TGF-b1 evokes human airway smooth muscle cell shortening and hyperresponsiveness via Smad3

Christie A. Ojiaku, Gaoyuan Cao, Wanqu Zhu, Edwin J. Yoo, Maya Shumyatcher, Blanca E. Himes, Steven S. An, Reynold A. Panettieri

Research output: Contribution to journalArticle

Abstract

Transforming growth factor b1 (TGF-b1), a cytokine whose levels are elevated in the airways of patients with asthma, perpetuates airway inflammation and modulates airway structural cell remodeling. However, the role of TGF-b1 in excessive airway narrowing in asthma, or airway hyperresponsiveness (AHR), remains unclear. In this study, we set out to investigate the direct effects of TGF-b1 on human airway smooth muscle (HASM) cell shortening and hyperresponsiveness. The dynamics of AHR and single-cell excitation-contraction coupling were measured in human precision-cut lung slices and in isolated HASM cells using supravital microscopy and magnetic twisting cytometry, respectively. In human precision-cut lung slices, overnight treatment with TGF-b1 significantly augmented basal and carbachol-induced bronchoconstriction. In isolated HASM cells, TGF-b1 increased basal and methacholine-induced cytoskeletal stiffness in a dose- and time-dependent manner. TGF-b1–induced single-cell contraction was corroborated by concomitant increases in myosin light chain and myosin phosphatase target subunit 1 phosphorylation levels, which were attenuated by small interfering RNA–mediated knockdown of Smad3 and pharmacological inhibition of Rho kinase. Strikingly, these physiological effects of TGF-b1 occurred through a RhoA-independent mechanism, with little effect on HASM cell [Ca 21 ] i levels. Together, our data suggest that TGF-b1 enhances HASM excitation-contraction coupling pathways to induce HASM cell shortening and hyperresponsiveness. These findings reveal a potential link between airway injury–repair responses and bronchial hyperreactivity in asthma, and define TGF-b1 signaling as a potential target to reduce AHR in asthma.

Original languageEnglish (US)
Pages (from-to)575-584
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume58
Issue number5
DOIs
StatePublished - May 1 2018

Keywords

  • Asthma
  • Bronchoconstriction
  • Contraction
  • Cytokines
  • Remodeling

ASJC Scopus subject areas

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

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