Rapamycin Inhibits Hepatic Fibrosis in Rats by Attenuating Multiple Profibrogenic Pathways
Rapamycin Inhibits Hepatic Fibrosis in Rats by Attenuating Multiple Profibrogenic Pathways
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DOI：
10.1002/lt.21804
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发表时间：
2009-10-01
影响因子：
4.6
通讯作者：
Crawford, Darrell H. G.
中科院分区：
文献类型：
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作者：
Bridle, Kim R.;Popa, Claudia;Crawford, Darrell H. G.
肝星状细胞转分化、上皮间质细胞转变和导管反应均有助于胆汁淤积性肝病中肝纤维化的发展。雷帕霉素哺乳动物靶标的抑制剂具有抗纤维化特性。我们评估了这样的假设：雷帕霉素的抗纤维化作用除了对上皮间质转化和导管反应有抑制作用外，还归因于肌成纤维细胞增殖减弱。通过胆管结扎诱导肝纤维化，啮齿动物皮下注射雷帕霉素1.5 mg/kg/天，持续21天。比较治疗和未治疗动物之间肝纤维化、星状细胞反式激活、上皮-间质转化和导管反应的各种标志物的表达。治疗动物的肝纤维化、1 型肝原胶原信使 RNA 和 α-平滑肌肌动蛋白表达显着降低。雷帕霉素也降低了肝星状细胞前胶原的表达和增殖。雷帕霉素治疗后，以下上皮-间质转化标志物——波形蛋白表达、S100钙结合蛋白A4和转化生长因子β1信使RNA，以及抗十五麻痹同源信号通路的母亲——均减少。根据组织病理学评分和细胞角蛋白 19 表达减少的评估，雷帕霉素降低了导管反应的强度。雷帕霉素导致肝祖细胞增殖减少。总之，这些数据表明，在胆汁淤积的动物模型中，多种促纤维化途径被激活，并且雷帕霉素减弱上皮-间质转化和导管反应以及肝星状细胞活化。肝脏移植 15:1315-1324, 2009。(C) 2009 AASLD。
Hepatic stellate cell transdifferentiation, epithelial-mesenchymal cell transition, and the ductular reaction each contribute to the development of hepatic fibrosis in cholestatic liver diseases. Inhibitors of mammalian target of rapamycin have antifibrotic properties. We evaluated the hypothesis that the antifibrotic action of rapamycin is due to attenuated myofibroblast proliferation in addition to an inhibitory effect on epithelial-mesenchymal transition and the ductular reaction. Hepatic fibrosis was induced by bile duct ligation, and rodents received 1.5 mg/kg/day rapamycin by subcutaneous infusion for 21 days. The expression of various markers of hepatic fibrosis, stellate cell transactivation, epithelial-mesenchymal transition, and the ductular reaction was compared between treated and untreated animals. Hepatic fibrosis, hepatic procollagen type 1 messenger RNA, and alpha-smooth muscle actin expression were significantly reduced in treated animals. Hepatic stellate cell procollagen expression and proliferation were also reduced by rapamycin. The following markers of epithelial-mesenchymal transition-vimentin protein expression, S100 calcium binding protein A4 and transforming growth factor beta 1 messenger RNA, and the mothers against decapentaplegic homolog signaling pathway-were all reduced after rapamycin treatment. The intensity of the ductular reaction was reduced by rapamycin as assessed by histopathological scoring and by reduced cytokeratin 19 expression. Rapamycin caused a reduction in hepatic progenitor cell proliferation. Together, these data show that multiple profibrogenic pathways are activated in an animal model of cholestasis and that rapamycin attenuates epithelial-mesenchymal transition and the ductular reaction as well as hepatic stellate cell activation. Liver Transpl 15:1315-1324, 2009. (C) 2009 AASLD.