Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation

被引:206
作者
Xia, JL [1 ]
Dai, CS [1 ]
Michalopoulos, GK [1 ]
Liu, YH [1 ]
机构
[1] Univ Pittsburgh, Sch Med, Dept Pathol, Div Cellular & Mol Pathol, Pittsburgh, PA 15261 USA
关键词
D O I
10.2353/ajpath.2006.050747
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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 a-smooth muscle actin (alpha SMA) expression, attenuated deposition of type I and type III collagen, and normalized total hydroxyproline content. HGF also suppressed transforming growth factor-beta 1 (TGF-beta 1) expression. Interestingly, colocalization of aSMA 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-beta 1 induced aSMA and fibronectin expression and suppressed cytokeratin-19. HGF abolished the phenotypic conversion of biliary epithelial cells induced by TGF-beta 1. These results suggest that HGF ameliorates hepatic biliary fibrosis in part by blocking bile duct epithelial to mesenchymal transition.
引用
收藏
页码:1500 / 1512
页数:13
相关论文
共 48 条
[1]  
Albanis E, 2001, Clin Liver Dis, V5, P315, DOI 10.1016/S1089-3261(05)70168-9
[2]   Wholesale hepatocytic differentiation in the rat from ductular oval cells, the progeny of biliary stem cells [J].
Alison, M ;
Golding, M ;
ElNasir, L ;
Nagy, P ;
Thorgeirsson, S ;
Sarraf, C .
JOURNAL OF HEPATOLOGY, 1997, 26 (02) :343-352
[3]   Hepatic stem cells: from inside and outside the liver? [J].
Alison, MR ;
Vig, P ;
Russo, F ;
Bigger, BW ;
Amofah, E ;
Themis, M ;
Forbes, S .
CELL PROLIFERATION, 2004, 37 (01) :1-21
[4]   Transforming growth factor β and the liver [J].
Bissell, DM ;
Roulot, D ;
George, J .
HEPATOLOGY, 2001, 34 (05) :859-867
[5]   β-Cell-specific ablation of the hepatocyte growth factor receptor results in reduced islet size, impaired insulin secretion, and glucose intolerance [J].
Dai, CS ;
Huh, CG ;
Thorgeirsson, SS ;
Liu, YH .
AMERICAN JOURNAL OF PATHOLOGY, 2005, 167 (02) :429-436
[6]  
Dai CS, 2002, J AM SOC NEPHROL, V13, P411, DOI 10.1681/ASN.V132411
[7]   Molecular basis of renal fibrosis [J].
Eddy, AA .
PEDIATRIC NEPHROLOGY, 2000, 15 (3-4) :290-301
[8]   Fibrogenesis I. New insights into hepatic stellate cell activation: the simple becomes complex [J].
Eng, FJ ;
Friedman, SL .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2000, 279 (01) :G7-G11
[9]   The development and compensation of biliary cirrhosis in interleukin-6-deficient mice [J].
Ezure, T ;
Sakamoto, T ;
Tsuji, H ;
Lunz, JG ;
Murase, N ;
Fung, JJ ;
Demetris, AJ .
AMERICAN JOURNAL OF PATHOLOGY, 2000, 156 (05) :1627-1639
[10]   Molecular mechanisms of hepatic fibrosis and principles of therapy [J].
Friedman, SL .
JOURNAL OF GASTROENTEROLOGY, 1997, 32 (03) :424-430