基于Kupffer细胞探讨Toll样受体4介导的免疫炎症反应在砷致肝纤维化损伤中的作用及机制

课题组前期研究发现，长期砷暴露除能导致皮肤损害之外，还可导致不同程度肝纤维化损伤。体外预实验结果亦显示砷暴露可诱导肝星状细胞（HSC）明显活化，但其具体分子机制目前尚不清楚。最近研究显示Kupffer细胞（KC）在HSC活化中发挥关键作用，且Toll样受体4（TLR4）介导的免疫炎症反应和上皮-间质转化（EMT）与肝纤维化发生发展均密切相关。然而，砷致肝纤维化过程中KC扮演着什么角色？TLR4介导的免疫炎症反应和EMT又通过何种途径参与砷致肝纤维化发生发展？这一系列科学问题均悬而未决。本项目拟在前期研究基础上，充分吸收近年来肝纤维化机制研究新成果，利用贵州特有的燃煤型砷中毒人群，结合动物实验及体外细胞等多个层面系统揭示TLR4介导的免疫炎症反应参与砷致肝纤维化损伤的分子机制，同时探讨KC、HSC及肝实质细胞在此过程中的相互作用，为砷中毒肝纤维化损伤的针对性防治提供新的突破口。

Our previous study showed that, in addition to cause several types of skin lesions, long-term exposure to arsenic can also lead to various degree of liver fibrosis. Besides, our preliminary experimental in vitro also found that arsenic exposure could significantly induce the activation of hepatic stellate cells (HSC), but the underlying mechanisms remain obscure. Recent studies suggested that Kupffer cell play a key role in HSC activation, moreover, Toll like receptor 4 (TLR4) mediated immuno-inflammatory responses and epithelial-mesenchymal transition (EMT) appear to play important roles in the process of liver fibrosis caused by various factors. However, it is all unclear whether or not KC, TLR4 mediated immuno-inflammatory responses and EMT are involved in arsenic-induced liver fibrosis. In the present project, on the basis of our previous study and the new mechanism of liver fibrosis, we will investigate the role and the molecular mechanisms of TLR4 mediated immuno-inflammatory responses in arsenic-induced liver fibrosis based on KC through both in vivo and in vitro studies, and also to explore the interaction effect among KC, HSC and parenchymal hepatic cells during this process. This project is likely to provide a new approach for scientific prevention and control of arsenic-induced liver fibrosis.