HMGB1参与日本血吸虫肝肉芽肿和纤维化的作用及其机制

Schistosomiasis is a world-wide chronic parasitic disease that seriously affects human health. It is now realized that egg-induced hepatic granuloma formation and subsequent fibrosis are the main cause of death for schistosomiasis. Despite decades of extensive studies, the mechanisms leading to granuloma formation and fibrosis, however, largely remanin elusive. Given the fact that HMGB1 acts as an important innate alarmin implicated in the pathogenesis of acute hepatic injury and lung fibrosis, we therefore explored its impact on schistosoma hepatic granuloma formation and fibrosis. The expression and release of HMGB1 in the liver is highly induced upon schistosoma infection, and blockade of extracellular HMGB1 significantly inhibits japonicum egg-induced liver granuloma formation and fibrosis. Based on these findings, we intend to systematically establish the role of HMGB1 in hepatic granuloma formation and fibrosis during the course of schistosomiasis. We will employ HMGB1 neutralizing antibodies and functional active recombinant protein to demonstrate that HMGB1 promotes Th17 development activates HSCs, which then initiates fibrotic process. The impact of HMGB1 on the activation of RAGE signaling will be next dissected to address the underlying mechanisms. The feasibility for HMGB1 to be an innate based therapeutic target for prevention/intervention of japonicum egg-induced liver granuloma formation and fibrosis will be finally assessed. Completion of these studies will not only provide novel insight into the understanding of the mechanisms leading to granuloma formation and fibrosis, but also pave the way for developing novel and effective therapeutic strategies against this devastating disease.

血吸虫病是一种严重威胁人类健康的寄生虫病，现已查明肝脏虫卵肉芽肿及纤维化是导致病人死亡的主要原因，但详细病理机制尚未明了。基于HMGB1作为一种重要的固有预警分子参与急性肝损伤和肺纤维化等多种病理进程，申报者率先探讨了其在血吸虫肝肉芽肿和纤维化病理机制中的作用，发现血吸虫感染后肝脏HMGB1的表达和释放明显增加，初步研究揭示阻断HMGB1能显著抑制血吸虫肝纤维化的形成。本课题拟以此为依据，系统探究HMGB1在血吸虫肝肉芽肿及纤维化发生和发展中的作用。以HMGB1阻断剂和重组HMGB1为手段，阐明HMGB1促进Th17细胞分化进而活化HSC启动肝纤维化的病理效应；解析HMGB1调控RAGE信号通路参与血吸虫肝纤维化的分子机制；研判以HMGB1为靶点防治血吸虫肝肉芽肿和纤维化的可行性。该课题研究不仅为厘清血吸虫肝肉芽肿及纤维化病理机制提供新思路，还能为开发有效的血吸虫病防治新策略奠定实验依据。