Transforming Growth Factor-b1 Decreases b2-Agonist–induced Relaxation in Human Airway Smooth Muscle

Christie A. Ojiaku, Elena Chung, Vishal Parikh, Jazmean K. Williams, Anthony Schwab, Ana Lucia Fuentes, Maia L. Corpuz, Victoria Lui, Sam Paek, Natalia M. Bexiga, Shreya Narayan, Francisco J. Nunez, Kwangmi Ahn, Rennolds S. Ostrom, Steven S. An, Reynold A. Panettieri

Research output: Contribution to journalArticlepeer-review

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)-b1, induces HASM cell shortening and airway hyperresponsiveness. Here, we assessed whether TGF-b1 affects the ability of HASM cells to relax in response to b2-agonists, a mainstay treatment for airway hyperresponsiveness in asthma. Overnight TGF-b1 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-b1–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-b1 selectively induced phosphodiesterase 4D gene expression in HASM cells in a Smad2/3-dependent manner. Together, these data suggest that TGF-b1 decreases HASM cell b2-agonist relaxation responses by modulating intracellular cAMP levels via a Smad2/3-dependent mechanism. Our findings further define the mechanisms underlying b2-agonist hyporesponsiveness in asthma, and suggest TGF-b1 as a potential therapeutic target to decrease asthma exacerbations in severe and treatment-resistant asthma.

Original languageEnglish (US)
Pages (from-to)209-218
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume61
Issue number2
DOIs
StatePublished - Aug 1 2019

Keywords

  • B-agonists
  • Human airway smooth muscle
  • Relaxation
  • Severe asthma
  • TGF-b1

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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