PAR2/β-catenin通过诱导气道上皮内质网应激参与调控COPD气道MUC5AC高分泌的机制研究

气道上皮细胞过度表达MUC5AC是COPD发病的关键环节。PAR2及β-catenin信号均与COPD发病密切相关，但其中作用机制尚不清楚。我们前期研究显示，香烟烟雾暴露12周显著上调小鼠气道上皮PAR2表达、促进气道上皮β-catenin活化及入核，阻断β-catenin信号可减轻香烟诱导的气道中性粒细胞浸润及上皮MUC5AC高表达；同时，我们还观察到模型鼠气道上皮内质网应激（ERS）相关标记蛋白表达增加，且能被β-catenin拮抗剂抑制。据此，我们提出“PAR2/β-catenin通过诱导气道上皮ERS参与调控COPD气道MUC5AC高分泌”的科学假说。本项目拟从动物和细胞水平阐明PAR2/β-catenin及ERS在COPD气道MUC5AC高分泌的作用、探讨PAR2/β-catenin通过诱导气道上皮ERS参与调控MUC5AC高分泌的分子机制，为防治COPD提供新的理论依据。

Overexpression of MUC5AC in the airway epithelial cells plays an important part in the pathogenesis of COPD. Proteinase-activated receptors 2 (PAR2) is an G protein-coupled receptor that is abundantly expressed in various tissues. Recently, both PAR2 and β-catenin are thought to be closely related to the pathogenesis of COPD, yet the roles and mechanisms involved are largely unknown. In our preliminary study, we found that the expression of PAR2 was significantly up-regulated in airway epithelia after mice were exposed to cigarette smoke for 12 weeks, and cigarette smoke exposure also led to a significantly increased activity of β-catenin, accompanied by increased cytoplasmic and nuclear translocation of β-catenin. Blocking β-catenin signaling with selective inhibitors dramatically attenuated cigarette smoke-induced airway neutrophil infiltration and MUC5AC overexpression in the airway epithelia. At the same time, we also observed that the expression of endoplasmic reticulum stress (ERS) markers were significantly increased in airway epithelia after cigarette smoke exposure, which could be reversed by β-catenin inhibition. Therefore, we propose that PAR2/β-catenin axis orchestrates airway MUC5AC hypersecretion through inducing endoplasmic reticulum stress of airway epithelia in COPD. This study will be further conducted in animal models and in vitro airway epithelial cells to test and to identify whether and how PAR2/β-catenin signaling and ERS mediate airway MUC5AC hypersecretion of COPD. This study will add to our understanding in the pathogenesis of COPD, and help to find potential therapeutic targets for COPD.