weekspost-bleomycin,theextentof?broticlesionsandOH-prolinecontentweresigni?cantl
5、ydecreasedintheTGmicecomparedtotheWTmice.Thedecreased?brosisinhMMP9-TGmicewasprecededbyasigni?cantreductionofneutrophilsandlymphocytesinbronchoalveolarlavage(BAL)at1and4weekspost-bleomycin,respectively,aswellasbysigni?cantlylessTIMP-1thantheWTmice.Fromavarietyofcytokines/chemokin
6、esinvestigated,wefoundthatBALlevelsofinsulin-likegrowthfactorbindingprotein-3(IGFBP3)aswellastheimmunoreactiveproteininthelungsweresigni?cantlylowerinhMMP9-TGmicecomparedwithWTmicedespitesimilarlevelsofgeneexpression.UsingIGFBP-3substratezymographywefoundthatBALfromTGmiceat1weeka
7、fterbleomycincleavedIGFBP-3.Further,wedemonstratedthatMMP9degradedIGFBP-3intolowermolecularmassfragments.These?ndingssuggestthatincreasedactivityofMMP9secretedbyalveolarmacrophagesinthelungmicroenvironmentmayhaveananti?broticeffectandprovideapotentialmechanisminvolvingIGFBP3degra
8、dation.?2007ElsevierLtd.Allrightsreserve
