Arterial thrombosis in the context of HCV-associated vascular disease can be prevented by protein C
Arterial thrombosis in the context of HCV-associated vascular disease can be prevented by protein C
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DOI：
10.1038/cmi.2016.10
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发表时间：
2017-12-01
影响因子：
24.1
通讯作者：
Woernle, Markus
中科院分区：
文献类型：
--
作者：
Bluem, Philipp;Pircher, Joachim;Woernle, Markus
丙型肝炎病毒(HCV)感染是一个世界性的重大问题。丙型肝炎病毒并不局限于肝脏疾病，还经常合并免疫介导的肝外表现，如肾小球肾炎或血管炎。丙型肝炎病毒相关血管疾病的致命并发症是血栓形成。多聚核苷：多核糖核酸(Poly(I：C))是一种合成的病毒RNA类似物，在体内诱导依赖Toll样受体3(TLR3)的小动脉血栓形成，而不会在小静脉中形成显著的血栓。这些促凝血作用是由于血管内皮细胞合成组织因子和PAI-1的增加而没有激活血小板所致。除了人脐静脉内皮细胞(HUVEC)外，人肾小球系膜细胞(HMC)在经来自丙型肝炎病毒感染者的聚(I：C)或含丙型肝炎病毒的冷沉淀物刺激后，也会产生促凝血因子、细胞因子和黏附分子。活化蛋白C(APC)能在体外阻止促凝血因子在HUVEC和HMC中的诱导，并阻断Poly(I：C)和丙型肝炎病毒RNA对HMC细胞因子和黏附分子表达的影响，但对HUVEC无影响。在体内，蛋白C抑制聚(I：C)诱导的小动脉血栓形成。因此，内皮细胞事实上能够积极参与病毒感染引起的免疫介导的血管血栓形成。最后，我们为蛋白C抑制丙型肝炎病毒感染引起的TLR3介导的小动脉血栓形成的能力提供了证据。
Hepatitis C virus (HCV) infection is a major problem worldwide. HCV is not limited to liver disease but is frequently complicated by immune-mediated extrahepatic manifestations such as glomerulonephritis or vasculitis. A fatal complication of HCV-associated vascular disease is thrombosis. Polyriboinosinic: polyribocytidylic acid (poly (I: C)), a synthetic analog of viral RNA, induces a Toll-like receptor 3 (TLR3)-dependent arteriolar thrombosis without significant thrombus formation in venules in vivo. These procoagulant effects are caused by increased endothelial synthesis of tissue factor and PAI-1 without platelet activation. In addition to human umbilical endothelial cells (HUVEC), human mesangial cells (HMC) produce procoagulatory factors, cytokines and adhesion molecules after stimulation with poly (I: C) or HCV-containing cryoprecipitates from a patient with a HCV infection as well. Activated protein C (APC) is able to prevent the induction of procoagulatory factors in HUVEC and HMC in vitro and blocks the effects of poly (I: C) and HCV-RNA on the expression of cytokines and adhesion molecules in HMC but not in HUVEC. In vivo, protein C inhibits poly (I: C)-induced arteriolar thrombosis. Thus, endothelial cells are de facto able to actively participate in immune-mediated vascular thrombosis caused by viral infections. Finally, we provide evidence for the ability of protein C to inhibit TLR3-mediated arteriolar thrombosis caused by HCV infection.