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Journal article
Transforming Growth Factor-β1 Decreases β2-Agonist–induced Relaxation in Human Airway Smooth Muscle
American journal of respiratory cell and molecular biology, v 61(2), pp 209-218
01 Aug 2019
PMID: 30742476
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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)-β1, induces HASM cell shortening and airway hyperresponsiveness. Here, we assessed whether TGF-β1 affects the ability of HASM cells to relax in response to β2-agonists, a mainstay treatment for airway hyperresponsiveness in asthma. Overnight TGF-β1 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-β1–treated 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-β1 selectively induced phosphodiesterase 4D gene expression in HASM cells in a Smad2/3-dependent manner. Together, these data suggest that TGF-β1 decreases HASM cell β2-agonist relaxation responses by modulating intracellular cAMP levels via a Smad2/3-dependent mechanism. Our findings further define the mechanisms underlying β2-agonist hyporesponsiveness in asthma, and suggest TGF-β1 as a potential therapeutic target to decrease asthma exacerbations in severe and treatment-resistant asthma.
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Details
- Title
- Transforming Growth Factor-β1 Decreases β2-Agonist–induced Relaxation in Human Airway Smooth Muscle
- Creators
- Christie A. Ojiaku - University of PennsylvaniaElena Chung - Rutgers, The State University of New JerseyVishal Parikh - Rutgers, The State University of New JerseyJazmean K. Williams - Drexel UniversityAnthony Schwab - Rutgers, The State University of New JerseyAna Lucia Fuentes - Rutgers, The State University of New JerseyMaia L. Corpuz - Chapman UniversityVictoria Lui - Johns Hopkins UniversitySam Paek - Johns Hopkins UniversityNatalia M. Bexiga - Johns Hopkins UniversityShreya Narayan - Johns Hopkins UniversityFrancisco J. Nunez - Chapman UniversityKwangmi Ahn - National Institutes of HealthRennolds S. Ostrom - Chapman UniversitySteven S. AnReynold A. Panettieri - University of Pennsylvania
- Publication Details
- American journal of respiratory cell and molecular biology, v 61(2), pp 209-218
- Publisher
- American Thoracic Society
- Number of pages
- 10
- Grant note
- National Institutes of Health (NIH): 3P01 HL114471-04S1, T32GM008076 Johns Hopkins UniversityPatrick C. Walsh Prostate Cancer Research FundNIH: GM107094
Supported by National Institutes of Health (NIH) grant 3P01 HL114471-04S1 and T32 Training Grant T32GM008076. S.S.A. was supported by Discovery Award and Catalyst Award from the Johns Hopkins University, and the Patrick C. Walsh Prostate Cancer Research Fund. R.S.O. was supported by NIH grant GM107094.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000484040500014
- Scopus ID
- 2-s2.0-85070915812
- Other Identifier
- 991021860797704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Respiratory System