Prevention of hepatic fibrosis by super-fibronectin

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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.