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

胸膜感染(俗称胸膜炎)在英国和美国每年影响超过65,000名患者，死亡率高达20%。胸膜炎的特征是胸腔积液。引流脓液是成功治疗的关键，但通常是困难的，因为脓液经常被纤维间隔锁在多个口袋中。了解这些间隔形成的病理生理学机制将有助于制定针对其形成的策略。我们最近的实验表明，胸膜炎导致凝血酶(一种参与凝血的酶)在胸腔内积聚，从而刺激体外培养的胸膜间皮细胞(胸腔内)释放转化生长因子-β。这一点很重要，因为我们之前已经证明，转化生长因子-β可以有效地刺激粘连和纤维化。拟议的项目将汇集五位资深研究人员在转化生长因子-β和间皮细胞生物学(Lee博士)、PARS(DRS Chambers&Moffatt)、胸膜疾病(Davies博士)和肺部感染(Brown博士)方面的专业知识。建议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来验证凝血酶诱导的转化生长因子-β的释放在胸膜炎粘连/间隔的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.