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LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD

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
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 COPD phenotypes; reversion of corticosteroid resistance; p38MAPK isoforms; long-acting-β2-agonist (LABA); non-type 2 inflammation
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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