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Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients
BACKGROUND: Inhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. By contrast, the recommendation of ICS in combination with long-acting muscarinic an...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101693/ https://www.ncbi.nlm.nih.gov/pubmed/27825347 http://dx.doi.org/10.1186/s12931-016-0467-8 |
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author | Milara, Javier Cervera, Angela de Diego, Alfredo Sanz, Celia Juan, Gustavo Gavaldà, Amadeu Miralpeix, Montserrat Morcillo, Esteban Cortijo, Julio |
author_facet | Milara, Javier Cervera, Angela de Diego, Alfredo Sanz, Celia Juan, Gustavo Gavaldà, Amadeu Miralpeix, Montserrat Morcillo, Esteban Cortijo, Julio |
author_sort | Milara, Javier |
collection | PubMed |
description | BACKGROUND: Inhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. By contrast, the recommendation of ICS in combination with long-acting muscarinic antagonist (LAMA) is not evidence-based. In this study, neutrophils obtained from COPD patients were used to compare the anti-inflammatory effects of aclidinium bromide (a long-acting muscarinic antagonist) with corticosteroids and their potential additive effect. METHODS: Human sputum and blood neutrophils were isolated from healthy individuals (n = 37), patients with stable COPD (n = 52) and those with exacerbated COPD (n = 16). The cells were incubated with corticosteroid fluticasone propionate (0.1 nM–1 μM), aclidinium bromide (0.1 nM–1 μM) or a combination thereof and stimulated with 1 μg of lipopolysaccharide/ml or 5 % cigarette smoke extract. Levels of the pro-inflammatory mediators interleukin-8, matrix metalloproteinase-9, CCL-5, granulocyte-macrophage colony-stimulating factor and interleukin-1β were measured and the mechanisms of corticosteroid resistance evaluated at the end of the incubation. RESULTS: The non-neuronal cholinergic system was over-expressed in neutrophils from COPD patients, as evidenced by increases in the expression of muscarinic receptors (M2, M4 and M5), choline acetyltransferase and vesicular acetylcholine transporter. Aclidinium bromide demonstrated anti-inflammatory effects on neutrophils from COPD patients, reversing their resistance to corticosteroids. Additive effects of combined aclidinium bromide and fluticasone propionate in blocking M2 receptor levels, inhibiting phosphoinositide 3-kinase-δ and enhancing the glucocorticoid response element transcription factor were demonstrated and were accompanied by an increase in the corticosteroid-induced expression of anti-inflammatory-related genes. CONCLUSIONS: LAMAs potentiate the anti-inflammatory effects of corticosteroids in neutrophils from COPD patients in vitro, thus providing a scientific rationale for their use in combination with corticosteroids in the treatment of COPD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-016-0467-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5101693 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-51016932016-11-10 Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients Milara, Javier Cervera, Angela de Diego, Alfredo Sanz, Celia Juan, Gustavo Gavaldà, Amadeu Miralpeix, Montserrat Morcillo, Esteban Cortijo, Julio Respir Res Research BACKGROUND: Inhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. By contrast, the recommendation of ICS in combination with long-acting muscarinic antagonist (LAMA) is not evidence-based. In this study, neutrophils obtained from COPD patients were used to compare the anti-inflammatory effects of aclidinium bromide (a long-acting muscarinic antagonist) with corticosteroids and their potential additive effect. METHODS: Human sputum and blood neutrophils were isolated from healthy individuals (n = 37), patients with stable COPD (n = 52) and those with exacerbated COPD (n = 16). The cells were incubated with corticosteroid fluticasone propionate (0.1 nM–1 μM), aclidinium bromide (0.1 nM–1 μM) or a combination thereof and stimulated with 1 μg of lipopolysaccharide/ml or 5 % cigarette smoke extract. Levels of the pro-inflammatory mediators interleukin-8, matrix metalloproteinase-9, CCL-5, granulocyte-macrophage colony-stimulating factor and interleukin-1β were measured and the mechanisms of corticosteroid resistance evaluated at the end of the incubation. RESULTS: The non-neuronal cholinergic system was over-expressed in neutrophils from COPD patients, as evidenced by increases in the expression of muscarinic receptors (M2, M4 and M5), choline acetyltransferase and vesicular acetylcholine transporter. Aclidinium bromide demonstrated anti-inflammatory effects on neutrophils from COPD patients, reversing their resistance to corticosteroids. Additive effects of combined aclidinium bromide and fluticasone propionate in blocking M2 receptor levels, inhibiting phosphoinositide 3-kinase-δ and enhancing the glucocorticoid response element transcription factor were demonstrated and were accompanied by an increase in the corticosteroid-induced expression of anti-inflammatory-related genes. CONCLUSIONS: LAMAs potentiate the anti-inflammatory effects of corticosteroids in neutrophils from COPD patients in vitro, thus providing a scientific rationale for their use in combination with corticosteroids in the treatment of COPD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-016-0467-8) contains supplementary material, which is available to authorized users. BioMed Central 2016-11-08 2016 /pmc/articles/PMC5101693/ /pubmed/27825347 http://dx.doi.org/10.1186/s12931-016-0467-8 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Milara, Javier Cervera, Angela de Diego, Alfredo Sanz, Celia Juan, Gustavo Gavaldà, Amadeu Miralpeix, Montserrat Morcillo, Esteban Cortijo, Julio Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients |
title | Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients |
title_full | Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients |
title_fullStr | Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients |
title_full_unstemmed | Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients |
title_short | Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients |
title_sort | non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101693/ https://www.ncbi.nlm.nih.gov/pubmed/27825347 http://dx.doi.org/10.1186/s12931-016-0467-8 |
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