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/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 TNF\(\alpha\) or LPS in stable disease stages or bacteria-induced exacerbations, respectively. p38-mitogen-activated-protein-kinases (p38MAPKs) are alternative therapeutic targets. Hypothesis: long-acting-\(\beta\)2-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 (p38MAPK\(\alpha\), -\(\gamma\), -\(\delta\) inhibitor), and/or SB203580 (p38MAPK\(\alpha\) and -\(\beta\) inhibitor) before stimulation with TNF\(\alpha\) or LPS. IL-8 and MAPK-activities were measured by ELISA. Formoterol, salmeterol, and fluticasone did not or hardly reduced TNF\(\alpha\)- or LPS-induced IL-8. BIRB796 and SB203580 reduced TNF\(\alpha\)-induced IL-8. SB203580 reduced LPS-induced IL-8. Fluticasone/formoterol, fluticasone/salmeterol, and fluticasone/BIRB796, but not fluticasone/SB203580 combinations, reduced TNF\(\alpha\)-induced IL-8 stronger than single treatments. All combinations including fluticasone/SB203580 reduced LPS-induced IL-8 stronger than single treatments. TNF\(\alpha\) induced p38MAPK\(\alpha\) and -\(\gamma\) activity. LPS induced p38MAPK\(\alpha\) activity. Formoterol reduced TNF\(\alpha\)-induced p38MAPK\(\gamma\) and LPS-induced p38MAPK\(\alpha\) activity. LABAs reverse the corticosteroid-insensitivity of IL-8 in airway smooth muscles via p38MAPK\(\gamma\) in stable disease and via p38MAPK\(\alpha\) 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.
Author: | Jürgen KnoblochORCiDGND, David JungckGND, Juliane KronsbeinGND, Erich StölbenGND, Kazuhiro ItoGND, Andrea KochGND |
---|---|
URN: | urn:nbn:de:hbz:294-69518 |
DOI: | https://doi.org/10.3390/jcm8122058 |
Parent Title (English): | Journal of clinical medicine |
Publisher: | MDPI |
Place of publication: | Basel |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2020/02/07 |
Date of first Publication: | 2019/11/22 |
Publishing Institution: | Ruhr-Universität Bochum, Universitätsbibliothek |
Tag: | Open Access Fonds COPD phenotypes; long-acting-beta2-agonist (LABA); non-type 2 inflammation; p38MAPK isoforms; reversion of corticosteroid resistance |
Volume: | 8 |
Issue: | 12 |
First Page: | 2058-1 |
Last Page: | 2058-10 |
Note: | Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum. |
Institutes/Facilities: | Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Medizinische Klinik III, Pneumologie, Allergologie, Schlaf- und Beatmungsmedizin |
Dewey Decimal Classification: | Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit |
open_access (DINI-Set): | open_access |
faculties: | Medizinische Fakultät |
Licence (English): | Creative Commons - CC BY 4.0 - Attribution 4.0 International |