Fibrin Structures and Lung Injury

描述（由申请人提供）：凝血级联的激活将可溶性纤维蛋白原转化为不溶性纤维蛋白，该纤维蛋白与血小板一起聚合产生止血凝块。虽然凝血级联的正常激活对生命至关重要，但不适当的激活或不能及时溶解沉积的纤维蛋白可能导致纤维蛋白依赖性器官病理。事实上，病理诱导的血栓形成产生静脉血栓栓塞（VTE），这是美国发病率和死亡率的主要原因。肺血管室是静脉血栓栓塞和其他以纤维蛋白沉积为特征的临床综合征的主要靶点。然而，纤维蛋白的结构和力学性质是否影响静脉血栓栓塞和肺部并发症的严重程度尚不清楚。最近的研究提供了关于冠状动脉疾病患者纤维蛋白结构改变和力学特性的新见解。这些新发现与先前记录的纤维蛋白原/纤维蛋白与心血管并发症风险之间的流行病学发现提供了机制关联。尽管存在类似的流行病学关联，但纤维蛋白网络对静脉血栓栓塞和肺功能障碍风险的功能后果和贡献仍未得到验证。因此，我们认为抵抗纤维蛋白溶解的异常纤维蛋白结构诱导的肺血管异常会增加静脉血栓栓塞和急性肺损伤的风险。这一假设将通过以下方法得到验证：1)量化临床记录的深静脉血栓患者的纤维蛋白凝块浊度、纤维蛋白结构、纤维蛋白溶解抵抗和氧化修饰纤维蛋白原水平。2)在肺血栓栓塞小鼠模型中测试从临床记录的深静脉血栓患者分离的纤维蛋白原产生的血栓栓塞的功能后果。3)在急性血栓栓塞小鼠模型中，确定从临床记录的深静脉血栓患者体内分离的纤维蛋白原在体内产生的纤维蛋白的功能后果。总的来说，这些小鼠模型旨在首次评估不同纤维蛋白结构对肺血管并发症的影响。这些特定目标的成功完成将为急性血栓栓塞风险受试者的纤维蛋白凝块的生化和生物物理特性提供系统的研究，并探索体内纤维蛋白组装改变的潜在生物学后果。

DESCRIPTION (provided by applicant): Activation of the coagulation cascade converts soluble fibrinogen to insoluble fibrin, which polymerizes to produce, along with platelets, the haemostatic clot. Whereas the normal activation of the coagulation cascade is essential for life, inappropriate activation or failure to dissolve deposited fibrin in a timely manner may result in fibrin-dependent organ pathology. Indeed pathologically induced thrombogenesis produces venous thromboembolism (VTE), a major cause of morbidity and mortality in the USA. The pulmonary vascular compartment is a major target for VTE and other clinical syndromes characterized by fibrin deposition. However, it is unclear if the structure and mechanical properties of fibrin influences the severity of VTE and pulmonary complications. Recent studies have provided provocative new insights regarding the presence of fibrin structures with altered architecture and mechanical properties in subjects with coronary artery disease. These new findings provide mechanistic associations with the previously documented epidemiological findings between fibrinogen/fibrin and risk of cardiovascular complications. Despite similar epidemiological associations, the functional consequences and contributions of fibrin networks for the risk of developing VTE and pulmonary dysfunction remain untested. Therefore we propose that abnormal fibrin structures that are resistant to fibrinolysis induce pulmonary vascular abnormalities confer a high risk for VTE and acute lung injury. This hypothesis will be tested by: 1) Quantifying fibrin-clot turbidity, fibrin structure, fibrinolytic resistance and levels of oxidatively-modified fibrinogen in patients with clinically documented deep venous thrombosis. 2) Testing the functional consequences of thromboemboli generated from fibrinogen isolated from clinically documented DVT subjects in a mouse model of pulmonary thromboemboli challenge. 3) Ascertaining the functional consequences of fibrin generated in vivo from fibrinogen isolated from clinically documented DVT subjects in a mouse model of acute thromboembolism. Collectively these mouse models aim to evaluate for the first time the influence of variant fibrin structures in deriving pulmonary vascular complications. Successful completion of these specific aims will provide a systematic study of the biochemical and biophysical properties of fibrin clots in subjects at risk for acute thromboembolism and explore the potential biological consequences of altered fibrin assemblies in vivo.