LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD
by
Jürgen Knobloch 1,*, David Jungck 1,2, Juliane Kronsbein 1, Erich Stoelben 3, Kazuhiro Ito 4 and Andrea Koch 5,6,7
Jürgen Knobloch 1,*, David Jungck 1,2, Juliane Kronsbein 1, Erich Stoelben 3, Kazuhiro Ito 4 and Andrea Koch 5,6,7
1
Medical Clinic III for Pneumology, Allergology and Sleep Medicine, Bergmannsheil University Hospital, Ruhr-University Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
2
Department of Internal Medicine II, Pneumology, Allergology and Respiratory Medicine, Bethel Teaching Hospital, 12207 Berlin, Germany
3
Lungclinic, Thoracic Surgery, Hospital of Cologne, Private University Witten Herdecke, 51109 Cologne, Germany
4
National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK
5
Zürcher RehaZentren Davos, 7272 Davos-Clavadel, Switzerland
6
Ludwig-Maximilians-University of Munich (LMU), 81377 Munich, Germany
7
DZL (German Center of Lung Science), Hannover, Germany
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(12), 2058; https://doi.org/10.3390/jcm8122058
Received: 9 October 2019 / Revised: 4 November 2019 / Accepted: 14 November 2019 / Published: 22 November 2019
(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine)
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.
Keywords:
COPD phenotypes; reversion of corticosteroid resistance; p38MAPK isoforms; long-acting-β2-agonist (LABA); non-type 2 inflammation
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Knobloch, J.; Jungck, D.; Kronsbein, J.; Stoelben, E.; Ito, K.; Koch, A. LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD. J. Clin. Med. 2019, 8, 2058.
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