Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD

Background: Combination inhaled therapy with long-acting beta(2) agonists (LABAs) and corticosteroids is beneficial in treating asthma and chronic obstructive pulmonary disease (COPD). Objective: In asthma, LABAs enhance glucocorticoid receptor (GR) nuclear translocation in the presence of corticosteroids. Whether this biological mechanism occurs in COPD, a relatively corticosteroid-resistant disease, is uncertain. Methods: Eight patients with mild/moderate COPD participated in a double-blind, placebo-controlled, crossover study and inhaled single doses of fluticasone propionate (FP) 100 mu g, FP 500 mu g, salmeterol xinafoate (SLM) 50 mu g, and combination FP 100 mu g + SLM 50 mu g. One hour postinhalation, sputum was induced, nuclear proteins isolated from purified macrophages, and levels of activated nuclear GR quantified by using a GR-glucocorticoid response element ELISA-based assay. Results: Nuclear GR significantly increased after the inhalation of FP 500 mu g(P<.01), but not after the inhalation of FP 100 mu g or SLM 50 mu g, compared with placebo. Interestingly, SLM in combination with FP 100 mu g increased nuclear GR levels equivalent to those of FP 500 mu g alone. This was significantly greater than either FP 100 mg (P<.05) or SLM 50 mu g (P<.01) alone. In vitro in a human macrophage cell line, SLM(10(-8) mol/L) enhanced FP (10(-9) mol/L)-induced mitogen-activated protein kinase phosphatase-1 mRNA (5.8 +/- 0.6 vs 8.4 +/- 1.1 x 10(-6) copies, P<.05) and 2 x glucocorticoid response element-luciferase reporter gene activity (250.1 +/- 5.6 vs 103.1 +/- 23.6-fold induction, P<.001). Addition of SLM (10(-9) mol/L) to FP (10(-11) mol/L) significantly enhanced FP-mediated suppression of IL-1 beta-induced CXCL8 (P<.05). Conclusions: Addition of SLM 50 mu g to FP 100 mu g enhanced GR nuclear translocation equivalent to that seen with a 5-fold higher dose of FP in sputum macrophages from patients with COPD. This may account for the superior clinical effects of combination LABA/corticosteroid treatment compared with either as monotherapy observed in COPD.