TGF-β1 Evokes Human Airway Smooth Muscle Cell Shortening and Hyperresponsiveness via Smad3
| Autor: | Steven S. An, Edwin J. Yoo, Reynold A. Panettieri, Gaoyuan Cao, Wanqu Zhu, Christie A. Ojiaku, Blanca E. Himes, Maya Shumyatcher |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Myosin Light Chains Myosin light-chain kinase Bronchoconstriction medicine.medical_treatment Myocytes Smooth Muscle Clinical Biochemistry Cell Transforming Growth Factor beta1 Myosin-Light-Chain Phosphatase 03 medical and health sciences medicine Humans Calcium Signaling Smad3 Protein Phosphorylation Molecular Biology Rho-associated protein kinase Cells Cultured Excitation Contraction Coupling Calcium signaling rho-Associated Kinases business.industry Muscle Smooth Cell Biology respiratory system Asthma respiratory tract diseases Cell biology 030104 developmental biology medicine.anatomical_structure Cytokine Immunology Myosin-light-chain phosphatase Bronchial Hyperreactivity medicine.symptom rhoA GTP-Binding Protein business Transforming growth factor |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 58:575-584 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2017-0247oc |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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