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 TNFalpha or LPS in stable disease stages or bacteria-induced exacerbations, respectively. p38-mitogen-activated-protein-kinases (p38MAPKs) are alternative therapeutic targets. Hypothesis: long-acting-beta2-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 (p38MAPKalpha, -gamma, -delta inhibitor), and/or SB203580 (p38MAPKalpha and -beta inhibitor) before stimulation with TNFalpha or LPS. IL-8 and MAPK-activities were measured by ELISA. Formoterol, salmeterol, and fluticasone did not or hardly reduced TNFalpha- or LPS-induced IL-8. BIRB796 and SB203580 reduced TNFalpha-induced IL-8. SB203580 reduced LPS-induced IL-8. Fluticasone/formoterol, fluticasone/salmeterol, and fluticasone/BIRB796, but not fluticasone/SB203580 combinations, reduced TNFalpha-induced IL-8 stronger than single treatments. All combinations including fluticasone/SB203580 reduced LPS-induced IL-8 stronger than single treatments. TNFalpha induced p38MAPKalpha and -gamma activity. LPS induced p38MAPKalpha activity. Formoterol reduced TNFalpha-induced p38MAPKgamma and LPS-induced p38MAPKalpha activity. LABAs reverse the corticosteroid-insensitivity of IL-8 in airway smooth muscles via p38MAPKgamma in stable disease and via p38MAPKalpha 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.
- Knobloch, J.
- Jungck, D.
- Kronsbein, J.
- Stoelben, E.
- Ito, K.
- Koch, A.
Keywords
- COPD phenotypes
- long-acting-beta2-agonist (LABA)
- non-type 2 inflammation
- p38MAPK isoforms
- reversion of corticosteroid resistance
- Actelion Pharmaceuticals, Teva Pharmaceutical Industries, and Boehringer
- Ingelheim. Jungck: served on an advisory board for Sanofi-Aventis, speaker fees
- from Novartis and Actelion Pharmaceuticals, travel grants from Actelion
- Pharmaceuticals, Boehringer-Ingelheim, Sanofi, Teva Pharmaceutical Industries,
- Roche. Kronsbein: none related to this study. Stoelben: none related to this
- study. Ito: K.I. is an employee of Pulmocide Ltd., a former head of biology in
- Respivert Ltd. and has an honorary contract with Imperial College. Koch: Speaker
- fees and travel grants from AstraZeneca, Boehringer, Novartis, Speaker fees from
- GSK.