PINK1-Parkin介导线粒体自噬调控巨噬细胞氧化应激诱导肥胖型哮喘激素抵抗机制研究

The key problem that obesity-associated asthma is difficult to control and more likely to develop to severe asthma, is greatly attributed to the steroid resistance of obesity-associated asthma. However, its underlying molecular mechanisms are unclear. Our previous study found phenotypic advantage of M1 macrophage and a decreased expression of ATG16L1 in the sputum from obesity-associated asthma. Based on our previous findings and the mechanism of oxidative stress induced by PINK1-Parkin-mediated mitophagy, we hypothesize that obesity-associated danger associated molecular patterns (DAMPs) inhibiting PINK1-Parkin pathway leads to macrophage mitophagy deficiency, further induces and increases oxidative stress, which may be the key molecular mechanisms of steroid resistance in obesity-associated asthma. Based on the concept of translational medicine, this project will apply some research techniques, such as sputum induction, flow cytometry and adoptive transfer to observe the relationship between macrophage mitophagy and steroid resistance in obesity-associated asthma. Furthermore, we will explore and reveal the mechanism of PINK1-Parkin-mediated mitophagy in the steroid resistance of obesity-associated asthma. This project could provide scientific evidence for precise treatments for obesity-associated asthma.

肥胖型哮喘难以控制且更易发展为重症哮喘的瓶颈问题，极大程度归结于肥胖型哮喘糖皮质激素抵抗，但其分子机制不明。线粒体是调控氧化应激和免疫炎症的重要枢纽，而肥胖可导致线粒体功能障碍。我们前期研究发现，肥胖型哮喘患者诱导痰巨噬细胞呈促炎经典活化M1型，自噬体形成关键蛋白ATG16L1表达减少。基于我们前期发现及PINK1-Parkin通路调控线粒体自噬所诱导的氧化应激机制，我们假设，肥胖损伤相关分子模式通过抑制PINK1-Parkin通路活化，导致巨噬细胞线粒体自噬缺陷，促发或加剧氧化应激，可能是肥胖型哮喘发生糖皮质激素抵抗的重要分子机制。本项目应用转化医学理念，采用诱导痰、流式细胞术和过继转移等研究方法，观察肥胖型哮喘巨噬细胞线粒体自噬及细胞表型与激素抵抗关系，探索并初步揭示PINK1-Parkin通路调控线粒体自噬参与肥胖型哮喘激素抵抗的发生机制，为肥胖型哮喘精准治疗提供科学证据。

肥胖型哮喘难以控制且更易发展为重症哮喘的瓶颈问题，极大程度归结于肥胖型哮喘糖皮质激素抵抗，但其分子机制不明。线粒体是调控氧化应激和免疫炎症的重要枢纽，而肥胖可导致线粒体功能障碍。前期研究发现，肥胖型哮喘患者诱导痰巨噬细胞呈促炎经典活化M1型，自噬体形成关键蛋白ATG16L1表达减少。基于我们前期发现及PINK1-Parkin通路调控线粒体自噬所诱导的氧化应激机制，我们假设，肥胖损伤相关分子模式通过抑制PINK1-Parkin通路活化，导致巨噬细胞线粒体自噬缺陷，促发或加剧氧化应激，可能是肥胖型哮喘发生糖皮质激素抵抗的重要分子机制。本项目首先通过基础研究，初步探索肥胖型哮喘患者自噬相关蛋白及基因表达，发现相对于正常体重哮喘患者，肥胖型哮喘患者全身自噬处于激活状态。再结合临床指标，探索自噬基因表达水平与人体测量学及体成分、中医证候积分的相关性，发现自噬水平与肥胖型哮喘患者的肥胖相关特征（如脂肪含量、内脏脂肪面积）及中医特征显著相关。最后，通过建立高脂叠加致敏的细胞模型，模拟肥胖型哮喘细胞状态，探索中医药对肥胖性哮喘自噬的影响。发现补中益气丸含药血清组肥胖型哮喘细胞模型自噬流通畅。进一步在此基础上，通过临床研究，探索多维度评估在支气管哮喘临床表型的发现及其结局评估中的运用。本项目首次识别了体成分特异性哮喘表型、急性哮喘表型，并探索了不同表型与哮喘不良结局发生风险的相关性。创新性的发现血清总IgE变异可作为特异的评估指标纳入哮喘多维度评估，并发现其与未来哮喘急性发作风险的相关性。本项目结合基础与临床研究，强调了识别包括肥胖型哮喘在内的哮喘临床表型的重要性，对哮喘患者个体化临床管理有重要的指导意义。