Lung Injury Protection by Coagulation Blockade

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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.