Science and Research

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 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.
Publication details
DOI: 10.3390/jcm8122058
Journal: J Clin Med
Number: 12
Work Type: Original
Location: BREATH, CPC-M
Disease Area: COPD
Partner / Member: LMU
Access-Number: 31766770
See publication on PubMed

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