血小板CLEC-2在内毒素血症所致肝损伤中的作用与机制研究

Endotoxemia is the key pathophysiological process to many diseases including bacterial infections and autoimmune reactions. The main reason for its high morbidity and mortality is that its pathogenesis is still unclear, so there is a lack of effective targeted therapies. It is of great clinical significance to further clarify the pathogenesis of endotoxemia, and to establish a new targeted intervention. Platelets play an essential role in maintaining vascular integrity during inflammation. The platelet receptor C-type lectin-like receptor 2(CLEC-2) prevents inflammation-induced vascular leakage and hemorrhage. However, the mechanism by which CLEC-2 protects liver injury during endotoxemia is unknown. Our preliminary study suggests that the liver of mice lacking platelets CLEC-2 don’t have hepatic lobule structure and liver blood sinus form. The liver cells become swelling and degeneration as compared to that of wild type mice during endotoxemia. Podoplanin is the only known physiological ligand for CLEC-2. Our preliminary study shows that bacterial lipopolysaccharide (LPS) stimulation induces podoplanin expression on liver cells. It would be significant to examine whether CLEC-2 on platelets associates with podoplanin on perivascular macrophages during endotoxemia. In this proposal, we will investigate the mechanism which platelet CLEC-2 regulates liver injury by interacting with podoplanin. We will use transgenic mice and the in vitro methods to study this research. We will examine how platelet CLEC-2 ameliorates liver injury to interact with perivascular cells that express podoplanin. We will also examine the mechanism for platelet CLEC-2 to prevent vascular leakage during endotoxemia. Our study will provide novel insights into regulation of liver injury during inflammation and may lead to new therapies for inflammatory diseases.

当机体受到创伤感染时，革兰氏阴性菌侵入血循环并生长繁殖，产生的内毒素造成肝损伤，进而危害生命。其高发病率和高死亡率的主要原因是当前对其发病机制仍然认识不清，因此缺乏有效的靶向治疗药物。进一步深入阐明内毒素血症的发病机制，创立新的靶向干预措施具有极为重要的临床意义。最近的研究表明血小板膜蛋白C型凝集素样受体-2(CLEC-2)在炎症反应中参与维持血管壁完整性，但是其机制并不清楚。本课题的前期研究发现血小板CLEC-2缺乏的小鼠表现出更为严重的肝损伤。我们还发现CLEC-2与其配体平足蛋白作用保护肝组织的完整性和稳定性。本课题将利用组织特异性基因敲除小鼠，体内炎症模型和体外细胞分子生物学方法阐明内毒素血症过程中血小板CLEC-2与平足蛋白发生作用的途径及缓解肝损伤的机制，并为开发针对新靶点的抗炎药物提供理论依据。

脓毒症的多器官衰竭是多个相互依赖的器官系统的进行性衰竭。肝功能障碍发生在脓毒血症早期，与患者死亡直接相关。然而，脓毒症中肝功能障碍的机制仍不清楚。有研究表明，血小板输注对脓毒症患者的治疗有效，抑制补体活化可保护脓毒症动物的肝功能。在此，我们探讨了血小板、补体活化与脓毒症肝功能障碍之间的潜在联系。血小板Clec-2缺乏小鼠在大肠杆菌感染的早期表现出补体过度活化、补体攻击以及血浆补体抑制物水平降低。循环血单核细胞在脓毒症早期表达血小板CLEC-2的配体Podoplanin（PDPN），PDPN与血小板CLEC-2相互作用诱导血小板释放补体抑制物。向脓毒症小鼠体内注射血小板释放的补体抑制物可以降低补体攻击，缓解肝功能障碍。我们的发现揭示了血小板在脓毒症发病过程中调节补体激活的新功能，这可能成为脓毒症的新的治疗选择。

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