Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways

Cortijo, Julio; Mata, M. M.; Milara, Javier; Donet, Eva; Gavaldà, Amadeu; Miralpeix, Montserrat; Morcillo, Esteban J.

doi:10.1183/09031936.00182009

Cited by 63 publications

(47 citation statements)

References 29 publications

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“…Previous reports have suggested that cigarette smoke may activate a non-neuronal cholinergic system in different cell types, including airways and human lung fibroblasts. For example, we have recently shown that CSE promotes synthesis and release of the mucin MUC5AC in differentiated bronchial epithelial cells by a mechanism mediated by release of acetylcholine, and can be inhibited by aclidinium bromide [8]. Furthermore, human lung fibroblasts from COPD patients have shown an increase of muscarinic receptors, as well as ChAT expression, an effect that was mimicked in healthy lung fibroblasts after CSE exposure [9].…”

Section: Discussionmentioning

confidence: 95%

“…Therefore, a dysfunction of a non-neuronal cholinergic system may contribute to the pathophysiology of asthma and COPD [7]. It has been shown that anticholinergic treatment inhibits cigarette smokeinduced mucin hypersecretion in human bronchial epithelial cells [8], as well as cigarette smoke-induced lung fibroblast proliferation [9]. Furthermore, choline acetyltransferase (ChAT), the intracellular enzyme responsible for acetylcholine production, is upregulated in both lung fibroblasts from COPD patients and fibroblasts stimulated with cigarette smoke [9].…”

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confidence: 99%

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Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition

Milara

Serrano

Peiró³

et al. 2012

Eur Respir J

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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.

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition

Milara

Serrano

Peiró³

et al. 2012

Eur Respir J

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“…The muscarinic agonist carbachol upregulates MUC5AC expression in these cells by activation of muscarinic receptors and transactivation of epidermal growth factor receptors (EGFR). Aclidinium has been shown to decrease this effect in vitro (67). Treatment with tiotropium has also been demonstrated to improve mucociliary clearance, as reflected by reduced nasal clearance time, in patients with COPD (68).…”

Section: Reduction Of Mucus Hypersecretion and Improvement Of Mucocilmentioning

confidence: 99%

“…MUC5AC is the predominant mucin gene expressed in human airway epithelial cells (66). The muscarinic agonist carbachol upregulates MUC5AC expression in these cells by activation of muscarinic receptors and transactivation of epidermal growth factor receptors (EGFR).…”

Section: Reduction Of Mucus Hypersecretion and Improvement Of Mucocilmentioning

confidence: 99%

How Do Dual Long-Acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?

Beeh

Burgel

Franssen³

et al. 2017

Am J Respir Crit Care Med

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Word Count: 187 At-a-Glance CommentaryResults from multiple clinical trials have demonstrated that fixed combinations of long-acting β-adrenergic agonists (LABA) and long-acting muscarinic antagonists (LAMA) are significantly superior to their monocomponents and to the combination LABA and an inhaled corticosteroid in decreasing the frequency of exacerbations in patients with chronic obstructive pulmonary disease. At present, the mechanism(s) underlying this clinical benefit are not fully understood.This review considers potential mechanisms whereby LABA/LAMA combinations might exert additive or synergistic effects that lead to a decrease in exacerbations. Mechanisms considered include effects on lung hyperinflation and mechanical stress, inflammation, excessive mucus production with impaired mucociliary clearance, and symptom severity and variability. Word count: 188

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“…Furthermore, the expression of the predominate mucin gene in human airways, MUC5AC, is augmented in asthmatics, patients with COPD, and normal smokers [66]. This overexpression can be blocked by aclidinium [67]. Acetylcholine has also been implicated in cell signaling that leads to fibrosis and airway remodeling in smokers [68].…”

Section: And Special Populationsmentioning

confidence: 96%

Anticholinergics/Antimuscarinic Drugs in Asthma

Soler

Ramsdell

2014

Curr Allergy Asthma Rep

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Anticholinergic alkaloids have been used for thousands of years for the relief of bronchoconstriction and other respiratory symptoms, and their use in the treatment of chronic obstructive pulmonary disease is well established. Acetylcholine, acting through muscarinic receptor (M) receptor, modulates multiple physiologic functions pertinent to asthma including airway muscle tone, mucus gland secretion, and various parameters of inflammation and remodeling. In addition, activation of M receptors may inhibit beta2 adrenoreceptor. These observations offer the rationale for the use of M receptors antagonists in the treatment of asthma. Short-acting antimuscarinic agents may be effective alone or in combination with short-acting beta agonists for the relief of acute symptoms. Long-acting antimuscarinic agents have emerged as potentially useful in the long-term treatment of difficult-to-control asthma. This review will analyze the mechanisms of action and therapeutic role of antimuscarinic agents on asthma including current guidelines regarding antimuscarinic drugs, recent studies in asthma, special populations to consider, and possible predictors of response.

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Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways

Cited by 63 publications

References 29 publications

Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition

Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition

How Do Dual Long-Acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?

Anticholinergics/Antimuscarinic Drugs in Asthma

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