细胞外组蛋白在重型肝炎发病中的作用及分子机制研究

重型肝炎病因复杂，病死率极高；继发性炎症反应和免疫功能紊乱在肝炎重症化转变中可能起关键作用，但具体机制不明。我们前期工作发现，一种新发现的"损伤相关分子模式"（DAMP）分子－细胞外组蛋白与肝脏炎症损伤反应密切相关，并可能是激活天然免疫细胞、诱发异常免疫反应的关键介质，特异性抗组蛋白抗体能显著减轻小鼠急性肝损伤，这为重肝的机制研究和治疗靶点探索等开辟了新的方向。本项目拟建立多病因的重肝动物和细胞模型，并结合临床重肝病人资料，重点研究细胞外组蛋白的变化情况及干预效果，以及与细胞凋亡、免疫细胞活化和炎症信号通路激活等事件的关系，从上游早期损伤事件、信号传导通路（TLR等）和下游代谢产物（炎性因子TNF-a等）等不同角度深入探讨细胞外组蛋白在重肝发病中的作用及分子机制，并给予干预措施验证假说。本研究将在更深层面揭示重肝发病的一些关键问题或核心关节，并为临床早期预警和干预治疗等提供科学线索。

Acute liver failure occurs in a variety of medical conditions and causes higher mortalities. It has been suggested that secondary inflammation and immunological disorders, following primary hepatocyte damage caused by viruses (HBV/HCV), alcohol, drug or chemical toxins, play a vital role in the initiation of acute hepatic failure. But the underlying molecular mechanisms remain largely unclear. Recently, extracellular histones have been identified as a new DAMP (Damage Associated Molecular Pattern) molecule and exhibited to be a major mediator of death in sepsis. In our pilot study, we found that extracellular histones were significantly released in the circulation of GalN/LPS-treated mice in a time-dependent manner, which likely contributed to the increase of inflammatory cytokines and the death of mice. Neutralization of histones by specific anti-histones antibodies strikingly improved the survival rate of GalN/LPS-treated mice. It thus indicated a dual role of extracellular histones either as a cell death marker for acute liver failure or as a new therapeutic target in the treatment of hepatic injury. In the present study, we aim to investigate the profile of extracellular histones levels following acute liver damage in in vivo and in vitro models as well as in clinical patients with severe liver failure. Moreover, the molecular pathways of extracellular histones involved in activation of innate immunity and inflammatory events will be examined. Most importantly, we will explore the protective effects and the potential therapeutic significance of specific anti-histones antibodies, which may serve as a new strategy in the treatment of acute liver failure. Our study will shed light on the pathogenesis of severe liver damage and provide valuable information for exploring its biomarker and therapeutic potential.