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Published ahead of print on January 19, 2006, doi:10.1164/rccm.200508-1321OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 7, April 2006, 736-743

A more recent version of this article appeared on April 1, 2006
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Submitted on August 25, 2005
Accepted on January 19, 2006

Anti-Inflammatory Effects of Salmeterol/Fluticasone Propionate in Chronic Obstructive Lung Disease

Neil C Barnes1, Yu-Sheng Qiu2, Ian D Pavord3, Debbie Parker3, Peter A Davis2, Jie Zhu2, Malcolm Johnson4, Neil C Thomson5, and Peter K Jeffery2*

1 Department of Respiratory Medicine, London Chest Hospital, London, United Kingdom, 2 Lung Pathology Unit, Imperial College London at the Royal Brompton Hospital, London, United Kingdom, 3 Glenfield Hospital, Institute for Lung Health, Leicester, Leicestershire, United Kingdom, 4 GlaxoSmithKline Research and Development Ltd, Greenford, Middlesex, United Kingdom, 5 Department of Respiratory Medicine, University of Glasgow, Glasgow, United Kingdom

* To whom correspondence should be addressed. E-mail: p.jeffery{at}imperial.ac.uk.

Rationale: No currently available treatment is reported to reduce the exaggerated airway wall inflammation of chronic obstructive pulmonary disease. Objectives: We tested the hypothesis that inhaled combined long-acting {beta}2-agonist (salmeterol) and corticosteroid (fluticasone propionate) will reduce inflammation Methods: Bronchial biopsies and induced sputum were taken from 140 current and former smokers (mean age 64 years) with moderate to severe disease, randomized in a 13-week double-blind study to placebo (n=73) or salmeterol/fluticasone propionate 50/500µg (n=67) twice daily. Biopsies were repeated at 12 and sputa at 8 and 13 weeks. Following adjustment for multiplicity, comparisons between active and placebo were made for median change from baseline in the numbers of biopsy CD8+ and CD68+ cells/mm2 and sputum neutrophils. Measurements and Main Results: Combination therapy was associated with a reduction in biopsy CD8+ cells of -118 cells/mm2 (95%CI -209,-42; p=0.02), a reduction of 36% over placebo (p=0.001). CD68+ cells were unaffected by combination treatment. Sputum differential (but not total) neutrophils reduced progressively and, at week 13, significantly with combination treatment (median treatment difference 8.5%; 95%CI 1.75%,15.25%; p=0.04). The combination also significantly reduced biopsy CD45+, CD4+ and cells expressing genes for tumor necrosis factor-{alpha} and interferon-{gamma} and sputum total eosinophils (all p≤0.03). These anti-inflammatory effects were accompanied by 173mL (95%CI 104,242; p<0.001) improvement in pre-bronchodilator forced expiratory volume in one second. Conclusions: Salmeterol/fluticasone propionate has a broad spectrum of anti-inflammatory effects in both current and former smokers with chronic obstructive pulmonary disease, which may contribute to clinical efficacy.
Key words: airway inflammation, biopsy, sputum, placebo, salmeterol/fluticasone propionate




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