{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:49:30Z","timestamp":1790794170897,"version":"4.1.0"},"reference-count":68,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T00:00:00Z","timestamp":1564617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Helper T effector cytokines implicated in asthma modulate the contractility of human airway smooth muscle (HASM) cells. We have reported recently that a profibrotic cytokine, transforming growth factor (TGF)-\u03b21, induces HASM cell shortening and airway hyperresponsiveness. Here, we assessed whether TGF-\u03b21 affects the ability of HASM cells to relax in response to \u03b22-agonists, a mainstay treatment for airway hyperresponsiveness in asthma. Overnight TGF-\u03b21 treatment significantly impaired isoproterenol (ISO)-induced relaxation of carbachol-stimulated, isolated HASM cells. This single-cell mechanical hyporesponsiveness to ISO was corroborated by sustained increases in myosin light chain phosphorylation. In TGF-\u03b21\u2013treated HASM cells, ISO evoked markedly lower levels of intracellular cAMP. These attenuated cAMP levels were, in turn, restored with pharmacological and siRNA inhibition of phosphodiesterase 4 and Smad3, respectively. Most strikingly, TGF-\u03b21 selectively induced phosphodiesterase 4D gene expression in HASM cells in a Smad2\/3-dependent manner. Together, these data suggest that TGF-\u03b21 decreases HASM cell \u03b22-agonist relaxation responses by modulating intracellular cAMP levels via a Smad2\/3-dependent mechanism. Our findings further define the mechanisms underlying \u03b22-agonist hyporesponsiveness in asthma, and suggest TGF-\u03b21 as a potential therapeutic target to decrease asthma exacerbations in severe and treatment-resistant asthma.<\/jats:p>","DOI":"10.1165\/rcmb.2018-0301oc","type":"journal-article","created":{"date-parts":[[2019,2,11]],"date-time":"2019-02-11T12:13:37Z","timestamp":1549887217000},"page":"209-218","source":"Crossref","is-referenced-by-count":29,"title":["Transforming Growth Factor-\u03b21 Decreases \u03b22-Agonist\u2013induced Relaxation in Human Airway Smooth Muscle"],"prefix":"10.1093","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2592-6710","authenticated-orcid":false,"given":"Christie A.","family":"Ojiaku","sequence":"first","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Rutgers Institute for Translational 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Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Paek","sequence":"additional","affiliation":[{"name":"Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia M.","family":"Bexiga","sequence":"additional","affiliation":[{"name":"Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland"},{"name":"Department of Pharmaceutical Biochemistry Technology, University of Sao Paulo, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya","family":"Narayan","sequence":"additional","affiliation":[{"name":"Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Nunez","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangmi","family":"Ahn","sequence":"additional","affiliation":[{"name":"National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rennolds S.","family":"Ostrom","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven S.","family":"An","sequence":"additional","affiliation":[{"name":"Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland"},{"name":"Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland; 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