Abstract
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.
Highlights
Airway inflammation is the hallmark of chronic obstructive pulmonary disease (COPD) pathophysiology and progression in stable and exacerbated disease stages because it induces airway remodeling processes that impair lung function
We investigated whether LABAs and inhibitors of p38-mitogen-activated-protein kinase (p38MAPK) and related MAPK families (ERK, JNK) can reverse the corticosteroid-insensitivity in Human airway smooth muscle cells (HASMCs) of COPD
We investigated the effects of the LABAs formoterol and salmeterol and the corticosteroid fluticasone-propionate and of the MAPK inhibitors BIRB796, SB203580 (p38MAPKα and -β inhibitor), PD098059, and SP600125
Summary
Airway inflammation is the hallmark of chronic obstructive pulmonary disease (COPD) pathophysiology and progression in stable and exacerbated disease stages because it induces airway remodeling processes that impair lung function. The nature of the remodeling processes depends on disease phenotypes but includes irreversible airway obstruction, an increase in airway smooth muscle mass, lung tissue fibrosis and/or destruction of the alveolar walls (emphysema). Anti-inflammatory therapies are desirable because they would prevent the induction of remodeling processes but are not yet available for most COPD phenotypes and disease stages. COPD therapy is complicated by the partial resistance/insensitivity of the airway inflammation to inhaled corticosteroids (ICS) [1]. ICS use increases the risk of pneumonia in COPD [2]. A careful assessment of ICS use in COPD is required, e.g., by identifying responder phenotypes
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