Accelerated CCl4-Induced Liver Fibrosis in Hjv-- Mice, Associated with an Oxidative Burst and Precocious Profibrogenic Gene Expression 英文参考文献.docVIP

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Accelerated CCl4-Induced Liver Fibrosis in Hjv-- Mice, Associated with an Oxidative Burst and Precocious Profibrogenic Gene Expression 英文参考文献.doc

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Accelerated CCl4-Induced Liver Fibrosis in Hjv-- Mice, Associated with an Oxidative Burst and Precocious Profibrogenic Gene Expression 英文参考文献

AcceleratedCCl4-InducedLiverFibrosisinHjv-/-Mice, AssociatedwithanOxidativeBurstandPrecocious ProfibrogenicGeneExpression GiadaSebastiani1,2,KostasGkouvatsos1,2,CarmenMaffettone1,2,GraziellaBusatto3,MariaGuido3,4, KostasPantopoulos1,2 * 1LadyDavisInstituteforMedicalResearch,JewishGeneralHospital,Montreal,Quebec,Canada,2DepartmentofMedicine,McGillUniversity,Montreal,Quebec,Canada, 3DepartmentofDiagnosticSciencesandSpecialTherapies,UniversityofPadova,Padova,Italy,4PathologyDepartment,AziendaULSS15VenetoRegion,Italy Abstract Hereditary hemochromatosis is commonly associated with liver fibrosis. Likewise, hepatic iron overload secondary to chronicliverdiseasesaggravatesliverinjury.Touncoverunderlyingmolecularmechanisms,hemochromatotichemojuvelin knockout(Hjv-/-)miceandwildtype(wt)controlswereintoxicatedwithCCl4.Hjv-/-micedevelopedearlier(by2-4weeks) and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severecoagulativenecrosisandfibrosis.Theseresponseswereassociatedwithanoxidativeburstandearlyupregulationof mRNAs encoding a1-(I)-collagen, the profibrogenic cytokines TGF-b1, endothelin-1 and PDGF and, notably, the iron- regulatory hormone hepcidin. Hence, CCl4-induced liver fibrogenesis was exacerbated and progressed precociously in Hjv2/2animals.Eventhoughliversofna?¨veHjv2/2miceweredevoidofapparentpathology,theyexhibitedoxidative stress and immunoreactivity towards a-SMA antibodies, a marker of hepatic stellate cells activation. Furthermore, they expressed significantly higher (2–3 fold vs. wt, p,0.05) levels of a1-(I)-collagen, TGF-b1, endothelin-1 and PDGF mRNAs, indicativeofearlyfibrogenesis.Ourdatasuggestthathepaticironoverloadinparenchymalcellspromotesoxidativestress andtriggers premature profibrogenic gene expression, contributingto accelerated onsetandprecipitous progression of liverfibrogenesis. Citation:SebastianiG,GkouvatsosK,MaffettoneC,BusattoG,GuidoM,etal.(2011)AcceleratedCCl4-InducedLiverFi