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Am J Respir Cell Mol Biol. 2018 May;58(5):575-584. doi: 10.1165/rcmb.2017-0247OC.

TGF-β1 Evokes Human Airway Smooth Muscle Cell Shortening and Hyperresponsiveness via Smad3.

Author information

1
1 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, and.
2
2 Rutgers Institute for Translational Medicine and Science, Child Health Institute, Rutgers University, New Brunswick, New Jersey; and.
3
3 Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, and.
4
4 Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania.
5
5 Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland.

Abstract

Transforming growth factor β1 (TGF-β1), 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-β1 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-β1 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-β1 significantly augmented basal and carbachol-induced bronchoconstriction. In isolated HASM cells, TGF-β1 increased basal and methacholine-induced cytoskeletal stiffness in a dose- and time-dependent manner. TGF-β1-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-β1 occurred through a RhoA-independent mechanism, with little effect on HASM cell [Ca2+]i levels. Together, our data suggest that TGF-β1 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-β1 signaling as a potential target to reduce AHR in asthma.

KEYWORDS:

asthma; bronchoconstriction; contraction; cytokines; remodeling

PMID:
28984468
DOI:
10.1165/rcmb.2017-0247OC

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