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dc.contributor.authorDamera, Gautam
dc.contributor.authorDruey, Kirk M.
dc.contributor.authorCooper, Philip R.
dc.contributor.authorKrymskaya, Vera P.
dc.contributor.authorSoberman, Roy Jason
dc.contributor.authorAmrani, Yassine
dc.contributor.authorHoshi, Toshinori
dc.contributor.authorBrightling, Christopher E.
dc.contributor.authorPanettieri, Reynold A.
dc.date.accessioned2012-08-09T13:04:46Z
dc.date.issued2012
dc.identifier.citationDamera, 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.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:9385637
dc.description.abstractIn 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.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0028504en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257220/pdf/en_US
dash.licenseLAA
dc.subjectbiologyen_US
dc.subjectbiochemistryen_US
dc.subjectcytochemistryen_US
dc.subjectproteinsen_US
dc.subjectmolecular cell biologyen_US
dc.subjectsignal transductionen_US
dc.subjectsignaling cascadesen_US
dc.subjectsignaling in cellular processesen_US
dc.subjectsignaling pathwaysen_US
dc.subjectmedicineen_US
dc.subjectanatomy and physiologyen_US
dc.subjectrespiratory systemen_US
dc.subjectpulmonologyen_US
dc.titleAn RGS4-Mediated Phenotypic Switch of Bronchial Smooth Muscle Cells Promotes Fixed Airway Obstruction in Asthmaen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorSoberman, Roy Jason
dc.date.available2012-08-09T13:04:46Z
dc.identifier.doi10.1371/journal.pone.0028504*
dash.contributor.affiliatedSoberman, Roy


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