肥胖型哮喘作为一特殊的哮喘临床表型，其难以控制且更易发展为重症哮喘的瓶颈问题，源于对肥胖型哮喘发生机制认识不明。我们前期研究发现，肥胖型哮喘诱导痰巨噬细胞呈促炎经典活化M1表型优势，且自噬体形成的关键蛋白ATG16L1表达减少。基于自噬在免疫炎症中的关键作用及项目组前期研究基础，我们假设，肥胖相关炎症信号通过AMPK介导自噬缺陷，促进NLRP3炎性小体异常活化，诱发肥胖型哮喘细胞免疫炎症，可能是肥胖型哮喘的重要病理机制。本项目结合临床研究和动物实验，从体内外、多层面，观察肥胖型哮喘自噬与全身及气道炎症关系，分析与此相关的全身及气道细胞炎症表型、巨噬细胞胞葬作用、糖皮质激素抵抗、中性粒细胞募集，并进一步探索自噬负向调控NLRP3炎性小体活化机制参与气道高反应性及气道炎症的发生，初步揭示自噬调控肥胖型哮喘全身及气道炎症的发生发展机制，为肥胖型哮喘精准治疗提供科学证据。

Obese asthma is a distinct clinical phenotype of asthma. The bottleneck problem that obese asthma is difficult to control and more likely to develop to severe asthma, is attributed to that the underlying mechanisms remain unclear. Our previous study has found that macrophages in induced sputum was characterized by M1 phenotype and ATG16L1, the key protein in the formation of autophagosome, decreased in obese asthma. Based on the pivotal role of autophagy in immune inflammation regulation and the results of our previous research, we hypothesize that obesity associated inflammation signals, facilitate autophagy deficiency mediated by AMPK and autophagy deficiency could contribute to the abnormal activation of NLRP3 inflammasome, which induce cellular immune inflammation and may be the key pathogenesis of obese asthma. This proposed project will utilize clinical subjects and animal model, to investigate autophagy and systemic and airway inflammation in obese asthma, and to analyze its association with systemic and airway cellular inflammation phenotype, macrophage efferocytosis, glucocorticoid resistance, neutrophils chemotaxis. Furthermore, we will explore the imbalance mechanism that autophagy negatively regulates NLRP3 inflammasome facilitates obesity-associated airway hyperreactivity and airway inflammation, which could tentatively reveal the pathogenesis of systemic inflammation and airway inflammation in obese asthma and provide scientific evidence for treatments of obese asthma with precision and personalized medicine.