Fibrin deposition commonly accompanies inflammation and may be involved in tissue repair. Coagulation abnormalities, intravascular and extravascular pulmonary fibrin deposition and the early development of pulmonary fibrosis are commonly found in the Adult Respiratory Distress Syndrome (ARDS). ARDS affects 150,000 patients annually and is lethal in half these cases. The participation of coagulation mechanisms in the pathogenesis of ARDS particularly with respect to lung repair and fibrosis is not well defined. A factor X activating procoagulant activity has been found in bronchoalveolar lavage (BAL) from the lungs of patients with ARDS. Similar activity has been found in BAL of marmosets following treatment with bleomycin, an agent which causes acute lung injury followed by pulmonary fibrosis. The purpose of this study is to characterize the origins and properties of BAL procoagulant activity and to define the relationship of BAL procoagulants to acute lung injury. This will be studied in humans and a well characterized animal model of lung injury. Further, we will examine the role of these procoagulants in the development of pulmonary fibrosis following acute lung injury. This proposal addresses the following questions: 1. What are the mechanisms of the activation of factor X in BAL in inflammatory lung disease? 2. Is the factor X activation the major procoagulant activity in ARDS BAL and in other forms of pulmonary inflammation? 3. Is the generation of BAL procoagulant correlated in vivo with physiologic impairment or pulmonary fibrosis in ARDS and bleomycin induced lung injury? 4. Which cells produce the procoagulants in BAL? Immunochemical and functional assays of procoagulant activators of factor X; in particular factor VII and tissue factor, will be used to investigate the mechanism of activation of factor X. Serial studies of patients and experimental animals will help to determine the physiologic importance of the procoagulant factor X activator. Lung cells in culture will be used to study the origins and mechanisms of expression of BAL procoagulants. Information from these studies will contribute to an understanding of the role of coagulation mechanisms in acute lung injury and repair.
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