title: Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition.
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.
authors.affiliation: Research Unit, University General Hospital Consortium, Valencia, Spain. xmilara@hotmail.com
authors.forename: Javier
authors.initials: J
authors.lastname: Milara
authors.forename: Adela
authors.initials: A
authors.lastname: Serrano
authors.forename: Teresa
authors.initials: T
authors.lastname: Peiró
authors.forename: Enrique
authors.initials: E
authors.lastname: Artigues
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.forename: Montse
authors.initials: M
authors.lastname: Miralpeix
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Morcillo
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
mesh_terms: D000199:Actins / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects; D002478:Cells, Cultured; D018680:Cholinergic Antagonists / Q000494:pharmacology; D024042:Collagen Type I / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D005355:Fibrosis; D005452:Fluoresceins / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D008168:Lung / Q000166:cytology / Q000187:drug effects; D008856:Microscopy, Fluorescence; D058628:Myofibroblasts / Q000166:cytology* / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012906:Smoke; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D014326:Tropanes / Q000494:pharmacology*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D018680:Cholinergic Antagonists; D024042:Collagen Type I; D005452:Fluoresceins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012906:Smoke; D014326:Tropanes; C065013:2',7'-dichlorodihydrofluorescein; D000242:Cyclic AMP; C542859:aclidinium bromide