Lung Injury Protection by Coagulation Blockade

这是一个修改后的应用程序，旨在研究肺凝血系统在急性肺损伤（All）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）的发病机制中很重要，特别是在败血症中。TF和其他凝血蛋白与炎症因子交流，增强肺损伤反应。此外，纤溶酶原激活剂抑制剂（PAI-1和-2）和抗纤溶酶的激活可抑制纤维蛋白溶解，从而促进纤维蛋白积累，导致毛细血管闭塞、透明膜形成、气体交换障碍和肺纤维化。我们在动物实验中发现，TF阻断可消除脂多糖（LPS）引起的肺损伤和革兰氏阴性脓毒症引起的肺损伤。虽然凝血在ARDS的发病机制中起着重要作用，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缓解急性肺损伤尚不清楚。为了解决这一问题，我们将验证以下假设：阻断凝血起始是一种最佳的肺保护策略，可以防止过度的炎症介质释放和细胞内流，从而降低ALI的结构、功能和延迟解决。我们进一步提出，除TF以外的凝血因子，特别是凝血酶和纤维蛋白，通过独立和协调的细胞因子信号传导事件，调节败血症中肺部炎症及其消退的特定方面。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2。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 （PAI-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。对凝血蛋白在急性肺损伤中的作用机制的深入了解，为通过干预这些活动来预防异常炎症和修复紊乱提供了新的机会。一个成功的优化策略可以大大减轻肺部炎症的持久性，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.