Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis
Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis
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DOI：
10.1016/s0002-9440(10)62323-1
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发表时间：
2005-04-01
影响因子：
6
通讯作者：
Nakamura, T
中科院分区：
文献类型：
--
作者：
Kim, WH;Matsumoto, K;Nakamura, T
肝硬化的特征是肝功能障碍，肝脏中纤维组织广泛积聚。在慢性肝损伤后，肝门肌成纤维细胞和活化的肝星状细胞（HSC）在肝纤维化中发挥作用。虽然肝细胞生长因子（HGF）的施用或基因表达导致肝纤维化/肝硬化的改善，但相关机制尚未完全了解。我们研究了肝细胞生长因子在肝硬化消退过程中的作用机制，着重于门脉肌成纤维细胞的生长调节和凋亡。培养的大鼠HSC不能增殖，传代后被撤回，并在传代过程中被增殖的门静脉肌成纤维细胞所取代。在静止的HSC中，未检测到c-Met受体表达，而在活化的HSC和表达α-平滑肌肌动蛋白（α-SMA）的肝肌成纤维细胞中检测到c-Met受体表达，表明活化的HSC和门静脉肌成纤维细胞是HGF的靶点。对于培养的大鼠门静脉肌成纤维细胞，HGF抵消了细胞外信号调节激酶（Erk）1/2的磷酸化和血小板源性生长因子诱导的促有丝分裂刺激，诱导c-jun N-末端激酶（JNK）1磷酸化，并促进细胞凋亡。在二甲基亚硝胺大鼠肝硬化模型中，给予HGF抑制了肝脏中α-SMA阳性细胞的增殖，同时促进了细胞凋亡，这些事件与α-SMA的肝脏表达减少和肝硬化的组织学消退相关。肝细胞生长因子抑制门脉肌成纤维细胞的生长和增强细胞凋亡是肝细胞生长因子辅助肝纤维化/肝硬化消退的新机制。
Liver cirrhosis is characterized by hepatic dysfunction with extensive accumulation of fibrous tissue in the liver. In response to chronic hepatic injury, hepatic portal myofibroblasts and activated hepatic stellate cells (HSCs) play a role in liver fibrosis. Although administration or gene expression of hepatocyte growth factor (HGF) leads to improvement in hepatic fibrosis/cirrhosis, the related mechanisms are not fully understood. We investigated mechanisms involved in resolution from liver cirrhosis by HGF, focusing on growth regulation and apoptosis in portal myofibroblasts. Cultured rat HSCs could not proliferate, were withdrawn after passage, and were replaced by proliferating portal myofibroblasts during the passages. In quiescent HSCs, c-Met receptor expression was undetected whereas c-Met receptor expression was detected in activated HSCs and liver myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA), suggesting that activated HSCs and portal myofibroblasts are targets of HGF. For cultured rat portal myofibroblasts, HGF counteracted phosphorylation of extracellular signal-regulated kinase (Erk) 1/2 and mitogenic stimulus induced by platelet-derived growth factor, induced c-jun N-terminal kinase (JNK) 1 phosphorylation, and promoted apoptotic cell death. In the dimethylnitrosamine rat model of liver cirrhosis, administration of HGF suppressed proliferation while promoting apoptosis of alpha-SMA-positive cells in the liver, events that were associated with reduced hepatic expressions of alpha alpha-SMA and histological resolution from liver cirrhosis. Growth inhibition and enhanced apoptosis in portal myofibroblasts by HGF are newly identified mechanisms aiding resolution from liver fibrosis/cirrhosis by HGF.