Tada S, Iwamoto H, Nakamuta M, Sugimoto R, Enjoji M, Nakashima Y, Nawata H
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
J Hepatol. 2001 Apr;34(4):529-36. doi: 10.1016/s0168-8278(00)00059-3.
p160ROCK is a direct Rho target which mediates Rho-induced assembly of focal adhesions and stress fibers. We previously reported that Rho signaling pathways are involved in the activation of hepatic stellate cells (HSC) in vitro. The aim of the present study was to test the hypothesis that an inhibitor specific for p160ROCK (Y27632) could prevent experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats.
Y27632 was given orally at 30 mg/kg daily for 4 weeks after the first injection of DMN. The degree of fibrosis was evaluated by image analysis and also by measurements of collagen and hydroxyproline content in the liver. The expression of alpha-smooth muscle actin (alpha-SMA) in the liver and in the primary cultured HSC was also evaluated. Semi-quantitative RT-PCR was performed to evaluate the expression of type I collagen mRNA in the liver.
Y27632 treatment significantly decreased the occurrence of DMN-induced hepatic fibrosis and reduced the collagen and hydroxyproline content and alpha-SMA expression in the liver. The expression of alpha-SMA in HSC was also suppressed in vitro.
These findings indicate that inhibitors of the Rho-ROCK pathway might be useful therapeutically in hepatic fibrosis.
p160ROCK是Rho的直接靶点，介导Rho诱导的粘着斑和应力纤维的组装。我们之前报道过Rho信号通路参与体外肝星状细胞（HSC）的激活。本研究的目的是验证一种针对p160ROCK的特异性抑制剂（Y27632）能否预防大鼠二甲基亚硝胺（DMN）诱导的实验性肝纤维化这一假说。
首次注射DMN后，Y27632以30 mg/kg的剂量每日口服给药，持续4周。通过图像分析以及测量肝脏中的胶原蛋白和羟脯氨酸含量来评估纤维化程度。还评估了肝脏和原代培养的HSC中α-平滑肌肌动蛋白（α-SMA）的表达。进行半定量逆转录-聚合酶链反应（RT-PCR）以评估肝脏中I型胶原蛋白mRNA的表达。
Y27632治疗显著降低了DMN诱导的肝纤维化的发生率，并降低了肝脏中的胶原蛋白和羟脯氨酸含量以及α-SMA的表达。体外实验中HSC中α-SMA的表达也受到抑制。
这些发现表明，Rho-ROCK通路抑制剂可能在肝纤维化治疗中具有应用价值。
