Combination of fluticasone propionate and salmeterol potentiates the suppression of cigarette smoke-induced IL-8 production by macrophages Hadi Sarir a,b , Esmaeil Mortaz a , Khalil Karimi c , Malcolm Johnson d , Frans P. Nijkamp a , Gert Folkerts a, ⁎ a Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, The Netherlands b Department of Animal Science, Birjand University, Iran c Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, 1200 Main St W, Hamilton, L8N 3Z5, Ontario, Canada d Respiratory Science, GlaxoSmithKline, Greenford, Middlesex, United Kingdom Received 18 December 2006; received in revised form 15 May 2007; accepted 22 May 2007 Available online 5 June 2007 Abstract Cigarette smoke is the major risk factor for the development of chronic obstructive pulmonary disease (COPD). Macrophages are suggested to orchestrate the chronic inflammatory response and tissue destruction associated with COPD by secreting interleukin (IL)-8, a major neutrophil chemoattractant. The combination of inhaled corticosteroids and long-acting β 2 -adrenoceptor agonists are increasingly used as maintenance therapy in patients with COPD. The aim of this study was to determine whether combined fluticasone propionate, a corticosteroid, and salmeterol, a long-acting β 2 -adrenoceptor agonist, can suppress IL-8 production by human macrophages. To mimic resident macrophages in the lung, human monocytes were cultured for 5 days in medium containing Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) and Macrophage Colony Stimulating Factor (M-CSF). In human Monocyte-Derived Macrophages, we found that cigarette smoke medium strongly enhanced IL-8 release in a time- and concentration-dependent manner. IL-8 release by cigarette smoke was significantly suppressed in a concentration-dependent manner by fluticasone and salmeterol. Coincubation of the drugs potentiated the inhibitory effect on cigarette smoke medium-induced IL-8 production and longer preincubation times resulted in more IL-8 inhibition. Interestingly, preincubation of cells with suboptimal concentration of salmeterol for 4 h before fluticasone administration for 30 min potentiates the inhibitory effect of fluticasone on IL-8 release. In conclusion, combination therapy may provide benefits over monotherapy for the treatment of COPD patients. © 2007 Elsevier B.V. All rights reserved. Keywords: Fluticasone; Salmeterol; Cigarette smoke; COPD and IL-8 1. Introduction Chronic obstructive pulmonary disease (COPD) is a weakening respiratory condition that is characterized by a progressive and mainly irreversible airflow limitation (Barnes, 2000). Cigarette smoking is the major risk factor for the development of COPD, and smoking cessation is the only intervention that slows disease progression. The pathophysiol- ogy of COPD is multifactorial with an inflammatory cell profile that includes macrophages, neutrophils and T lymphocytes. COPD is characterized by an abnormal inflammatory response in the lungs (Jeffery, 2000). Macrophages are suggested to be the orchestrators of the chronic inflammatory response and tissue destruction associated with COPD (Shapiro, 1999). Macro- phages from COPD patients compared to nonsmokers produce more interleukin (IL)-8 (Lohmann-Matthes et al., 1994). The concentration of IL-8, a potent chemoattractant and an activator for neutrophils and other immune cells (Mukaida, 2003), is increased in bronchoalveolar lavage fluid of patients suffering from COPD (Tanino et al., 2002). Production of reactive oxygen species and different proteinases by neutrophils leads to destruction of elastin in the alveolar wall. This suggests that neutrophils play an important role in perpetuation of inflamma- tory responses in the pathogenesis of COPD. Inhaled corticosteroids are now widely prescribed for COPD patients, but the beneficial effects are questionable. Even high doses of corticosteroids have little effect in suppressing European Journal of Pharmacology 571 (2007) 55 – 61 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Tel.: +30 30 253 4509; fax: +31 30 253 7420. E-mail address: G.Folkerts@pharm.uu.nl (G. Folkerts). 0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.05.034