An RGS4-mediated phenotypic switch of bronchial smooth muscle cells promotes fixed airway obstruction in asthma

• Published in: PloS one 2012-01, Vol.7 (1), p.e28504-e28504
• Main Authors: Damera, Gautam, Druey, Kirk M, Cooper, Philip R, Krymskaya, Vera P, Soberman, Roy J, Amrani, Yassine, Hoshi, Toshinori, Brightling, Christopher E, Panettieri, Jr, Reynold A
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Air flow; Airway management; Airway obstruction; Airway Obstruction - complications; Airway Obstruction - pathology; Airway Obstruction - physiopathology; Asthma; Asthma - complications; Asthma - pathology; Asthma - physiopathology; Biology; Biopsy; Biotechnology; Bronchi - pathology; Bronchoconstriction; Bronchoconstriction - drug effects; Bronchodilators; Calcium; Carbachol - pharmacology; Cell culture; Cell proliferation; Cell Proliferation - drug effects; Clinical trials; Critical care; Epidermal growth factor; Excitation Contraction Coupling - drug effects; Experiments; Female; G protein-coupled receptors; G proteins; Gene expression; Genomes; Humans; Hyperplasia; Hypertension; In Vitro Techniques; Inhibition; Kinases; Lungs; Male; Medicine; Membrane proteins; Middle Aged; Mitogens; Mitogens - pharmacology; Models, Biological; Muscle contraction; Muscles; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Ovarian cancer; Phenotype; Phenotypes; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Platelet-derived growth factor; Platelet-Derived Growth Factor - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pulmonary functions; Respiratory function; Respiratory tract; RGS Proteins - metabolism; Rodents; Signaling; Smooth muscle; Sputum - drug effects; Sputum - metabolism; Stiffness; Studies
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0028504

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 proteins was determined in stimulating human ASM proliferation and inhibiting bronchoconstriction. RGS4 expression was restricted to a subpopulation of ASM and was specifically upregulated by mitogens, which induced a hyperproliferative and hypocontractile ASM phenotype similar to that observed in recalcitrant asthma. RGS4 expression was markedly increased in bronchial smooth muscle of patients with severe asthma, and expression correlated significantly with reduced pulmonary function. Whereas RGS4 inhibited G protein-coupled receptor (GPCR)-mediated bronchoconstriction, unexpectedly RGS4 was required for PDGF-induced proliferation and sustained activation of PI3K, a mitogenic signaling molecule that regulates ASM proliferation. These studies indicate that increased RGS4 expression promotes a phenotypic switch of ASM, evoking irreversible airway obstruction in subjects with severe asthma.