p62/SQSTM1通过Nrf2/ARE/HO-1途径抑制COPD气道粘液高分泌的作用及机制研究

香烟烟雾诱导的气道粘液高分泌是慢性阻塞性肺疾病(COPD)重要的发病机制及预后影响因素，我们前期研究发现p62/SQSTM1参与调控气道粘液分子MUC5AC表达，但具体机制不详,进一步研究发现在香烟烟雾干预的支气管上皮细胞中增加p62/SQSTM1表达可促进与炎症及氧化应激相关分子Nrf2入核以及HO-1的表达。因此，我们推测p62/SQSTM1可能通过激活Nrf2/ARE/HO-1途径抑制COPD气道粘液高分泌。本研究拟首先建立香烟烟雾诱导的p62/SQSTM1基因敲除鼠和野生鼠的COPD模型，对比两者气道黏膜p62/SQSTM1表达及粘液分泌情况的差异，其次在细胞层面采用慢病毒转染敲低p62/SQSTM1表达，分析其减少香烟烟雾诱导的气道粘液高分泌的作用，最后联合使用FRET、免疫共沉淀技术进一步探讨其抑制作用的具体信号通路。本研究旨在为COPD气道粘液高分泌的调控提供新思路及新靶点。

Airway mucus hypersecretion induced by cigarette smoke is an important pathogenesis and prognostic factor for chronic obstructive pulmonary disease (COPD). Our previous research found that p62/SQSTM1 is involved in regulating the expression of airway mucus molecule MUC5AC, but the specific mechanism is unknown. Further study found that increasing the expression of p62/SQSTM1 in bronchial epithelial cells intervened by cigarette smoke can promote the expression of Nrf2 and HO-1, which are related to inflammation and oxidative stress. Therefore, we speculated that p62/SQSTM1 may inhibit COPD airway mucus hypersecretion by activating the Nrf2/ARE/HO-1 pathway. In this study,the COPD models of p62/SQSTM1 gene knockout mice and wild mice induced by cigarette smoke were established firstly, and the expression of p62/SQSTM1 and mucus secretion in airway mucosa were compared.Secondly, at the cell level, the expression of p62/SQSTM1 was knocked down by lentivirus transfection, and its effect on reducing airway mucus hypersecretion induced by cigarette smoke was analyzed. Finally, the specific signal pathways of its inhibitory effect were further explored by using FRET and co-immunoprecipitation.The purpose of this study is to provide new ideas and targets for the regulation of airway mucus hypersecretion in COPD.