CONTROL OF FIBRIN TURNOVER IN PLEURAL DISEASE

紊乱的纤维蛋白周转与胸膜炎症和修复的发病机制有关。 我们假设间皮细胞反应在这些事件中起着至关重要的作用。 胸膜间皮瘤细胞对纤溶酶原激活物抑制剂-1（派-1）和尿激酶受体（uPAR）的调节紊乱似乎是石棉暴露或其他形式的纤维化胸膜炎后局部纤溶受损和胸膜内重塑的关键决定因素。 石棉相关或其他形式的纤维化胸膜炎中涉及的石棉和细胞因子改变了这些分子的局部调节，但目前对这些反应的机制知之甚少。我们的研究解决了我们对间皮细胞生物学的理解中的这些重要空白。 我们将确定间皮细胞调节派-1和uPAR表达的机制，以响应石棉或其他介质的纤维化胸膜损伤。石棉影响这些分子的表达和uPA介导的反应的直接和间接机制将被定义。 这些途径与促凝血途径的间皮细胞的相互作用也将在体外阐明。 四环素（TCN）诱导的胸膜损伤的已建立的兔模型将用于定义胸膜间皮瘤细胞中uPA-uPAR系统的体内反应，其有助于局部紊乱的纤维蛋白溶解和胸膜重塑。 我们最近已经确定派-1以及uPAR在转录后水平受到间皮细胞的调控，现在将确定这些途径对石棉或其他纤维化胸膜炎介质的反应机制。 这些途径在石棉诱导的间皮细胞反应或TCN诱导的胸膜损伤中的作用将被确定。最后，我们将利用我们的初步数据，开发新的介入方法，以选择性地防止胸膜纤维蛋白沉积和胸膜纤维化。 我们将在兔模型中测试这些方法安全有效地阻断胸膜腔形成和纤维化的能力。为了实现这些目标，我们将使用一系列的分子，生物化学和免疫组织化学技术，所有这些都是在我们的实验室建立。 这些研究将使我们能够确定间皮细胞在uPA-uPAR系统调节中的作用，并了解这些细胞如何促进损伤后胸膜重塑。 这项工作可以确定更好的，临床上可行的治疗方法，以防止胸膜纤维化。

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.