an rgs4-mediated phenotypic switch of bronchial smooth muscle cells promotes fixed airway obstruction in asthma一个rgs4-mediated支气管平滑肌细胞的表型转换促进固定在哮喘气道阻塞.pdfVIP

An RGS4-Mediated Phenotypic Switch of Bronchial Smooth Muscle Cells Promotes Fixed Airway Obstruction in Asthma 1 2 1 1 3 Gautam Damera , Kirk M. Druey , Philip R. Cooper , Vera P. Krymskaya , Roy J. Soberman , Yassine 4 5 4 1 Amrani , Toshinori Hoshi , Christopher E. Brightling , Reynold A. Panettieri Jr * 1 Airways Biology Initiative, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 2 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America, 3 Harvard Medical School, Boston, Massachusetts, United States of America, 4 University of Leicester, Leicester, United Kingdom, 5 Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Abstract In severe asthma, bronchodilator- and steroid-insensitive airflow obstruction develops through unknown mechanisms characterized by increased lung airway smooth muscle (ASM) mass and stiffness. We explored the role of a Regulator of G- protein Signaling protein (RGS4) in the ASM hyperplasia and reduced contractile capacity characteristic of advanced asthma. Using immunocytochemical staining, ASM expression of RGS4 was determined in endobronchial biopsies from healthy subjects and those from subjects with mild, moderate and severe asthma. Cell proliferation assays, agonist-induced calcium mobilization and bronchoconstriction were determined in cultured human ASM cells and in human precision cut lung slices. Using gain- and loss-of-function approaches, the precise role of RGS protein