Coagulation and inflammation
Coagulation and inflammation
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DOI：
10.1177/09680519030090030901
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发表时间：
2001-08
期刊：
影响因子：
--
通讯作者：
C. Esmon
中科院分区：
文献类型：
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作者：
C. Esmon
蛋白C抗凝途径是控制微血管血栓形成的关键途径，当凝血酶与内皮细胞表面的血栓调节蛋白(TM)结合时启动。蛋白C的激活被内皮细胞蛋白C受体(EPCR)所增强。EPCR通过炎症介质和凝血酶从血管系统中脱落。EPCR在一个涉及蛋白酶3和Mac-1的过程中与激活的中性粒细胞结合，似乎抑制了白细胞的外渗。EPCR可以从质膜转位到细胞核，在那里它重定向基因表达。在易位过程中，EPCR可以将活化蛋白C(APC)携带到细胞核，这可能是APC调节内皮细胞炎症介质反应的原因。肿瘤坏死因子-α等炎症介质可下调EPCRs和TM的表达。蛋白C途径功能的抑制增加了内毒素引起的细胞因子分泌、内皮细胞损伤和白细胞外渗，而APC的输注则逆转了这些过程。在体外，APC已被报道抑制单核细胞产生肿瘤坏死因子-α，并阻断白细胞与选择素的黏附。由于凝血酶可在微血管内皮细胞中引发多种炎症反应，蛋白C途径功能受损导致的微血管凝血酶生成失去控制可能是脓毒症微血管功能障碍的原因之一。
The protein C anticoagulant pathway is critical for controlling microvascular thrombosis and is initiated when thrombin binds to thrombomodulin (TM) on the surface of the endothelium. Protein C activation is augmented by an endothelial cell protein C receptor (EPCR). EPCR is shed from the vasculature by inflammatory mediators and thrombin. EPCR binds to activated neutrophils in a process that involves proteinase 3 and Mac-1 and appears to inhibit leukocyte extravasation. EPCR can undergo translocation from the plasma membrane to the nucleus where it re-directs gene expression. During translocation, EPCR can carry activated protein C (APC) to the nucleus, possibly accounting for the ability of APC to modulate inflammatory mediator responses in the endothelium. TNF-α and other inflammatory mediators can down-regulate EPCR and TM. Inhibition of protein C pathway function increases cytokine elaboration, endothelial cell injury and leukocyte extravasation in response to endotoxin and infusion of APC reverses these processes. In vitro, APC has been reported to inhibit TNF-α elaboration from monocytes and to block leukocyte adhesion to selectins. Since thrombin can elicit many inflammatory responses in microvascular endothelium, loss of control of microvascular thrombin generation due to impaired protein C pathway function probably contributes to microvascular dysfunction in sepsis.