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Knobloch, Jürgen; Jungck, David; Kronsbein, Juliane; Stoelben, Erich; Ito, Kazuhiro and Koch, Andrea (2019): LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD. In: Journal of Clinical Medicine, Vol. 8, No. 12, 2058

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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.

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