TRPC5通过激活NLRP3炎症小体介导哮喘气道上皮MUC5AC高分泌的机制研究

气道黏液增生聚集是哮喘重要的病理表现，而气道上皮细胞高表达MUC5AC是黏液高分泌的关键环节。NLRP3炎症小体及TRPC5均与哮喘发病密切相关，但其中详细作用及机制尚未完全阐明。申请者前期发现TDI诱导的哮喘模型小鼠肺组织及气道上皮MUC5AC表达显著升高；阻断NLRP3信号可抑制TDI哮喘气道炎症及肺组织MUC5AC表达，然其上游机制仍不清楚。我们前期预实验观察到，TDI哮喘小鼠肺组织TRPC5表达上调，用特异性拮抗剂阻断TRPC5不仅明显减轻气道中性粒及嗜酸性粒细胞浸润，也抑制了气道上皮NLRP3活化，并能下调气道上皮MUC5AC表达。因此，我们猜想：TRPC5通过激活NLRP3炎症小体介导TDI哮喘气道上皮MUC5AC高分泌。本项目拟从动物和细胞水平探索TRPC5/NLRP3在TDI哮喘气道上皮MUC5AC高分泌中的作用及机制，为未来开发新的哮喘靶向治疗药物提供科学依据。

Airway mucus hypersecretion is a cardinal pathological feature of asthma, which is dominated by secretion of mucin 5ac (MUC5AC) by the airway epithelial cells. Several researchers have already demonstrated the vital role for MUC5AC in the initiation of airway inflammation and mucus secretion, yet the upstream mechanism of MUC5AC is still largely unknown. Emerging evidence suggested that Nod-like receptor protein 3 (NLRP3) inflammasome and transient receptor potential canonical 5 (TRPC5) in airway epithelia are critically involved in the pathogenesis of asthma, but the exact mechanisms involved are yet to be discovered. Previously, we’ve found that blockade of NLRP3/caspase-1 signaling could attenuate TDI-induced airway hyperreactivity, inflammation and MUC5AC secretion. Our preliminary data demonstrated that TDI-induced neutrophilc and eosinophilic airway inflammation together with airway hyperreactivity were markedly alleviated by TRPC5 antagonist. Immunohistochemistry revealed that the activation of NLRP3 and caspase-1 in the airway epithelial cells were also suppressed, accompanied by decreased pulmonary MUC5AC expression. Thus, we proposed that TRPC5 mediates the overproduction of MUC5AC in airway epithelial cells through activating NLRP3 inflammasome. This study will be further conducted in animal models and airway epithelial cell lines to explore whether and how TRPC5/NLRP3 signaling mediates MUC5AC hypersecretion in TDI-induced asthma, thereby providing an in-depth understanding of TRPC5/NLRP3 signaling in asthma.