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-tomyofibroblast 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 a-smooth muscle actin (a-SMA) expression were measured by realtime 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 a-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.

Ginsenoside Rg1 Ameliorates Cigarette Smoke-Induced Airway Fibrosis by Suppressing the TGF-β1/Smad Pathway In Vivo and In Vitro

“…The activated fibroblasts contribute to the deposition of collagen and other ECM components [21, 22], which increase the thickness of small airways and contribute to airflow limitation, leading to pulmonary fibrosis and airway remodeling. CS is a key risk factor in COPD and has been reported to promote the transition of fibroblasts to myofibroblasts [4]. In the present study, we observed by immunohistochemistry and western blotting that COPD rats displayed high expression of α -SMA, which is a hallmark of myofibroblasts, in lung tissues, whereas the variations could be attenuated by ginsenoside Rg1 treatment.…”

“…In response to inflammatory stimulation, the persistent activated pulmonary fibroblasts/myofibroblasts secrete various cytokines and growth factors, leading to a protease/antiprotease imbalance and abnormal production of extracellular matrix (ECM). Cigarette smoke (CS) is a major risk factor for the development of COPD [3] and has been shown to cause chronic airway inflammation and induce lung fibroblast-to-myofibroblast transition [4, 5]. Thus, inhibiting the activation of pulmonary fibroblasts could be an attractive therapeutic target in treating small airway fibrosis.…”

Acetylcholine beyond bronchoconstriction: roles in inflammation and remodeling

“…Tiotropium and 4-DAMP have been shown to inhibit alveolar macrophage mediated migration of neutrophils from patients with COPD patients [27]. Moreover, tiotropium inhibited TGF-b-induced matrix metalloproteinase-1 (MMP-1) and MMP-2 expression in human lung fibroblasts [57], and aclidinium has been shown to inhibit TGF-b and cigarette smoke-induced fibroblast to myofibroblast differentiation [37,58]. These studies indicate that non-neuronal acetylcholine might contribute to airway inflammation and remodeling of airway cells in an autocrine or paracrine manner.…”

The Non-Neuronal Cholinergic System in Health and Disease

“…This takes place under chronic inflammatory conditions. Recently it has been shown that the remodelling into myofibroblasts could be reversed by administration of the anticholinergic aclidinium bromide, by silencing M1, M2 or M3 mAChR mRNA or by degradation of ACh using AChE treatment [47]. Thus, the NNCS is involved in one of the key steps of COPD and asthma consolidation.…”