尘螨过敏原诱导的细胞自噬通过β-catenin/Smad2/3-Snail信号途径影响气道上皮紧密连接的机制研究

Dysfunctioned airway barrier has been considered a key effector of asthma pathogenesis. It is critical to improve airway barrier function to prevent and treat of asthma. Autophagy, promoting airway remodeling and mucus hypersecretion, is induced by some environmental factors (such as cigarette smoke extracts and fine particulate matter). House dust mites (HDM) allergens are widespread environmental factors, but it is still unclear if HDM could induced autophagy in airway epithelium cells. Previous studies have found that high concentration HDM may destroy the tight junction which is known to be maintaining epithelial barrier function by inducing autophagy, however, the details of the mechanisms remain further studies. Based on our previous work, we will focus on analysis the association between autophagy and dysfunction of tight junctions in mice. And to explore how autophagy influences tight junctions by promoting phosphorylation of β-catenin and Smad2/3, and to unlock the mechanisms of HDM induced autophagy. Taken together, our study will demonstrate that how HDM-induced autophagy regulate airway epithelium tight junctions, which will be great significance therapeutic candidate for asthma.

气道屏障功能的破坏在哮喘病情进展中发挥关键作用，故改善气道屏障功能对哮喘防治至关重要。烟草提取物、超细颗粒物等环境因素诱导的细胞自噬参与了气道重构以及粘液高分泌。然而，屋尘螨过敏原（HDM）作为广泛存在的环境因素，其与细胞自噬的关系仍不明确。紧密连接是位于上皮细胞间调控上皮屏障功能的连接复合体。前期研究发现，高浓度HDM可能通过诱导细胞自噬破坏气道上皮紧密连接，但相关机制有待进一步研究。因此本研究拟在前期研究基础上，通过动物实验分析细胞自噬与气道上皮紧密连接破坏的关系；通过细胞实验探索自噬通过促进β-catenin和Smad2/3磷酸化影响气道上皮紧密连接的分子机制，以及HDM诱导细胞自噬的机制。本研究拟探索HDM诱导的细胞自噬调控气道上皮紧密连的机制，对哮喘的治疗有重要意义。

气道屏障功能的破坏在哮喘病情进展中发挥关键作用，故改善气道屏障功能对哮喘防治至关重要。本研究通过动物实验和细胞实验探索了尘螨过敏原诱导的细胞自噬影响气道上皮紧密连接的机制。结果显示，屋尘螨（HDM）通过促进气道上皮细胞氧化应激诱导细胞自噬；HDM诱导的细胞自噬可以促进β-catenin和Smad2/3的磷酸化；进一步，p-β-catenin和p-Smad2/3通过促进转录抑制因子Snail的表达抑制紧密连接蛋白Occludin, ZO-1, E-cadherin等的表达，从而破坏气道上皮细胞间的紧密连接。该研究为细胞自噬参与哮喘紧密连接调控的机制研究提供了理论基础。