合胞病毒感染对呼吸道上皮两种氯离子通道的作用及机制研究

Respiratory syncytial virus( RSV) is the leading viral pathogen causing lower respiratory tract infection in children. Clinically, Mainly cause asthmatic diseases and an increased susceptibility to asthma is observed in children with severe RSV infection. Respiratory epithelium is the initial site of encounter between host cells and RSV. The volume and composition of airway surface liquids (ASL) lining the epithelium are regulated by ion-transport systems (e.g., channels and transporters) in the epithelial cell membrane. Severe RSV infection can lead to the increase of some Th2-signature cytokines （e.g., IL-4）, which in turn enhance the expression and function of the CFTR Cl- channel and TMEM16A Ca2+-activated Cl- channel. The application aims to understand how the expression and function of respiratory epithelial CFTR and TMEM16A Cl- channels are altered after RSV infection in epithelial cells in vitro, and in experimental asthma mouse model, and examine whether these changes of CFTR and TMEM16A Cl- channels in expression and function are related to RSV induced cytokines. The results of this study will significantly help us to understand the roles that CFTR and TMEM16A Cl- channels play during the incidence and development of airway mucus hypersecretion and the hyperresponsiveness after RSV infection. It may also help to identify novel pharmacological targets to treat inflammation and asthma induced by RSV and other causes.

呼吸道合胞病毒(RSV)是引起儿童下呼吸道感染最常见的病毒。主要导致喘息性疾病，且相当部分发展为哮喘。呼吸道上皮细胞是机体防御RSV感染的第一道屏障。支气管上皮表面覆盖着一层菲薄的液体层，其厚度及水盐成分受上皮细胞膜离子通道和转运体的活动所控制。RSV严重感染会导致Th2类细胞因子(如IL-4)表达和释放增加, 而IL-4等Th2类细胞因子又可使支气管上皮CFTR氯离子通道以及跨膜蛋白16A (TMEM16A) Ca2+激活氯离子通道的表达和功能加强。本课题将以离体上皮细胞、正常及哮喘小鼠为实验模型，研究CFTR与TMEM16A的表达和功能在RSV感染后的改变，以及与细胞因子变化的关系。本课题的实验结果将极大促进对CFTR和TMEM16A在RSV感染后上皮黏液分泌亢进、气道高反应性的发生及发展过程中所起作用的理解。也可能为控制RSV或其它原因引起的呼吸道炎症或哮喘找到新的药物作用靶点。

呼吸道合胞病毒(RSV)是引起儿童下呼吸道感染最常见的病毒。主要导致喘息性疾病，且相当部分发展为哮喘。呼吸道上皮细胞是机体防御RSV感染的第一道屏障。支气管上皮表面覆盖着一层菲薄的液体层，其厚度及水盐成分受上皮细胞膜离子通道和转运体的活动所控制。RSV严重感染会导致Th2类细胞因子(如IL-4)表达和释放增加, 而IL-4等Th2类细胞因子又可使支气管上皮CFTR氯离子通道以及跨膜蛋白16A (TMEM16A) Ca2+激活氯离子通道的表达和功能加强。本课题将以Caalu-3细胞为实验模型，研究CFTR与TMEM16A的表达和功能在RSV感染后的改变。.本研究中我们发现RSV 感染 Calu-3 细胞后 CFTR 氯离子通道和钙激活氯离子通道的基因表达水平增高、功能活动增强。CFTR 氯离子通道和钙激活氯离子通道可能是 RSV 感染后引起呼吸道上皮分泌亢进的下游靶标。在氯离子分泌增加的同时水也通过细胞旁路或水通道进入黏液, 此时黏液更好地被水合而有利于将病原体排出体外,这过程可能是机体本身的一种保护机制,也为治疗RSV感染引起的毛细支气管炎、哮喘及囊性纤维化(cystic fibrosis,CF) 提供新的方向。