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Published ahead of print on January 19, 2006, doi:10.1165/rcmb.2005-0385OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 616-624, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2005-0385OC

Combination Therapy

Synergistic Suppression of Virus-Induced Chemokines in Airway Epithelial Cells

Michael R. Edwards, Malcolm W. Johnson and Sebastian L. Johnston

Department of Respiratory Medicine, National Heart Lung Institute and Wright Fleming Institute of Infection & Immunity, Imperial College London, London; and Respiratory Science, GlaxoSmithKline R&D, Greenford, Middlesex, United Kingdom

Correspondence and requests for reprints should be addressed to Dr. Michael R. Edwards, Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, Norfolk Place, W2 1PG, London, UK. E-mail: michael.edwards{at}ic.ac.uk

Viruses are associated with the majority of exacerbations of asthma and chronic obstructive pulmonary disease. Virus induction of neutrophil and lymphocyte chemokines in bronchial epithelium is important in exacerbation pathogenesis. Combined corticosteroid/beta2 agonists synergistically suppress airway smooth muscle chemokine production. Because bronchial epithelium expresses glucocorticoid and beta2 receptors, we investigated whether combination therapy can synergistically suppress rhinovirus-induced bronchial epithelial cell neutrophil (CXCL5, CXCL8) and lymphocyte (CCL5, CXCL10) chemokine production. We investigated modulation of rhinovirus- and IL-1beta–induced bronchial epithelial cell chemokine production by salmeterol and fluticasone propionate, used at therapeutic concentrations, alone and in combination. After 1 h pretreatment, combined treatment significantly inhibited rhinovirus 16, 1B, and IL-1beta–induced CCL5 and CXCL8 protein and mRNA production in BEAS-2B cells compared with fluticasone alone. When used 4 h after treatment, the combination significantly reduced virus-induced CCL5 but not CXCL8. Salmeterol alone had no effect; therefore, this inhibition was synergistic. Kinetic analysis demonstrated that combination therapy reduced by 5-fold the concentration of corticosteroid required to inhibit CXCL8 mRNA expression. In primary cells, salmeterol alone reduced rhinovirus-induced CCL5 and CXCL10 and increased CXCL5 production in a dose-dependent manner but had no effect on CXCL8. Fluticasone alone reduced CCL5, CXCL8, and CXCL10 but had no effect on CXCL5. Combination therapy augmented inhibition of CXCL8, CCL5, and CXCL10 but had no effect on CXCL5. Corticosteroids and beta2 agonists suppress rhinovirus-induced chemokines in bronchial epithelial cells through synergistic and additive mechanisms. This effect was greater for lymphocyte- than for neutrophil-related chemokines.

Key Words: asthma • combination therapy • COPD • inflammation • rhinovirus




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