Abstract
Cigarette smoking contributes to lung remodelling in chronic obstructive pulmonary disease (COPD). As part of this remodelling, peribronchiolar fibrosis is observed in the small airways of COPD patients and contributes to airway obstruction. Fibroblast-to-myofibroblast transition is a key step in peribronchiolar fibrosis formation.
This in vitro study examined the effect of cigarette smoke on bronchial fibroblast-to-myofibroblast transition, and whether aclidinium bromide inhibits this process. Human bronchial fibroblasts were incubated with aclidinium bromide (10−9–10−7 M) and exposed to cigarette smoke extract. Collagen type I and α-smooth muscle actin (α-SMA) expression were measured by real-time PCR and Western blotting, as myofibroblast markers. Intracellular reactive oxygen species, cyclic AMP (cAMP), extracellular signal-regulated kinase (ERK)1/2 and choline acetyltransferase were measured as intracellular signalling mediators.
Cigarette smoke-induced collagen type I and α-SMA was mediated by the production of reactive oxygen species, the depletion of intracellular cAMP and the increase of ERK1/2 phosphorylation and choline acetyltransferase. These effects could be reversed by treatment with the anticholinergic aclidinium bromide, by silencing the mRNA of muscarinic receptors M1, M2 or M3, or by the depletion of extracellular acetylcholine by treatment with acetylcholinesterase.
A non-neuronal cholinergic system is implicated in cigarette smoke-induced bronchial fibroblast-to-myofibroblast transition, which is inhibited by aclidinium bromide.
Footnotes
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Support Statement
This work was supported by Almirall S.A. (Barcelona, Spain) and, in part, by grants SAF2011-26443 (to J. Cortijo), SAF2009-08913 (to E.J. Morcillo), FIS (Miguel Servet CP11/00293 (to J. Milara)), CIBERES (CB06/06/0027) and research grants from Regional Government (Prometeo/2008/045, “Generalitat Valenciana”; research grants from “Generalitat Valencia” AP-178/11 (to J. Milara)). T. Peiró received a research grant from Conselleria de Educacion, Generalitat Valenciana ACIF/2010/114. We thank C. Bryant from Complete Medical Communications (Macclesfield, UK) who provided copy-editing support funded by Almirall S.A.
Statement of Interest
Conflict of interest information can be found alongside the online version of this article at www.erj.ersjournals.com
- Received January 28, 2012.
- Accepted August 27, 2012.
- ©ERS 2013