Lung Injury Protection by Coagulation Blockade

这是一个修改后的应用程序，旨在研究肺的凝血系统在急性肺损伤（所有）中的作用。组织因子（TF）启动凝血和促凝状态的持续在急性呼吸窘迫综合征（ARDS），特别是脓毒症的发病机制中很重要。 TF和其他凝血蛋白与增强肺损伤反应的炎性成分沟通。 此外，纤溶酶原激活物抑制剂（派-1和PAI-2）和抗纤溶酶的激活抑制了纤维蛋白溶解，这促进了纤维蛋白积聚并导致毛细血管闭塞、透明膜形成、气体交换障碍和肺纤维化。 我们在动物中发现，TF阻断消除了脂多糖（LPS）引起的肺损伤和革兰氏阴性脓毒症引起的肺损伤中的炎症。 虽然凝血在ARDS的发病机制中是不可或缺的，但凝血级联的不同组分如何与炎症和纤溶途径相互作用以促进或解决急性肺损伤尚不清楚。 为了解决这个问题，我们将测试的假设：凝血启动的封锁是一个最佳的策略，通过防止过度的炎症介质释放和细胞流入，降低结构，功能，并延迟解决的ALI肺保护。 我们进一步提出，凝血因子以外的TF，特别是凝血酶和纤维蛋白，调节特定方面的肺部炎症和它的决议，在败血症通过独立和协调的丝氨酸信号传导事件。提出了三个目标：目标1。确定TF如何与影响急性肺损伤中白细胞募集和炎症消退的特定细胞因子/趋化因子产生相互作用。 目标二。确定凝血酶受体-1（PAR-1）如何与影响急性肺损伤中白细胞募集和炎症消退的特定细胞因子/趋化因子产生相互作用。 目标3：确定纤溶酶原激活物-1（派-1）如何与影响急性肺损伤中白细胞募集和炎症消退的特异性丝氨酸-趋化因子产生相互作用。 对凝血蛋白在急性肺损伤中的作用的改进的机制洞察的意义是提供新的机会，通过针对这些活动的干预来预防异常炎症和紊乱的修复。 一个成功的优化策略可以大大减轻肺部炎症的持续性，促进人类ARDS的解决。

This is an amended application designed to investigate the role of the lung's coagulation system in acute lung injury (All). Initiation of coagulation by tissue factor (TF) and persistence of the pro-coagulant state are important in the pathogenesis of acute respiratory distress syndrome (ARDS), especially in sepsis. TF and other coagulation proteins communicate with inflammatory elements that enhance the lung's injury response. In addition, fibrinolysis is inhibited by activation of plasminogen activator inhibitors (PAI-1 and -2) and antiplasmins, which promotes fibrin accumulation and contributes to capillary obliteration, hyaline membrane formation, gas exchange impairment, and lung fibrosis. We show in animals that TF blockade abrogates inflammation in lung injury by lipopolysaccharide (LPS) and lung injury in Gram-negative sepsis. Although coagulation is integrally involved in the pathogenesis of ARDS, it is not clear how the different components of the coagulation cascade interact with inflammatory and fibrinolytic pathways to promote or resolve acute lung injury. To address this issue, we will test the hypothesis: blockade of coagulation initiation is an optimal strategy for lung protection by preventing excessive inflammatory mediator release and cell influx that degrades structure, function, and delays resolution of ALI. We further propose that coagulation factors other than TF, especially thrombin and fibrin, regulate specific aspects of lung inflammation and its resolution in sepsis through independent and coordinate cytokine-signaling events. Three aims are proposed: Aim 1. Determine how TF interacts with specific cytokine/chemokine production that influences leukocyte recruitment and resolution of inflammation in acute lung injury. Aim 2. Determine how thrombin receptor-1 (PAR-1) interacts with specific cytokine/chemokine production that influences leukocyte recruitment and resolution of inflammation in acute lung injury. Aim 3. Determine how plasminogen activator-1 (PAI-1) interacts with specific cytokine-chemokine production that influences leukocyte recruitment and resolution of inflammation in acute lung injury. The implications of improved mechanistic insight into the role of coagulation proteins in acute lung injury are to provide new opportunities to prevent abnormal inflammation and disordered repair through interventions directed at these activities. A successfully optimized strategy could greatly attenuate persistence of pulmonary inflammation and facilitate the resolution of human ARDS.