MECHANISMS OF MICROVASULAR THROMBOSIS IN BABOONS

狒狒微血管血栓形成机制

• 批准号: 6385663
• 负责人: FLETCHER B TAYLOR
• 金额: $ 40.38万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6385663
• 关键词: Escherichia coli infections; anticoagulants; antifibrinolytic agents; antiinflammatory agents; baboons; binding proteins; blood coagulation; carboxypeptidase; coagulation factor X; complement; disease /disorder model; fibrinogen; interleukin 6; luminescence; monoclonal antibody; neutrophil; plasminogen activator; protein C; protein S; protein structure function; thrombin; thrombomodulin; tumor necrosis factor alpha; vascular endothelium; venous thrombosis

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).

描述：（研究者摘要）既往研究记录了 炎症介质的作用（例如，TNF、IL-6）、止血介质（例如， 组织因子/VIIa）、止血调节剂（例如蛋白C和S），和 止血调节剂（例如C4 b结合蛋白）在驱动和控制血管生成中的作用。 狒狒对E.杆菌止血药的抗炎作用 调节剂，特别是蛋白质C系统的调节剂，以及最近的发现， 内皮蛋白C受体（EPCR）和凝血酶的参与 激活的纤溶抑制剂（TADI）在这个系统中，使我们研究 它们对其抗炎和抗凝血特性的贡献。EPCR 是内皮细胞/蛋白C网络的最新成员， C本身在控制对E的反应中是必不可少的。杆菌EOCR的形式 其独特之处在于，虽然它在体外抑制蛋白C抗凝活性， 它还抑制了流动下中性粒细胞/内皮细胞的紧密相互作用， 条件我们计划在体外研究这些的病理生理相关性 在灵长类动物非炎性（凝血酶）和炎性（E.大肠杆菌） DIC模型TAFI是纤溶抑制剂的最新成员， 连接到蛋白质C网络，也是独特的，（1）虽然它是 在凝血酶/血栓调节蛋白复合物的激活下， 由活化的蛋白C调节，该蛋白C也由该复合物产生，（2） 它是一种羧肽酶，具有潜在抗炎作用， 抗纤维蛋白溶解活性。同样，这些体外观察结果的相关性 目前还不清楚，也不知道在什么病理生理条件下TAFI发生 发挥作用我们计划在上面提到的灵长类动物模型中检查TAFI功能 C4 bBP/亚致死E.大肠杆菌微血管血栓形成模型。 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 纤维蛋白溶解“备份”反应拯救了这些动物。我们计划确定 蛋白C系统的哪些成分是导致这种失败的原因， 除了评估这种糖尿病缺乏对 内皮对炎症应激的敏感性（例如，TNF、IL-6）。