Prevention of hepatic fibrosis by super-fibronectin

慢性肝病患者会发生肝纤维化，例如持续性病毒性肝炎、酒精超负荷和自身免疫性肝病，这是严重肝损害的结果。无论原因如何，肝纤维化都涉及细胞外基质成分的异常积聚，尤其是胶原蛋白。肝星状细胞(HSCs，又称Ito细胞、储脂细胞或脂肪细胞)是位于Disse窦周隙的非实质肝细胞，是ECM的主要细胞来源。本课题研究了III型纤维连接蛋白重复序列(CIII_1)片段、超纤维连接蛋白和RGD多肽对HSCs活性的影响。CIII1片段、超纤维连接蛋白和RGD多肽分别抑制HSCs的生长，抑制I型胶原的产生和基因表达。它们还抑制FAK的磷酸化和应力纤维的形成。这些结果表明它们影响了Rho-ROCK信号通路，我们接下来使用一种特定的抑制剂来研究Rho-ROCK信号通路在肝纤维化中的作用。肉毒杆菌毒素C3和岩石抑制剂Y27632都可以阻止胶原生成和应力纤维形成。Y27632还抑制MAP激酶ERK的磷酸化。在体内，Y27632和RGD多肽对二甲基亚硝胺(DMN)诱导的肝纤维化有明显的抑制作用，提示整合素-FAK-Rho-ROCK信号通路在肝纤维化中起重要作用，该信号通路的抑制剂，如Cl11_1片段、超纤维连接蛋白、RGD多肽和Y27632可能有助于预防肝纤维化的发展。

epatic fibrosis occurs in patients with chronic liver disease, e.g., persistent viral hepatitis, alcohol overload, and autoimmune liver disease, as a consequenoc of severe liver damage. Regardless of causes, hepatic fibrosis involves the abnormal accumulation of ECM components, particularly collagens. Hepatic stellate cells (HSCs, also referred to as Ito cells, fat-storing cells, or lipocytes) are nonparenchymal liver cells residing in the perisinusoidal space of Disse, have been found to be the major cellular source of ECM.n this project, we evaluated the effects of type III fibronectin repeat (CIII_1) fragment, superfibronectin, and RGD peptide on activity of HSCs. CIII_1 fragment, super-fibronectin, and RGD peptide respectively suppressed the growth of HSCs, and inhibited the production and mRNA expression of type I collagen. They also suppressed the phosphorylation of FAK and stress fiber formation. Theses results indicated they affected Rho-ROCK signaling pathway, and we next investigated a role of Rho-ROCK signaling pathway in hepatic fibrosis using a specific inhibitor. Botulinus toxin C3 and ROCK inhibitor Y27632 both prevented collagen production and stress fiber formation. Y27632 also suppressed the phosphorylation of MAP kinase, Erk. In vivo, Y27632 and RGD peptide significantly suppressed Dimethylnitrosamaine- (DMN-) induced hepatic fibrosis.ur data suggested Integrin-FAK-Rho-ROCK signaling pathway plays an important role in hepatic fibrosis, and indicated Inhibitor of this signaling pathway, such as Clll_1 fragment, super-fibronectin, RGD peptide, and Y27632 may be potentially useful for preventing the development of hepatic fibrosis.