Rac1信号调控香烟诱导气道上皮细胞－间充质细胞转化的分子机制

慢性气道炎症性疾病包括COPD、哮喘、特发性肺纤维化等都有不同原因和程度的上皮细胞损伤，损伤引起的上皮-间充质细胞转化(EMT)被认为是导致气道重塑和纤维化的关键。吸烟是呼吸系统疾病的重要诱导因素。之前的研究我们已经证明LPS或吸烟激活肺组织中Rac1抑制剂能显著减少吸烟所导致的中性粒细胞和巨噬细胞的肺组织内的浸润、氧化损伤和炎症介质的产生，揭示了Rac1在吸烟所致的肺部炎症中的重要地位。同时我们发现香烟暴露小鼠可导致肺上皮细胞EMT和香烟提取物诱导人肺上皮细胞引起EMT，这些变化可被Rac特异性抑制剂所减轻。为了进一步深入研究，我们将以Rac1作为影响EMT的潜在信号，采用Rac1基因敲除的小鼠、siRNA干扰、Rac1特异性抑制剂等工具和分子药理学方法，探索Rac1信号在吸烟引起的气道EMT，上皮细胞增殖、分泌和凋亡的调节机制，为COPD治疗建立新的药物靶点。

Chronic airway inflammatory diseases including chronic obstructive pulmonary diseases(COPD), asthma, idiopathic pulmonary fibrosis has a different reason and degree of epithelial cell damage. Damage-induced epithelial-to－mesenchymal transformation (EMT) is recognized as a key cause of airway remodeling and fibrosis.Cigarette smoking is an important risk factor for the respiratory system diseases. Our previous research has shown cigarette smoking can lead to Rac1 and Rac2 activation in lung tissue, but Rac1 inhibitor could significantly reduce increase in neutrophils and macrophages, oxidative stress and proinflammatory factors, and suggested the important regulatory effect of Rac1 signal pathway on the lung inflammation caused by smoking. And we found that the mice exposed to cigarette can cause lung epithelial cells to EMT. Cigarette smoking extract can induced lung epithelial cells to EMT in vitro, which can be inhibited by Rac1 specific inhibitors. In the studies, we presume Rac1 as a potential signal pathway in lung epithelial cells to EMT. We will apply the Rac1 knockout mice, Rac specificity inhibitor and molecular pharmacological methods, to explore regulatory mechanism of the Rac1 signal pathway on smoking-induced EMT in the lung, epithelial cell proliferation and secretion and apoptosis. We suggest that Rac may be a potential target for therapeutic intervention of epithelial-mesenchymal cells transformation.