Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation.
Hepatic fibrosis is a common outcome of a variety of chronic liver diseases. Here we evaluated the therapeutic efficacy of hepatocyte growth factor (HGF) on liver fibrosis induced by bile duct ligation (BDL) and investigated potential mechanisms. Mice underwent BDL, followed by intravenous injections of naked HGF expression plasmid or control vector. HGF gene therapy markedly ameliorated hepatic fibrotic lesions, as demonstrated by reduced alpha-smooth muscle actin (alphaSMA) expression, attenuated deposition of type I and type III collagen, and normalized total hydroxyproline content. HGF also suppressed transforming growth factor-beta1 (TGF-beta1) expression. Interestingly, colocalization of alphaSMA and cytokeratin-19 in bile duct epithelium was observed, suggesting the possibility of biliary epithelial to myofibroblast transition after BDL. Cells that were still positive for cytokeratin-19 but actively producing type I collagen were found in the biliary epithelia and periductal region. Laminin staining revealed an impaired basement membrane of the bile duct epithelium in diseased liver. These lesions were largely prevented by HGF administration. In vitro, treatment of human biliary epithelial cells with TGF-beta1 induced alphaSMA and fibronectin expression and suppressed cytokeratin-19. HGF abolished the phenotypic conversion of biliary epithelial cells induced by TGF-beta1. These results suggest that HGF ameliorates hepatic biliary fibrosis in part by blocking bile duct epithelial to mesenchymal transition.
Xia
Jing-Lin
JL
Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Dai
Chunsun
C
Michalopoulos
George K
GK
Liu
Youhua
Y
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000502:physiology*; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D002465:Cell Movement; D024042:Collagen Type I / Q000378:metabolism; D004847:Epithelial Cells; D005355:Fibrosis / Q000517:prevention & control*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D008026:Ligation; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015415:Biomarkers; D024042:Collagen Type I; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor