Fibrinolytic Pathways in Lung Injury and Repair

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DESCRIPTION (provided by applicant): Abnormalities in the plasminogen activator (PA) pathways have been implicated in the pathogenesis of acute lung (All) and pleural injury. Recent interventional trials suggest that targeting these pathways can reduce mortality in sepsis and protect against acute lung or pleural injury. The Project Leaders of this PPG have developed evidence that these pathways can influence ALI and pleural injury through newly recognized mechanisms. However the pathogenic mechanisms that link the PA pathways to ALI and pleural injury are poorly understood and are likely to involve non-proteolytic signal-transducing pathways. Our thematic objective is to address this gap by defining novel mechanisms by which urokinase (uPA), its receptor (uPAR), other novel uPA receptors and its inhibitor PAI-1 influence the course of inflammation, remodeling of transitional matrix and accelerated fibrosis in ALI and pleural injury. In Project 1, pathways that regulate PAI-1 and uPAR expression by the.mesothelium at the posttranscriptional level will be defined and a novel fibrinolytic intervention to prevent pleural loculation will be further evaluated. Project 2 will elucidate novel posttranscriptional mechanisms by which uPA and uPAR are regulated by the lung epithelium. Project 3 will define novel pathways by which uPA interacts with cell surface signaling adapter molecules to regulate pulmonary vasoconstriction and lung edema after ALI and ascertain the role of defensin in the process. These interactive projects derive from active programs directed by experienced Project Leaders and are now oriented to our thematic objective. In vitro, in vivo and interventional methods will be used. This PPG will accelerate the acquisition of new, clinically relevant information that will hasten the development of better treatments for ALI and/or pleural injury.