骨桥蛋白(OPN)作为急性重症肝衰竭早期关键细胞损伤相关分子(DAMPs)诱发免疫紊乱的分子机制研究

急性/慢加急性肝衰竭（ALF/ACLF）患者主要特征是肝细胞大量急性坏死，释放DAMPs，诱发严重免疫紊乱进而导致多脏器功能衰竭。然而，肝衰竭中的关键DAMP及它们如何诱发免疫紊乱的分子机制尚不十分清楚。对肝衰竭和肝硬化病人肝组织及血清基因表达分析发现，OPN在肝衰竭患者中显著升高，体外细胞实验证明，OPN由受损肝细胞表达分泌并具有激活NKT细胞的功能，提示OPN是一种新的肝衰竭早期关键DAMP。进一步研究发现，OPN-/-小鼠对乙酰氨基酚打击引起的肝坏死、天然免疫细胞浸润及激活、炎症因子风暴及死亡呈明显耐受。因此，我们提出ALF/ACLF中OPN是由损伤肝细胞释放，通过募集、活化免疫细胞促发全身炎症因子风暴的“放大器”的发病机制假说。拟通过本项目资助，对OPN在ALF/ACLF中的作用及其介导免疫风暴的靶细胞和分子机制为主要研究内容，在免疫细胞，动物模型以及病人标本等层面来验证上述假说。

The major characteristics of acute/acute on chronic liver failure (ALF/ACLF) are acute and tremendous hepatocellular necrosis, release of damage/danger associated molecular patterns (DAMPs), and subsequent induction of severe immunologic disorder and multiple organs failure. However, the key DAMPs and the mechanism by which they induce immunologic disorder remain largely unknown. By comparing the gene expression changes in liver tissues and sera from cirrhosis and ACLF patients, we found that the expression of OPN was significantly higher in ACLF patients compared to cirrhosis ones. Meanwhile, we demonstrated that OPN was secreted from injured hepatocytes and could activate NKT cells in vitro. These findings indicate that OPN is a novel key DAMP of ALF/ACLF. In an acetaminophen (APAP) induced ALF murine model, we found that OPN-/- mice showed greater tolerance to APAP induced liver injury, innate immune cell infiltration and activation, cytokine storm and death compared to WT mice. Therefore, we hypothesized that OPN secreted from injured hepatocytes, serves as a key “amplifier” to amplify cytokine storm through recruiting and activating innate immune cells in ALF/ACLF. In this study, we will combine the investigation from innate immune cells, murine models and patient samples to disclose the function and mechanism of OPN in mediating the cytokine storm in ALF/ACLF.