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。我们假设胸膜间皮瘤细胞中纤溶酶原激活物抑制剂-1（派-1）和尿激酶受体（uPAR）的紊乱调节是石棉暴露或纤维化性胸膜炎后局部纤溶受损和胸膜重塑的关键决定因素。调节这些蛋白质在间皮细胞中表达的机制现在知之甚少。我们将扩大以往供资周期所做的工作，以弥补这些重要差距。我们将通过四个紧密结合的具体目标来实现这一目标。在目的1中，我们将确定机制，调节派-1和uPAR在间皮细胞暴露于石棉或介质的纤维化胸膜损伤的表达。在目标2和3中，我们将阐明派-1在转录后水平受胸膜间皮细胞调节的机制，并确定在此水平的控制如何影响这些细胞的病理生理反应。在目标4中，我们将进一步测试一种新的介入方法;胸膜内给予单链uPA（scuPA）以预防胸膜腔形成。我们将在这些研究中使用我们建立的四环素或多杀性巴氏杆菌诱导的胸膜损伤的兔模型。为了完成这项工作，我们将使用广泛的分子，生物化学和组织学技术，所有这些都是在我们的实验室建立良好的。这些研究将促进人们更好地了解 在派-1-uPA-uPAR系统的调节中，间皮细胞的作用将增加我们的 了解这些细胞如何促进损伤后胸膜重塑。该项目还将促进开发新的、临床适用的非手术方法，以预防胸膜内房形成及其相关的发病率。

Disordered fibrin turnover has been implicated in the pathogenesis of pleural inflammation and repair. We hypothesize that deranged regulation of plasminogen activator inhibitor-1 (PAI-1) and of the urokinase receptor (uPAR) in pleural mesothelial cells are critical determinants of locally impaired fibrinolysis and intrapleural remodeling after asbestos exposure or in fibrosing pleuritis. Mechanisms that regulate expression of these proteins in mesothelial cells are now poorly understood. We will extend work done in previous funding cycles to address these important gaps. We will achieve this objective in four closely integrated specific aims. In Aim 1, we will determine mechanisms that regulate the expression of PAI-1 and uPAR in mesothelial cells exposed to asbestos or mediators of fibrosing pleural injury. In Aims 2 and 3, we will elucidate mechanism(s) by which PAI-1 is regulated by pleural mesothelial cells at the posttranscriptional level and will determine how control at this level influences pathophysiologic responses of these cells. In Aim 4, we will further test a novel interventional approach; intrapleural administration of single-chain uPA (scuPA) to prevent pleural loculation. We will use our established rabbit models of tetracycline- or P. multocida induced pleural injury in these studies. To accomplish the work, we will use a wide range of molecular, biochemical and histologic techniques, all of which are well-established in our laboratory. These studies will foster better understanding of the role of the mesothelial cell in the regulation of the PAI-1-uPA-uPAR system and will increase our understanding of how these cells contribute to pleural remodeling after injury. The project will also facilitate the development of novel, clinically applicable non-surgical approaches to prevent intrapleural loculation and its associated morbidity.