Disordered fibrin turnover has been implicated in the pathogenesis of pleural inflammation and repair. We hypothesize the mesothelial cell responses play a crucial role in these events. Derangements of the regulation of plasminogen activator inhibitor -1 (PAI-1) and the urokinase receptor (uPAR) by pleural mesothelial cells appear to be critical determinants of locally impaired fibrinolysis and intrapleural remodeling after asbestos exposure or other forms of fibrosing pleuritis. Asbestos and cytokines implicated in asbestos-related or other forms of fibrosing pleuritis alter local regulation of these molecules, but the mechanisms responsible for these responses are poorly understood at this time. Our studies address these important gaps in our understanding of mesothelial cell biology. We will determine mechanisms by which mesothelial cells regulate PAI-1 and uPAR expression in response to asbestos or other mediators of fibrosing pleural injury. Direct and indirect mechanisms by which asbestos influences expression of these molecules and uPA-mediated responses by mesthelial cells will be defined. Interactions of these pathways with procoagulant pathways of mesothelial cells will also be elucidated in vitro. An established rabbit model of tetracycline (TCN)-induced pleural injury will be used to define in vivo responses of the uPA-uPAR system in pleural mesothelial cells that contribute to locally disordered fibrinolysis and pleural remodeling. We have recently determined that PAI-1 as well as uPAR are regulated at the posttranscriptional level by mesothelial cells and will now determine the mechanisms by which these pathways respond to asbestos or other mediators of fibrosing pleuritis. The role of these pathways in asbestos- induced responses of mesothelial cells or in TCN-induced pleural injury will be determined. Lastly, we will use our preliminary data to develop novel interventional approaches to selectively prevent pleural fibrin deposition and pleural fibrosis. We will test the ability of these approaches to safely and effectively block pleural loculation and fibrosis in the rabbit model. To accomplish these goals, we will use an array of molecular, biochemical and immunohistochemical techniques, all of which are well-established in our laboratory. These studies will allow us to define the role of the mesothelial cell in the regulation of the uPA-uPAR system and to understand how these cells thereby contribute to pleural remodeling after injury. This work could identify better, clinically feasible therapeutic approaches to prevent pleural fibrosis.
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