支气管上皮细胞来源自噬小体诱导中性粒细胞ROS/NETs/TGF-β促进哮喘气道重塑的机制研究

哮喘发病率逐年升高，已成为全球性的重要公共卫生问题，亟需开发一种哮喘病的治疗策略。分泌型自噬小体具有重要的生物学功能，近年来文献报道其可作为阿尔茨海默病和克罗恩病等治疗靶点。课题组前期研究发现：①BEAS-2B细胞能够释放自噬小体到细胞外的新现象；②中性粒细胞能够吞噬人支气管上皮细胞来源自噬小体并产生ROS和TGF-β；③自噬小体诱导的中性粒细胞能够促进支气管上皮细胞凋亡；提示支气管上皮细胞、自噬小体、中性粒细胞三者在哮喘发生发展过程中相互作用。本课题拟从临床标本、细胞实验和动物模型三方面着手，探讨自噬小体诱导中性粒细胞ROS、NETs和TGF-β产生的机制、自噬小体诱导的中性粒细胞调节上皮细胞凋亡与EMT的机制，阐明“支气管上皮细胞-自噬小体-中性粒细胞-ROS/NETs/TGF-β-支气管上皮细胞”调控机制对肺组织损伤和气道重塑的作用。研究以自噬小体为靶点，为哮喘病治疗提供了新的方向。

The incidence rate of asthma is increasing year by year, which has become a major global public health problem. Therefore, it is of great importance and urgency to develop a treatment strategy for asthma. In recent years, secretory autophagosomes have important biological functions and have been reported as therapeutic targets for Alzheimer disease and Crohn's disease. In the preliminary study, we observed that (i) BEAS-2B cells can release autophagosomes to the outside of the cell; (ii) neutrophils can phagocytize human bronchial epithelial cell-derived autophagosomes and produce ROS and TGF-β; (iii) neutrophils induced by human bronchial epithelial cell-derived autophagosomes can promote the apoptosis of bronchial epithelial cells. Taken together, the above findings suggest that there is a close relationship among bronchial epithelial cells, autophagosomes and neutrophils in asthma. This project intends to explore the effects and underlying mechanisms of autophagosomes inducing the production of ROS, NETs and TGF-β in neutrophils and the mechanisms by which autophagosome-induced neutrophils regulate epithelial cell apoptosis and epithelial mesenchymal transition utilizing clinical specimens, cell experiments and animal models, and systematically elucidates the relationship between the regulatory mechanisms of bronchial epithelial cell-autophagosome-neutrophil-ROS/NETs/TGF-β-bronchial epithelial cell and lung tissue damage and airway remodeling in children with allergic asthma and asthmatic mice. It is expected to provide a novel avenue for the therapy of asthma by targeting autophagosomes in the future.