PI3K信号通路介导骨桥蛋白调控EMT过程在COPD气道重塑中的作用

Airway inflammation and remodeling are the main events of chronic obstructive pulmonary disease (COPD). Repeated external stimuli and excessive airway inflammation will cause epithelial cell damage and abnormal repair, promote airway remodeling and COPD progression, but its mechanism remains unclear. More and more studies have confirmed that EMT process of alveolar epithelial cells is an important part of lung tissue repair and airway remodeling. Our previous studies found the over-production of OPN in the circulation of patients with COPD, of which some showed disease-specific and severity-associated. It can induce EMT phenotypes in epithelial cells and play an important role in inflammatory response and fibrosis in lung injury. In the process of chronic lung injury, inhibition of PI3K signaling pathway can maintain normal morphology and function of epithelial cells, reduce fibroblast proliferation and collagen deposition, thus maintain normal alveolar structure. We attempt to isolate and culture pulmonary epithelial cells from COPD patients, construct rat models, interfere OPN expression by siRNA, and up-regulate OPN by over-expression plasmid, to verify the disease-specificity of OPN, investigate the key role of OPN-- PI3K--EMT signaling pathways in airway remodeling of COPD, which may provide new insights on COPD pathogenesis and new strategies for clinical treatment.

在COPD中，气道的慢性炎症和重塑是其主要发病机制和病理特点。反复的外来物质刺激和气道过度炎症都将造成上皮细胞的不断受损和异常修复，促使气道重塑的形成和COPD的进展，具体调控机制仍不清楚。越来越多的研究证实肺泡上皮细胞EMT过程是肺组织损伤修复及气道重塑的重要环节。前期我们通过临床生物信息学发现，骨桥蛋白(osteopontin，OPN)具有COPD疾病特异性，并可诱导上皮细胞EMT表型变化，在肺损伤炎症反应和纤维化过程中发挥了重要作用。而在慢性肺损伤过程中，PI3K通路的抑制可维持上皮细胞的正常形态和功能，减少成纤维母细胞增生和胶原沉积，从而维持正常肺泡结构。本研究通过临床标本检测、COPD大鼠模型构建、siRNA干扰及过表达等方法，全方位探讨OPN--PI3K--EMT--的炎症信号通路在COPD的气道重塑中的关键性作用，该研究结果可为COPD气道重塑的预防和治疗提供新的理论依据。

在慢性阻塞性肺疾病（COPD）中，气道的慢性炎症和重塑是其主要发病机制和病理特点。反复的外来物质刺激和气道过度炎症都将造成上皮细胞的不断受损和异常修复，促使气道重塑的形成和COPD的进展，但具体调控机制仍不清楚。本课题通过临床标本检测发现，骨桥蛋白（OPN）在COPD患者外周血及肺组织中表达均明显升高，且与疾病病程密切相关。通过一系列体外试验发现，OPN通过诱导上皮细胞EMT过程，在炎症因子释放、气道上皮细胞增殖与重塑过程中发挥了重要作用，而PI3K信号通路在这一过程中起到了关键作用。通过干预OPN和PI3K信号的表达，调控EMT转化过程，从而阻断后续的一系列过程，可为COPD气道重塑的预防和治疗提供新的理论依据。