uPAR在慢性阻塞性肺疾病小气道上皮细胞EMT中作用的研究

Thicken small airway wall is the main cause of irreversible air?ow limitation characteristic in COPD,which is significantly related to the severity of COPD. Myo?broblast around small airway play a key role in the process of thicken small airway wall. Myo?broblast is partly from epithelial to mesenchymal transition (EMT). Our previous study showed that the EMT process was obviously present in small airway epithelium of patients with COPD.We indicated that the level of urokinase type Plasminogen Activator Receptor (uPAR) was significantly elevated in COPD patients compared to control group in small airway epithelium, and the expression of uPAR in small airway epithelium was significantly related to EMT. CSE-induced EMT was inhibited by uPAR gene silencing in HSAEpiC cells. Taken together with previous reports, we postulate that uPAR may play an important role in the process of EMT of small airway epithelium.To test our hypothesis, we planned to: ①clarify that uPAR participate in the EMT of small airway epithelium in COPD;②explore the possible signal transduction mechanism of EMT induced by uPAR in small airway epithelium;③verify the role of signal transduction factor in EMT induced by uPAR in small airway epithelial cells.These will further help us understand the pathogenesis of COPD, and will shed new lights on prevention and treatment of COPD.

小气道壁增厚是COPD气流受限的主要原因之一，与COPD的严重程度显著相关。小气道周围肌成纤维细胞在小气道壁增厚过程中具有重要作用，肌成纤维细胞部分来源于上皮-间质转化（EMT）。我们前期研究发现：COPD肺组织标本中小气道上皮细胞存在明显的EMT现象，并与表达异常增高的尿激酶型纤溶酶原激活物受体（uPAR）显著相关；干扰小气道上皮细胞（HSAEpiC）uPAR的表达，能够有效抑制香烟烟雾提取物诱导的小气道上皮细胞的EMT。这些研究结果强烈提示uPAR对于COPD小气道上皮细胞EMT发生可能具有调控作用。本研究试图①明确uPAR参与调控COPD小气道上皮细胞EMT的发生；②研究uPAR调控小气道上皮细胞发生EMT的相关信号转导机制；③验证uPAR调控小气道上皮细胞EMT的信号转导因子的作用，并寻找有效的干预措施，从而深入阐明COPD气道重塑的机制，为其有效防治提出新的靶点。

EMT是指极化的上皮细胞经历多种生物化学的改变最终表现出间质细胞特性的过程。多项研究证实，EMT与多种器官纤维化的发生、发展有着密切的关系。近年来，EMT在COPD疾病发生发展中的作用日益为研究者所重视。新近研究表明，EMT在COPD患者小气道上皮明显存在，且与COPD的主要危险因素吸烟密切相关，经历了EMT的小气道上皮细胞能穿透基底膜迁移到黏膜下层转化成成纤维细胞/肌成纤维细胞。这些结果显示小气道上皮细胞EMT的发生是COPD小气道壁增厚和纤维化的重要因素。本课题研究了尿激酶型纤溶酶原激活物（urokinase-type plasminogen activator，uPA）及其受体（uPA receptor，uPAR）在COPD的组织重塑中的作用及发生机制。结果显示：COPD患者小气道上皮细胞uPA、uPAR的表达均显著高于不患 COPD的对照者，且分别与肺功能气流阻塞程度密切相关。体外实验证实uPAR对香烟烟雾提取物诱导的人小气道上皮细胞EMT具有调控作用，其通过PI3K/ Akt信号通路介导香烟烟雾提取物诱导的EMT过程；香烟烟雾提取物诱导小气道上皮细胞EMT的同时能促进uPA表达上调，而上调的uPA表达促进了小气道上皮细胞EMT的发生，并促进细胞转移。由此可见，uPA和uPAR在COPD患者小气道上皮细胞EMT的发生中发挥着重要作用。本研究从新的角度探讨了COPD小气道重塑的发病机制，同时为COPD的防治提供了新的科学资料。