An RGS4-Mediated Phenotypic Switch of Bronchial Smooth Muscle Cells Promotes Fixed Airway Obstruction in Asthma

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An RGS4-Mediated Phenotypic Switch of Bronchial Smooth Muscle Cells Promotes Fixed Airway Obstruction in Asthma

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dc.contributor.author Damera, Gautam
dc.contributor.author Druey, Kirk M.
dc.contributor.author Cooper, Philip R.
dc.contributor.author Krymskaya, Vera P.
dc.contributor.author Amrani, Yassine
dc.contributor.author Hoshi, Toshinori
dc.contributor.author Brightling, Christopher E.
dc.contributor.author Panettieri, Reynold A.
dc.contributor.author Soberman, Roy Jason
dc.date.accessioned 2012-08-09T13:04:46Z
dc.date.issued 2012
dc.identifier.citation Damera, Gautam, Kirk M. Druey, Philip R. Cooper, Vera P. Krymskaya, Roy J. Soberman, Yassine Amrani, Toshinori Hoshi, Christopher E. Brightling, and Reynold A. Panettieri. 2012. An RGS4-mediated phenotypic switch of bronchial smooth muscle cells promotes fixed airway obstruction in asthma. PLoS ONE 7(1): e28504. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:9385637
dc.description.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 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. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pone.0028504 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257220/pdf/ en_US
dash.license LAA
dc.subject biology en_US
dc.subject biochemistry en_US
dc.subject cytochemistry en_US
dc.subject proteins en_US
dc.subject molecular cell biology en_US
dc.subject signal transduction en_US
dc.subject signaling cascades en_US
dc.subject signaling in cellular processes en_US
dc.subject signaling pathways en_US
dc.subject medicine en_US
dc.subject anatomy and physiology en_US
dc.subject respiratory system en_US
dc.subject pulmonology en_US
dc.title An RGS4-Mediated Phenotypic Switch of Bronchial Smooth Muscle Cells Promotes Fixed Airway Obstruction in Asthma en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Soberman, Roy Jason
dc.date.available 2012-08-09T13:04:46Z

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