Prevention of hepatic fibrosis by super-fibronectin

超纤连蛋白预防肝纤维化

• 批准号: 10670485
• 负责人: NAKAMUTA Makoto
• 金额: $ 1.98万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670485/
• 关键词: Hepatic fibrosis; Liver cirrhosis; Hepatic stellate cells; Super-fibronectin; Fibronectin; Extracellullar matorix; Stress fiber; ROCK; 伊東細胞; 肝癌; Rho; 細胞内骨格; シグナル伝達系

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.

肝纤维化发生在慢性肝病患者中，例如，持续性病毒性肝炎、酒精过量和自身免疫性肝病，作为严重肝损伤的后果。无论何种原因，肝纤维化都涉及ECM成分，特别是胶原蛋白的异常积累。肝星状细胞（hepatic stellate cells，HSCs，也称Ito细胞、贮脂细胞或脂细胞）是位于肝窦周隙的非实质性肝细胞，是肝细胞外基质（ECM）的主要来源。CIII_1片段、超纤连蛋白和RGD肽分别抑制HSC的生长，抑制I型胶原的生成和mRNA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，我们接下来使用特定的抑制剂研究了Rho-ROCK信号通路在肝纤维化中的作用。肉毒杆菌毒素C3和ROCK抑制剂Y27632均阻止胶原蛋白的产生和应力纤维的形成。Y27632还抑制MAP激酶Erk的磷酸化。在体内实验中，Y27632和RGD肽能显著抑制DMN-诱导的肝纤维化，提示整合素-FAK-Rho-ROCK信号通路在肝纤维化中起重要作用，提示该信号通路的抑制剂，如Clll_1片段、超纤连蛋白、RGD肽和Y27632可能对预防肝纤维化的发展有潜在的作用。

项目成果

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