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Tiotropium inhibits methacholine-induced extracellular matrix production via β-catenin signaling in human airway smooth muscle cells

BACKGROUND: Airway remodeling is an important feature of chronic obstructive pulmonary disease (COPD) that is associated with disease severity and irreversible airflow limitation. An extensive alteration of the extracellular matrix (ECM) surrounding the airway smooth muscle (ASM) bundle is one of th...

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Autores principales: Huo, Yating, Guan, Lili, Xu, Jiawen, Zhou, Luqian, Chen, Rongchang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939907/
https://www.ncbi.nlm.nih.gov/pubmed/29765214
http://dx.doi.org/10.2147/COPD.S158552
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author Huo, Yating
Guan, Lili
Xu, Jiawen
Zhou, Luqian
Chen, Rongchang
author_facet Huo, Yating
Guan, Lili
Xu, Jiawen
Zhou, Luqian
Chen, Rongchang
author_sort Huo, Yating
collection PubMed
description BACKGROUND: Airway remodeling is an important feature of chronic obstructive pulmonary disease (COPD) that is associated with disease severity and irreversible airflow limitation. An extensive alteration of the extracellular matrix (ECM) surrounding the airway smooth muscle (ASM) bundle is one of the pathological manifestations of airway remodeling, which contributes to the decline in lung function. Tiotropium, a long-acting inhaled muscarinic receptor antagonist, has been confirmed to play a role in preventing airway remodeling including ECM deposition beyond bronchodilation in vivo, but the relationship between ASM cell (ASMC) relaxation and ECM production remains unclear. PURPOSE: In this study, we attempted to investigate the influence of tiotropium on ECM production by ASMCs and the underlying mechanism. METHODS: Tiotropium was added 30 minutes before the addition of methacholine to primary cultured human ASMCs. Protein expression was analylized by Western Blot and mRNA abundance was determined by real-time PCR. RESULTS: We found that tiotropium reduced collagen I protein expression, and the mRNA abundance of collagen I, fibronectin, and versican. β-catenin signaling was inactivated by inhibiting glycogen synthase kinase 3β (GSK3β) phosphorylation in this process. Tiotropum inhibited the amount of active β-catenin and its transcription activity. Furthermore, overexpression of active β-catenin by adenoviruses carrying the S33Y mutant resisted the suppressive effect of tiotropium on collagen I protein expression. However, silencing β-catenin by specific small interfering RNA enhanced the negative effect of tiotropium. CONCLUSION: These findings suggest that relaxation of ASMCs by tiotropium can prevent ECM production through β-catenin signaling.
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spelling pubmed-59399072018-05-14 Tiotropium inhibits methacholine-induced extracellular matrix production via β-catenin signaling in human airway smooth muscle cells Huo, Yating Guan, Lili Xu, Jiawen Zhou, Luqian Chen, Rongchang Int J Chron Obstruct Pulmon Dis Original Research BACKGROUND: Airway remodeling is an important feature of chronic obstructive pulmonary disease (COPD) that is associated with disease severity and irreversible airflow limitation. An extensive alteration of the extracellular matrix (ECM) surrounding the airway smooth muscle (ASM) bundle is one of the pathological manifestations of airway remodeling, which contributes to the decline in lung function. Tiotropium, a long-acting inhaled muscarinic receptor antagonist, has been confirmed to play a role in preventing airway remodeling including ECM deposition beyond bronchodilation in vivo, but the relationship between ASM cell (ASMC) relaxation and ECM production remains unclear. PURPOSE: In this study, we attempted to investigate the influence of tiotropium on ECM production by ASMCs and the underlying mechanism. METHODS: Tiotropium was added 30 minutes before the addition of methacholine to primary cultured human ASMCs. Protein expression was analylized by Western Blot and mRNA abundance was determined by real-time PCR. RESULTS: We found that tiotropium reduced collagen I protein expression, and the mRNA abundance of collagen I, fibronectin, and versican. β-catenin signaling was inactivated by inhibiting glycogen synthase kinase 3β (GSK3β) phosphorylation in this process. Tiotropum inhibited the amount of active β-catenin and its transcription activity. Furthermore, overexpression of active β-catenin by adenoviruses carrying the S33Y mutant resisted the suppressive effect of tiotropium on collagen I protein expression. However, silencing β-catenin by specific small interfering RNA enhanced the negative effect of tiotropium. CONCLUSION: These findings suggest that relaxation of ASMCs by tiotropium can prevent ECM production through β-catenin signaling. Dove Medical Press 2018-05-03 /pmc/articles/PMC5939907/ /pubmed/29765214 http://dx.doi.org/10.2147/COPD.S158552 Text en © 2018 Huo et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Huo, Yating
Guan, Lili
Xu, Jiawen
Zhou, Luqian
Chen, Rongchang
Tiotropium inhibits methacholine-induced extracellular matrix production via β-catenin signaling in human airway smooth muscle cells
title Tiotropium inhibits methacholine-induced extracellular matrix production via β-catenin signaling in human airway smooth muscle cells
title_full Tiotropium inhibits methacholine-induced extracellular matrix production via β-catenin signaling in human airway smooth muscle cells
title_fullStr Tiotropium inhibits methacholine-induced extracellular matrix production via β-catenin signaling in human airway smooth muscle cells
title_full_unstemmed Tiotropium inhibits methacholine-induced extracellular matrix production via β-catenin signaling in human airway smooth muscle cells
title_short Tiotropium inhibits methacholine-induced extracellular matrix production via β-catenin signaling in human airway smooth muscle cells
title_sort tiotropium inhibits methacholine-induced extracellular matrix production via β-catenin signaling in human airway smooth muscle cells
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939907/
https://www.ncbi.nlm.nih.gov/pubmed/29765214
http://dx.doi.org/10.2147/COPD.S158552
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