Man Jia1, Xiaoyi Yan1,2, Xinyu Jiang1, Yunhui Wu1, Jiayan Xu1, Yaqi Meng1, Yi Yang1, Xia Shan2, Xiuwedi Zhang2, Shan Mao3, Wei Gu3, Stelios Pavlidis4, Peter J Barnes5, Ian M Adcock5, Mao Huang1, Xin Yao1. 1. 1 Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 2. 2 Department of Respiratory Medicine, Nanjing Jiangning Hospital, Nanjing, China. 3. 3 Department of Respiratory Medicine, Nanjing First Hospital, Nanjing, China. 4. 4 Data Science Institute, Imperial College London, London, United Kingdom; and. 5. 5 Airway Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
Abstract
RATIONALE: Bronchial epithelial cell damage occurs in patients with bronchial asthma. Ezrin, a membrane-cytoskeleton protein, maintains cellular morphology and intercellular adhesion and protects the barrier function of epithelial cells. OBJECTIVES: To study the role of ezrin in bronchial epithelial cells injury and correlate its expression with asthma severity. METHODS: Levels of ezrin were measured in exhaled breath condensate (EBC) and serum in patients with asthma and BAL fluid (BALF) from a mouse model of asthma by ELISA. The regulation of IL-13 on ezrin protein levels was studied in primary bronchial epithelial cells. Ezrin knockdown using shRNA was studied in human bronchial epithelial 16HBE cells. MEASUREMENTS AND MAIN RESULTS: Ezrin levels were decreased in asthmatic EBC (92.7 ± 34.99 vs. 150.5 ± 10.22 pg/ml, P < 0.0001) and serum (700.7 ± 55.59 vs. 279.2 ± 25.83 pg/ml, P < 0.0001) compared with normal subjects. Levels were much lower in uncontrolled (P < 0.001) and partly controlled patients (P < 0.01) compared with well-controlled subjects. EBC and serum ezrin levels correlated with lung function in patients with asthma and serum ezrin levels were negatively correlated with serum IL-13 and periostin. IL-13-induced downregulation of ezrin expression in primary bronchial epithelial cells was significantly attenuated by the Janus tyrosine kinase 2 inhibitor, TG101348. Ezrin knockdown changed 16HBE cell morphology, enlarged intercellular spaces, and increased their permeability. Ezrin expression was decreased in the lung tissue and BALF of "asthmatic" mice and negatively correlated with BALF IL-13 level. CONCLUSIONS: Ezrin downregulation is associated with IL-13-induced epithelial damage and might be a potential biomarker of asthma control.
RATIONALE: Bronchial epithelial cell damage occurs in patients with bronchial asthma. Ezrin, a membrane-cytoskeleton protein, maintains cellular morphology and intercellular adhesion and protects the barrier function of epithelial cells. OBJECTIVES: To study the role of ezrin in bronchial epithelial cells injury and correlate its expression with asthma severity. METHODS: Levels of ezrin were measured in exhaled breath condensate (EBC) and serum in patients with asthma and BAL fluid (BALF) from a mouse model of asthma by ELISA. The regulation of IL-13 on ezrin protein levels was studied in primary bronchial epithelial cells. Ezrin knockdown using shRNA was studied in human bronchial epithelial 16HBE cells. MEASUREMENTS AND MAIN RESULTS: Ezrin levels were decreased in asthmatic EBC (92.7 ± 34.99 vs. 150.5 ± 10.22 pg/ml, P < 0.0001) and serum (700.7 ± 55.59 vs. 279.2 ± 25.83 pg/ml, P < 0.0001) compared with normal subjects. Levels were much lower in uncontrolled (P < 0.001) and partly controlled patients (P < 0.01) compared with well-controlled subjects. EBC and serum ezrin levels correlated with lung function in patients with asthma and serum ezrin levels were negatively correlated with serum IL-13 and periostin. IL-13-induced downregulation of ezrin expression in primary bronchial epithelial cells was significantly attenuated by the Janus tyrosine kinase 2 inhibitor, TG101348. Ezrin knockdown changed 16HBE cell morphology, enlarged intercellular spaces, and increased their permeability. Ezrin expression was decreased in the lung tissue and BALF of "asthmatic" mice and negatively correlated with BALF IL-13 level. CONCLUSIONS: Ezrin downregulation is associated with IL-13-induced epithelial damage and might be a potential biomarker of asthma control.
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