免疫微环境失衡是肝纤维化发生发展的重要因素，中医药在调节免疫与防治肝纤维化领域具有独特优势，鉴定肝脏免疫调节靶标及开发天然靶向制剂将对肝纤维化防治提供安全有效的崭新手段。临床试验证实保肝宁对肝纤维化具有阻断及逆转作用，但其药效靶标与分子机制尚不完全清楚。基于哚胺2, 3-双加氧酶（IDO）干预色氨酸代谢以及调控树突状细胞（DCs）免疫呈递功能，我们前期研究发现肝纤维化诱导IDO显著上调，同时伴随DCs增多与富集以及微环境中炎症因子释放增加；而保肝宁在显著改善纤维化的同时，降低肝脏DCs富集并减少微环境中炎症因子的释放。由此我们设想保肝宁通过介导IDO调控免疫微环境的动态平衡，从而达到延缓或逆转肝纤维化发展的作用。本项目拟通过基因重组、细胞三维培养及现代血清药理学等技术探讨保肝宁干预肝纤维化的免疫微环境机制内涵及IDO靶向调控机制。本研究的开展将为肝纤维化机制探索及药物开发提供新思路。

Imbalance of hepatic immune microenvironment is an important mechanism for the development of liver fibrosis. Traditional Chinese Medicine and drugs have a unique advantage in the fields of the immune regulation and liver fibrosis prevention. It will provide safe and effective new tools for prevention hepatic fibrosis by Identification of key hepatic immunomodulatory signaling protein and development of natural drugs with clear targets. Clinical trials have indicated that Baoganning could block and reverse hepatic fibrosis, but its efficacy targets and molecular mechanisms are still not fully understood. Our previous study found that hepatic fibrosis induced the significantly up-regulation of indole amine 2,3-dioxygenase (IDO), with the elevated of dendritic cells expression and inflammatory cytokines releasing in the hepatic microenvironment. Interestingly, Baoganning could effectively reduce the liver fibrosis and the dendritic cells (DCs) expression and distribution in hepatic sinusoid, as well as the down-regulation of inflammatory cytokines. Based on the critical roles of IDO in tryptophan metabolism and DCs immune transmitting functions, we hypothesis that Baoganning could prevent hepatic fibrosis by improving hepatic immune microenvironment through IDO signal pathway. In this project, three-dimensional cell culture, gene recombination technology and current serum pharmacology will be used to investigate the mechanisms of Baoganning intervention immune microenvironment and the IDO-targeted regulation in liver fibrosis. This study will provide new ideas and new tools for further investigating of the mechanisms of liver fibrosis and related drug discoveries.