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