Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD.
BACKGROUND
Combination inhaled therapy with long-acting β2 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 μg, FP 500 μg, salmeterol xinafoate (SLM) 50 μg, and combination FP 100 μg + SLM 50 μg. 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 μg (P < .01), but not after the inhalation of FP 100 μg or SLM 50 μg, compared with placebo. Interestingly, SLM in combination with FP 100 μg increased nuclear GR levels equivalent to those of FP 500 μg alone. This was significantly greater than either FP 100 μg (P < .05) or SLM 50 μg (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 × 10(-6) copies, P < .05) and 2 × glucocorticoid response element-luciferase reporter gene activity (250.1 ± 15.6 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-1β-induced CXCL8 (P < .05).


CONCLUSIONS
Addition of SLM 50 μg to FP 100 μg 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.
Airway Disease Section, National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, United Kingdom.
Rubaiyat
R
Haque
Amir
A
Hakim
Thunicia
T
Moodley
Alfonso
A
Torrego
Sarah
S
Essilfie-Quaye
Elen
E
Jazrawi
Malcolm
M
Johnson
Peter J
PJ
Barnes
Ian M
IM
Adcock
Omar Sharif
OS
Usmani
D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000627:therapeutic use; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000368:Aged; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D020218:Response Elements; D013183:Sputum / Q000166:cytology; D020298:U937 Cells
D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D053583:Interleukin-1beta; D016209:Interleukin-8; D011965:Receptors, Glucocorticoid; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
COPD; Chronic obstructive pulmonary disease; FP; Fluticasone propionate; GR; GRE; Glucocorticoid receptor; Glucocorticoid response element; ICS; Inhaled corticosteroids; LABAs; Long-acting β(2) agonist; Long-acting β(2) agonists; MKP-1; Mitogen-activated protein kinase phosphatase-1; SLM; Salmeterol xinafoate; corticosteroid; glucocorticoid receptor; macrophage; sputum