基于内质网应激（ERS）的非经典途径参与哮喘粘液高分泌的机制研究

The inhibition of mucus hypersecretion plays a key role in the treatment of severe asthma, given that mucus hypersecretion is a chiefly difficult problem during acute severe asthma. Endoplasmic Reticulum (ER) stress plays an important role in the progress of the asthma, however, the mechanism of which in mucus hypersecretion remains elusive. We find the evidence of ER stress in the mucus hypersecretion of asthmatic mice model, and the inhibition of ER stress can reverse phosphorylation of STAT6 and alleviate mucus hypersecretion in our previous research, the mechanism of which needs to be further studied. Based on our previous research, we prepare to analyze how the level of phosphorylation of STAT6, STING, TBK1, JAK1/2/3 and expression of MUC5AC are affected by ER stress through animal experiment, and analyze the mechanism of both ER stress-induced phosphorylation and the expression of MUC5AC protein regulated by STAT6 in vitro experiments. These researches will explore the role and machinery of ER stress engaged in mucus hypersecretion, which may offer significant insight for the treatment of asthma.

粘液高分泌是重症哮喘发作面临的首要难题，故抑制粘液高分泌对重症哮喘的治疗有关键作用。内质网应激在哮喘病情进展中有重要作用，但其在哮喘粘液高分泌中的机制不明。前期研究发现，小鼠哮喘粘液高分泌模型中存在内质网应激，内质网应激的抑制可逆转STAT6的磷酸化并减轻小鼠气道粘液高分泌，但其机制有待进一步研究。因此本研究拟在前期基础上，通过动物实验分析内质网应激对STAT6，STING，TBK1，JAK1/2/3磷酸化水平以及MUC5AC蛋白水平的影响；通过体外细胞实验分析内质网应激影响STAT6磷酸化的机制，以及STAT6调控MUC5AC表达的机制。该研究拟探索内质网应激参与粘液高分泌的机制，对哮喘的治疗具有重要意义。

粘液高分泌是哮喘面临的首要难题，故抑制粘液高分泌对哮喘的治疗有关键作用。内质网应激在哮喘病情进展中有重要作用，但其在哮喘粘液高分泌中的机制不明。我们在体内外分析了内质网应激与哮喘粘液高分泌的关系，分析了内质网应激促进MUC5AC表达上调的分子机制；同时，在体内外分析了TGF-β3与氧化应激、细胞自噬以及哮喘粘液高分泌的关系，研究了TGF-β3促进MUC5AC表达上调的分子机制。研究结果显示，尘螨过敏原(HDM)诱导的内质网应激在哮喘粘液高分泌中发挥关键作用；HDM诱导的内质网应激可以通过激活TBK1-STAT6/NF-kB信号通路促进MUC5AC表达上调。同时，TGF-β3可以诱导氧化应激、细胞自噬以及哮喘粘液高分泌；TGF-β3激活的Smad2/3信号通路通过促进NOX4表达上调诱导气道上皮细胞氧化应激，氧化应激通过促进细胞自噬激活c-Jun通路，从而诱导MUC5AC表达上调。这些研究表明，内质网应激以及细胞自噬均可参与调控哮喘气道粘液高分泌，TGF-β3中和抗体和内质网应激抑制剂可能作为治疗哮喘粘液高分泌的潜在药物。