Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients

作者：Milara Javier^*; Cervera Angela; de Diego Alfredo; Sanz Celia; Juan Gustavo; Gavalda Amadeu; Miralpeix Montserrat; Morcillo Esteban; Cortijo Julio

来源：Respiratory Research, 2016, 17(1): 145.

DOI：10.1186/s12931-016-0467-8

• Neutrophils
• COPD
• Corticosteroid resistance
• Aclidinium bromide
• Non-neuronal cholinergic system

Background: Inhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. By contrast, the recommendation of ICS in combination with long-acting muscarinic antagonist (LAMA) is not evidence-based. In this study, neutrophils obtained from COPD patients were used to compare the anti-inflammatory effects of aclidinium bromide (a long-acting muscarinic antagonist) with corticosteroids and their potential additive effect.
Methods: Human sputum and blood neutrophils were isolated from healthy individuals (n = 37), patients with stable COPD (n = 52) and those with exacerbated COPD (n = 16). The cells were incubated with corticosteroid fluticasone propionate (0.1 nM-1 mu M), aclidinium bromide (0.1 nM-1 mu M) or a combination thereof and stimulated with 1 mu g of lipopolysaccharide/ml or 5 % cigarette smoke extract. Levels of the pro-inflammatory mediators interleukin-8, matrix metalloproteinase-9, CCL-5, granulocyte-macrophage colony-stimulating factor and interleukin-1 beta were measured and the mechanisms of corticosteroid resistance evaluated at the end of the incubation.
Results: The non-neuronal cholinergic system was over-expressed in neutrophils from COPD patients, as evidenced by increases in the expression of muscarinic receptors (M2, M4 and M5), choline acetyltransferase and vesicular acetylcholine transporter. Aclidinium bromide demonstrated anti-inflammatory effects on neutrophils from COPD patients, reversing their resistance to corticosteroids. Additive effects of combined aclidinium bromide and fluticasone propionate in blocking M2 receptor levels, inhibiting phosphoinositide 3-kinase-d and enhancing the glucocorticoid response element transcription factor were demonstrated and were accompanied by an increase in the corticosteroid-induced expression of anti-inflammatory-related genes.
Conclusions: LAMAs potentiate the anti-inflammatory effects of corticosteroids in neutrophils from COPD patients in vitro, thus providing a scientific rationale for their use in combination with corticosteroids in the treatment of COPD.

• 出版日期2016-11-8