Thrombin & its Major Receptor in Transforming Growth Factor-beta Release and Adhesion Formation in Pleural Infection

在英国和美国，每年有超过65,000名患者受到胸膜感染（通常称为胸膜炎）的影响，死亡率高达20%。胸膜炎的特点是胸腔积液。脓液的引流是成功治疗的关键，但通常是困难的，因为脓液经常被纤维分隔锁在多个口袋中。了解这些分离形成的病理生理学将有助于制定针对其形成的策略。我们最近的实验表明，胸膜炎诱导凝血酶（一种参与血液凝固的酶）在胸部积聚，从而刺激转化生长因子(TGF)- β从体外的间皮细胞（胸膜腔）释放。这一点很重要，因为我们之前已经证明tgf - β可以有效地刺激粘连和纤维化。拟议的项目将汇集tgf - β和间皮细胞生物学（Lee博士）、PARs （Chambers & Moffatt博士）、胸膜疾病（Davies博士）和肺部感染（Brown博士）方面的五位知名研究人员的专业知识。我们提出的研究将建立在我们的初步数据基础上，并使用各种体外技术和体内实验模型，验证凝血酶诱导的tgf - β释放在胸膜炎粘稠/分隔形成中起重要作用的假设。

Pleural infection (commonly known as pleurisy) affects over 65,000 patients each year in the UK and USA, with a high mortality of 20%. Pleurisy is characterized by pus collection in the chest. Drainage of the pus is crucial to successful management, but is often difficult as pus is often locked into multiple pockets by fibrous septations. Understanding the pathophysiology of formation of these septations will allow strategies to target their formation. Our recent experiments suggest that pleurisy induces accumulation of thrombin (an enzyme involved in blood clotting) in the chest, which stimulates transforming growth factor (TGF)-beta release from mesothelial cells (that line the pleural cavity) in vitro. This is important as we have previously showed that TGF-beta can potently stimulate adhesions and fibrosis. The proposed project will bring together the expertise of five established researchers on TGF-beta and mesothelial cell biology (Dr Lee), PARs (Drs Chambers & Moffatt), pleural disease (Dr Davies) and pulmonary infection (Dr Brown). The proposed studies will build on our preliminary data and test the hypothesis that thrombin-induced release of TGF-beta plays an important role in the formation of adhesions / septations in pleurisy, using a variety of in vitro techniques and in vivo experimental models.