Crosstalk between inflammation and thrombosis
Crosstalk between inflammation and thrombosis
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DOI：
10.1016/j.maturitas.2003.10.015
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发表时间：
2004-04-15
期刊：
影响因子：
4.9
通讯作者：
Esmon, CT
中科院分区：
文献类型：
--
作者：
Esmon, CT
炎症改变了止血机制，有利于血栓形成。多种机制起作用，包括组织因子的上调导致凝血的开始，通过增加细胞凝血磷脂的暴露来放大凝血过程，通过升高纤溶酶原激活物抑制剂I（派- 1）来抑制纤维蛋白溶解，以及天然抗凝剂途径的减少，特别是通过多种机制针对蛋白C抗凝剂途径的下调。天然抗凝剂途径的功能降低可能特别成问题，因为这些途径似乎在抑制炎症反应中起作用。蛋白C抗凝途径为炎症对凝血的影响提供了一个有用的模型。该通路在预防微血管血栓形成中起主要作用。当凝血酶与内皮细胞表面的血栓调节蛋白（TM）结合时，该途径启动。内皮细胞蛋白C受体（EPCR）增强蛋白C激活凝血酶-TM复合物在体内超过10倍。EPCR通过炎症介质和凝血酶从内皮脱落。EPCR在涉及蛋白酶3和Mac-1的过程中与活化的中性粒细胞结合，并似乎抑制白细胞外渗。EPCR可以经历从质膜到细胞核的易位，在细胞核中它重定向基因表达。在易位过程中，它可以携带活化的蛋白C（APC）到细胞核，可能是APC调节内皮细胞中炎症介质反应的能力。在实验动物中，TNF α和其他炎症介质可下调EPCR，TM和IL-6可降低蛋白S水平。蛋白C途径功能的抑制会增加细胞因子的产生、内皮细胞损伤和白细胞对内毒素的反应，而这些过程会通过输注APC而减少。体外APC抑制TNF α从单核细胞的加工，并阻断白细胞粘附到选择素。由于凝血酶可在微血管内皮中引起许多炎症反应，因此由于蛋白C通路功能受损而导致的微血管凝血酶生成失控可能有助于败血症中的微血管功能障碍。(C)2004爱思唯尔爱尔兰有限公司版权所有。炎症改变了有利于血栓形成的止血机制。多种机制起作用，包括组织因子的上调导致凝血的开始，通过增加细胞凝血磷脂的暴露来放大凝血过程，通过升高纤溶酶原激活物抑制剂1（派-1）来抑制纤维蛋白溶解，以及天然抗凝剂途径的减少，特别是通过多种机制针对蛋白C抗凝剂途径的下调。天然抗凝剂途径的功能降低可能特别成问题，因为这些途径似乎在抑制炎症反应中起作用。蛋白C抗凝途径为炎症对凝血的影响提供了一个有用的模型。该通路在预防微血管血栓形成中起主要作用。当凝血酶与内皮细胞表面的血栓调节蛋白（TM）结合时，该途径启动。内皮细胞蛋白C受体（EPCR）增强蛋白C激活凝血酶-TM复合物在体内超过10倍。EPCR通过炎症介质和凝血酶从内皮脱落。EPCR在涉及蛋白酶3和Mac-1的过程中与活化的中性粒细胞结合，并且似乎抑制白细胞渗出。EPCR可以经历从质膜到细胞核的易位，在细胞核中它重定向基因表达。在易位过程中，它可以携带活化的蛋白C（APC）到细胞核，可能是APC调节内皮细胞中炎症介质反应的能力。在实验动物中，TNF α和其他炎症介质可下调EPCR，TM和IL-6可降低蛋白S水平。蛋白C途径功能的抑制增加了响应于内毒素的细胞因子产生、内皮细胞损伤和白细胞外渗，这些过程通过输注APC而减少。在体外，APC抑制TNF α从单核细胞的加工，并阻止白细胞粘附到选择素。由于凝血酶可在微血管内皮中引起许多炎症反应，因此由于蛋白C通路功能受损而导致的微血管凝血酶生成失控可能有助于败血症中的微血管功能障碍。(C)2004爱思唯尔爱尔兰有限公司保留所有权利。
Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Multiple mechanisms are at play including up regulation of tissue factor leading to the initiation of clotting, amplification of the clotting process by augmenting exposure of cellular coagulant phospholipids, inhibition of fibrinolysis by elevating plasminogen activator inhibitor I (PAI- 1) and decreases in natural anticoagulant pathways, particularly targeted toward down regulation of the protein C anticoagulant pathway through multiple mechanisms. The decreased function of the natural anticoagulant pathways may be particularly problematic because these appear to play a role in dampening inflammatory responses. The protein C anticoagulant pathway provides a useful model for the impact of inflammation on coagulation. This pathway plays a major role in preventing microvascular thrombosis. The pathway is initiated when thrombin binds to thrombomodulin (TM) on the surface of the endothelium. An endothelial cell protein C receptor (EPCR) augments protein C activation by the thrombin-TM complex more than 10-fold in vivo. EPCR is shed from the endothelium 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 extravisation. EPCR can undergo translocation from the plasma membrane to the nucleus where it redirects gene expression. During translocation it 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 alpha and other inflammatory mediators can down-regulate EPCR and TM and IL-6 can depress levels of protein S in experimental animals. Inhibition of protein C pathway function increases cytokine elaboration, endothelial cell injury and leukocyte extravisation in response to endotoxin, processes that are decreased by infusion of APC. In vitro. APC inhibits TNF alpha 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. (C) 2004 Elsevier Ireland Ltd. All rights reserved.Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Multiple mechanisms are at play including up regulation of tissue factor leading to the initiation of clotting, amplification of the clotting process by augmenting exposure of cellular coagulant phospholipids, inhibition of fibrinolysis by elevating plasminogen activator inhibitor 1 (PAI-1) and decreases in natural anticoagulant pathways, particularly targeted toward down regulation of the protein C anticoagulant pathway through multiple mechanisms. The decreased function of the natural anticoagulant pathways may be particularly problematic because these appear to play a role in dampening inflammatory responses. The protein C anticoagulant pathway provides a useful model for the impact of inflammation on coagulation. This pathway plays a major role in preventing microvascular thrombosis. The pathway is initiated when thrombin binds to thrombomodulin (TM) on the surface of the endothelium. An endothelial cell protein C receptor (EPCR) augments protein C activation by the thrombin-TM complex more than 10-fold in vivo. EPCR is shed from the endothelium by inflammatory mediators and thrombin. EPCR binds to activated neutrophils in a process that involves protemase 3 and Mac-1 and appears to inhibit leukocyte extravisation. EPCR can undergo translocation from the plasma membrane to the nucleus where it redirects gene expression. During translocation it 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 alpha and other inflammatory mediators can down-regulate EPCR and TM and IL-6 can depress levels of protein S in experimental animals. Inhibition of protein C pathway function increases cytokine elaboration, endothelial cell injury and leukocyte extravisation in response to endotoxin, processes that are decreased by infusion of APC. In vitro, APC inhibits TNF alpha 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. (C) 2004 Elsevier Ireland Ltd. All rights reserved.