ELUCIDATION OF SIGNIFICANCE OF c-met EXPRESSION IN ACTIVATED HEPATIC STELLATE GELLS AND ITS APPLICATION OF THERAPEUTIC STRATEGY

(1)我们发现活化的大鼠肝星状细胞表达肝细胞生长因子（HGF）受体c-met。在培养激活的星状细胞中，通过Northern和Western提示分析测定c-met的表达。HGF与活化的星状细胞特异性结合，Scatchard分析显示表观K_d为1.5 nM。此外，在四氯化碳处理8周的大鼠星状细胞中检测c-met mRNA的表达。(2)在培养激活的星状细胞中，HGF增加了c-met mRNA的表达。HGF增强了细胞的DNA合成和转化生长因子β 1 （tgfβ 1）的产生，而HGF不影响胶原合成和平滑肌α -肌动蛋白的表达。(3)鉴于HGF是由星状细胞产生的，HGF可能通过自分泌机制影响星状细胞。由于星状细胞的增殖是肝纤维化的主要特征之一，TGFbeta1被认为是一种纤维化细胞因子，我们的研究结果表明HGF可能加速肝纤维化的发生。然而，最近的证据显示，在四氯化碳或二甲基亚硝胺处理的大鼠中，HGF消除了肝纤维化。我们推测，HGF对肝纤维化的抑制作用可能不是由于对星状细胞的直接作用，而是通过HGF可能的细胞保护作用间接作用。

(1) We have found that activated rat hepatic stellate cells express c-met, the receptor of hepatocyte growth factor (HGF). In culture-activated stellate cells, c-met expression was determined by Northern and Western hint analyses. Specific binding of HGF to activated stellate cells was determined, and Scatchard analysis indicated an apparent K_d of 1.5 nM.Moreover, c-met mRNA expression was detected in stellate cells isolated from rats treated with carbon tetrachloride for 8 weeks.(2) In culture-activated stellate cells, HGF increased c-met mRNA level. HGF enhanced DNA synthesis and transforming growth factor beta1 (TGFbeta1) production by the cells, whereas HGF did not affect collagen synthesis nor smooth muscle alpha-actin expression.(3) Considering that HGF is produced by stellate cells, HGF may affect those cells by autocrine mechanism. Because the proliferation of stellate cells is one of the main features of hepatic fibrosis and TGFbeta1 is known as a fibrogenic cytokine, our results suggest that HGF might accelerate hepatic fibrogenesis. However, recent evidence has revealed that HGF abrogates hepatic fibrosis in rats treated with carbon tetrachloride or dimethylnitrosamine. We speculate that this inhibitory effect of HGF on hepatic fibrosis may not be due to the direct action on stellate cells, but to the indirect action through, say possible cytoprotective effect of HGF.