MECHANISMS OF MICROVASULAR THROMBOSIS IN BABOONS

描述：(调查者摘要)之前的研究记录了 炎症介质(如肿瘤坏死因子、白介素6)、止血介质(如： 组织因子/VIIa)、止血调节剂(例如蛋白质C和S)，以及 止血调节剂(如C4b结合蛋白)在驱动和控制血液动力学中的作用 狒狒对大肠杆菌的反应。止血药的抗炎作用 调节器，特别是蛋白C系统的调节器，以及最近的发现 内皮蛋白C受体和凝血酶的参与 活化的纤溶抑制物(TADI)在这一系统中的作用，已经引导我们进行了研究 它们对其抗炎和抗凝性能的贡献。电子聚合酶链反应 是内皮/蛋白C网络的最新成员，它和蛋白质一样 C本身在控制对大肠杆菌的反应方面是必不可少的。EOCR的形式 它的独特之处在于，它在体外抑制蛋白C的抗凝活性 它还抑制流动状态下紧密的中性粒细胞/内皮细胞相互作用 条件。我们计划在体外检测这些细胞的病理生理学相关性。 灵长类非炎症性(凝血酶)和炎症性(E.Coli)的观察 DIC的型号。TAFI，纤溶抑制剂的最新成员 连接到蛋白C网络，也是独特的，(1)虽然它是 被凝血酶/血栓调节蛋白复合体激活，其形成减少 受激活的蛋白C调节，该蛋白C也由该复合体产生，(2) 它是一种具有潜在抗炎作用的羧基肽酶 抗纤溶活性。再一次，这些体外观察的相关性 目前尚不清楚，也不知道TAFI是在什么病理生理条件下发生的 开始发挥作用。我们计划研究上述灵长类动物模型中的TAFI功能 在C4bBP/亚致死性大肠杆菌微血管血栓模型中也是如此。 最后，我们最近发现糖尿病患者的内皮/蛋白C网络 狒狒未能对fXaPCPS产生抗凝反应。这只是一个 纤溶“备份”反应拯救了这些动物。我们计划确定 蛋白C系统的哪些组件对这种故障负责？ 除了评估这种糖尿病缺乏对 内皮对炎性应激(如肿瘤坏死因子、白介素6)的易感性。

DESCRIPTION: (Investigator's abstract) Previous studies have documented the role of inflammatory mediators (e.g., TNF, IL-6), hemostatic mediators (e.g. tissue factor/VIIa), hemostatic regulators (e.g. proteins C and S), and hemostatic modulators (e.g C4b binding protein) in driving and controlling the baboon response to E. coli. The anti-inflammatory effects of the hemostatic regulators particularly those of the protein C system, and the recent discovery of the involvement of the endothelial protein C receptor (EPCR) and thrombin activated fibrinolytic inhibitor (TADI) in this system, have led us to study their contribution to its anti-inflammatory and anticoagulant properties. EPCR is the newest member of the endothelial/protein C network and it, like protein C itself, is essential in controlling the response to E. coli. The form of EOCR is unique in that while it inhibits protein C anticoagulant activity in vitro it also inhibits tight neutrophil/endothelial cell interactions under flow conditions. We plan to examine the pathophysiologic relevance of these in vitro observations in primate non-inflammatory (thrombin) and inflammatory (E. Coli) models of DIC. TAFI, the newest member of fibrinolytic inhibitors which are connected to the protein C network, also is unique in that, (1) while it is activated by the thrombin/thrombomodulin complex, its formation is down regulated by activated protein C which also is generated by this complex, (2) it is a carboxypeptidase with potential anti-inflammatory as well as antifibrinolytic activity. Again the relevance of these in vitro observations is unknown, nor is it known under what pathophysiologic conditions TAFI comes into play. We plan to examine TAFI function in the primate models noted above as well as in the C4bBP/sublethal E. coli model of microvascular thrombosis. Finally, we recently found that the endothelial/protein C network of diabetic baboons failed to mount an anticoagulant response to fXaPCPS. It was only the fibrinolytic "back up" response that saved these animals. We plan to determine which components of the protein C system are responsible for this failure and in addition to assess what effect this diabetic deficiency has on the endothelial susceptibility to inflammatory stress (e.g., TNF, IL-6).