凋亡信号调节激酶1信号通路促进原发性硬化性胆管炎肝纤维化的作用及其机制研究

Primary sclerosing cholangitis(PSC) is a comparatively rare disease characterised by the multifocal biliary stricture caused by idiopathic inflammation of the intra- and extra-hepatic bile ducts and liver fibrosis, which processes into biliary cirrhosis. PSC is a fatal disease ,but lack of valid medication by now. It has been reported that apoptosis signal-regulating kinase 1 is hiked in patient of cholestatic liver disease. However, the corelation between ASK1 signaling pathway and PSC remains unknown,and the mechanism has not been fully understood. In our preliminary work: We found that apoptosis signal regulating kinase1(ASK1) was up-regulated by bile acid and the apoptosis of hepatic cell was aroused, vice versa. The apoptotic cell would release the mitochondrial damage associated molecular patterns(mito-DAMPs) which could directly irritate the hepatic stellate cell. It is suggestive that the ASK1 signaling pathway might be a stimulus during the progression of liver fibrosis in PSC. In this project, we are about to investigate the mechanism of the liver fibrosis induced by ASK1 signaling pathway in PSC(with ABCB4-knockdown mouse model and cell model), and verify the anti-fibrotic effect of the ASK1 inhibitor(ASK1i) in PSC. The research may be the theoretical basis of new-drug development, which makes PSC curable.

原发性硬化性胆管炎（PSC）因特发多灶性胆管狭窄导致胆汁淤积而诱发肝纤维化，进而发展为肝硬化。既往研究报道慢性胆汁性肝病患者体内凋亡信号调节激酶1（ASK1）上调，但ASK1信号通路与PSC肝纤维化的关系尚不清楚。我们前期研究发现：①胆汁酸刺激肝细胞可上调ASK1并促进细胞凋亡，阻断ASK1可抑制肝细胞凋亡；②凋亡的肝细胞释放大量的线粒体损伤相关分子（mito-DAMPs）；③mito-DAMPs可以直接刺激肝星状细胞（HSC）增殖。由此提出科学假设：PSC病程中，胆汁酸激活ASK1信号通路促进肝细胞凋亡，释放mito-DAMPs直接刺激HSC增殖及产生胶原沉积，促进肝纤维化。本项目拟通过ABCB4基因敲除小鼠模型和小鼠肝原代细胞模型，进一步阐明ASK1信号通路促进PSC肝纤维化的作用及分子机制，并在小鼠实验证实阻断ASK1通路可延缓PSC肝纤维化，为PSC提供潜在的靶向治疗依据。

原发性硬化性胆管炎（PSC）因特发多灶性胆管狭窄导致胆汁淤积而诱发肝纤维化，进而发展为肝硬化，最终肝衰竭致人死亡。近年来研究报道PSC的发病逐年增加，病程终末期致死率高，外科治疗局限性明显，目前缺乏有效的药物治疗。既往研究报道慢性胆汁性肝病患者体内凋亡调节信号调节激酶1（ASK1）上调，但ASK1信号通路与PSC肝纤维化的关系尚不清楚。本研究通过ABCB4基因敲除小鼠模型和小鼠肝原代细胞模型，成功模拟PSC病程，并证明了在该病程中，胆汁酸激活肝细胞的ASK1信号通路（ASK1-p38信号轴）促进细胞凋亡，释放线粒体损伤相关分子（mito-DAMPs）直接刺激肝星状细胞（HSC）增殖及产生胶原沉积，促进肝纤维化进程。进一步，本研究在细胞及动物实验中证实了阻断ASK1信号通路的激活可以显著减少PSC相关肝纤维化进程。与此同时，ASK1抑制剂（ASK1i）在动物实验中展现出有效刺激正常肝细胞增殖的作用，提示阻断该通路能有效逆转PSC所致肝硬化进程。基于本研究成果，我们提出围绕ASK1信号通路为靶标设计靶向药物，可能是治疗PSC的潜在有效方案。