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LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD
Airway inflammation in chronic obstructive pulmonary disease (COPD) is partially insensitive/resistant to inhaled corticosteroids (ICS). ICS plus bronchodilator therapy has been discussed for COPD phenotypes with frequent exacerbations and participation of corticosteroid-sensitive type 2/eosinophili...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947523/ https://www.ncbi.nlm.nih.gov/pubmed/31766770 http://dx.doi.org/10.3390/jcm8122058 |
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author | Knobloch, Jürgen Jungck, David Kronsbein, Juliane Stoelben, Erich Ito, Kazuhiro Koch, Andrea |
author_facet | Knobloch, Jürgen Jungck, David Kronsbein, Juliane Stoelben, Erich Ito, Kazuhiro Koch, Andrea |
author_sort | Knobloch, Jürgen |
collection | PubMed |
description | Airway inflammation in chronic obstructive pulmonary disease (COPD) is partially insensitive/resistant to inhaled corticosteroids (ICS). ICS plus bronchodilator therapy has been discussed for COPD phenotypes with frequent exacerbations and participation of corticosteroid-sensitive type 2/eosinophilic inflammation. Neutralization of non-type 2/IL-8-associated airway inflammation by reversion of its corticosteroid-resistance might be a future strategy for other phenotypes. Human airway smooth muscle cells (HASMCs) produce corticosteroid-insensitive IL-8 in response to TNFα or LPS in stable disease stages or bacteria-induced exacerbations, respectively. p38-mitogen-activated-protein-kinases (p38MAPKs) are alternative therapeutic targets. Hypothesis: long-acting-β2-agonists (LABAs) reverse the corticosteroid-insensitivity of IL-8 by p38MAPK inhibition in HASMCs. Cultivated HASMCs from COPD subjects were pre-incubated with formoterol, salmeterol, fluticasone-propionate, BIRB796 (p38MAPKα, -γ, -δ inhibitor), and/or SB203580 (p38MAPKα and -β inhibitor) before stimulation with TNFα or LPS. IL-8 and MAPK-activities were measured by ELISA. Formoterol, salmeterol, and fluticasone did not or hardly reduced TNFα- or LPS-induced IL-8. BIRB796 and SB203580 reduced TNFα-induced IL-8. SB203580 reduced LPS-induced IL-8. Fluticasone/formoterol, fluticasone/salmeterol, and fluticasone/BIRB796, but not fluticasone/SB203580 combinations, reduced TNFα-induced IL-8 stronger than single treatments. All combinations including fluticasone/SB203580 reduced LPS-induced IL-8 stronger than single treatments. TNFα induced p38MAPKα and -γ activity. LPS induced p38MAPKα activity. Formoterol reduced TNFα-induced p38MAPKγ and LPS-induced p38MAPKα activity. LABAs reverse the corticosteroid-insensitivity of IL-8 in airway smooth muscles via p38MAPKγ in stable disease and via p38MAPKα in exacerbations. Our pre-clinical data indicate a utility for also adding ICS in non-type 2 inflammatory COPD phenotypes to bronchodilator therapy. Depending on phenotype and disease stage, isoform-specific p38MAPK blockers might also reverse corticosteroid-resistance in COPD. |
format | Online Article Text |
id | pubmed-6947523 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69475232020-01-13 LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD Knobloch, Jürgen Jungck, David Kronsbein, Juliane Stoelben, Erich Ito, Kazuhiro Koch, Andrea J Clin Med Communication Airway inflammation in chronic obstructive pulmonary disease (COPD) is partially insensitive/resistant to inhaled corticosteroids (ICS). ICS plus bronchodilator therapy has been discussed for COPD phenotypes with frequent exacerbations and participation of corticosteroid-sensitive type 2/eosinophilic inflammation. Neutralization of non-type 2/IL-8-associated airway inflammation by reversion of its corticosteroid-resistance might be a future strategy for other phenotypes. Human airway smooth muscle cells (HASMCs) produce corticosteroid-insensitive IL-8 in response to TNFα or LPS in stable disease stages or bacteria-induced exacerbations, respectively. p38-mitogen-activated-protein-kinases (p38MAPKs) are alternative therapeutic targets. Hypothesis: long-acting-β2-agonists (LABAs) reverse the corticosteroid-insensitivity of IL-8 by p38MAPK inhibition in HASMCs. Cultivated HASMCs from COPD subjects were pre-incubated with formoterol, salmeterol, fluticasone-propionate, BIRB796 (p38MAPKα, -γ, -δ inhibitor), and/or SB203580 (p38MAPKα and -β inhibitor) before stimulation with TNFα or LPS. IL-8 and MAPK-activities were measured by ELISA. Formoterol, salmeterol, and fluticasone did not or hardly reduced TNFα- or LPS-induced IL-8. BIRB796 and SB203580 reduced TNFα-induced IL-8. SB203580 reduced LPS-induced IL-8. Fluticasone/formoterol, fluticasone/salmeterol, and fluticasone/BIRB796, but not fluticasone/SB203580 combinations, reduced TNFα-induced IL-8 stronger than single treatments. All combinations including fluticasone/SB203580 reduced LPS-induced IL-8 stronger than single treatments. TNFα induced p38MAPKα and -γ activity. LPS induced p38MAPKα activity. Formoterol reduced TNFα-induced p38MAPKγ and LPS-induced p38MAPKα activity. LABAs reverse the corticosteroid-insensitivity of IL-8 in airway smooth muscles via p38MAPKγ in stable disease and via p38MAPKα in exacerbations. Our pre-clinical data indicate a utility for also adding ICS in non-type 2 inflammatory COPD phenotypes to bronchodilator therapy. Depending on phenotype and disease stage, isoform-specific p38MAPK blockers might also reverse corticosteroid-resistance in COPD. MDPI 2019-11-22 /pmc/articles/PMC6947523/ /pubmed/31766770 http://dx.doi.org/10.3390/jcm8122058 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Communication Knobloch, Jürgen Jungck, David Kronsbein, Juliane Stoelben, Erich Ito, Kazuhiro Koch, Andrea LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD |
title | LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD |
title_full | LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD |
title_fullStr | LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD |
title_full_unstemmed | LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD |
title_short | LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD |
title_sort | labas and p38mapk inhibitors reverse the corticosteroid-insensitivity of il-8 in airway smooth muscle cells of copd |
topic | Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947523/ https://www.ncbi.nlm.nih.gov/pubmed/31766770 http://dx.doi.org/10.3390/jcm8122058 |
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