A specific anti-inflammatory effect of salmeterol in symptomatic asthmatic patients already on low dose ICS

Introduction. In asthmatic patients, already on inhaled corticosteroids (ICS), who remain symptomatic, studies have demonstrated better outcomes by introducing long-acting inhaled β-agonists rather than increasing ICS (Greening A. Lancet 1994; 344:219-224). However, there remains an on-going debate on whether salmeterol has pro-or anti-inflammatory effects. To contribute to this debate, we undertook a bronchoscopic study looking at the role of endogenously produced nitric oxide (NO). Methods. 45 asthmatics, symptomatic despite treatment with ICS (100-500 μg/day), were enrolled into a double-blind, randomised, placebo-controlled and parallel-grouped trial. Patients remained on their normal dose of ICS and were subsequently randomised to receive either salmeterol (50 μg bd), fluticasone (100 μg bd) or placebo for 12 weeks. Airway biopsies and bronchoalveolar fluid (BALF) were obtained at baseline and after 12 weeks. Frozen biopsies were immunostained for inducible (iNOS) and constitutive nitric oxide synthase (cNOS) using monoclonal antibodies. Staining in the epithelium and in cells of the lamina propria (LP) was assessed using image analysis (Image Pro Plus), as were measurements of epithelial integrity. The BAL nitrite content was analysed with a modified fluorometric assay. For each treatment arm comparisons were made with regard to epithelial integrity (mean height above the basement membrane), inflammatory cells in the LP staining for iNOS or cNOS, vascularity (number and area occupied by cNOS staining vessels), epithelial iNOS staining and BALF nitrite concentration as a surrogate of exhaled NO. Results. There was no significant difference between pre and post treatment levels with regard to epithelial integrity, number of iNOS and cNOS positive cells in the LP, epithelial iNOS staining nor in BALF nitrite levels. There was however a significant increase in the number of vessels staining positive for cNOS (77±63 vs 140±113, p=0.03) in those asthmatics who had salmeterol added to the ICS (p=0.03 vs placebo). Summary. We have previously shown in this group that the addition of salmeterol leads to an overall reduction in vascularity (Orsida et al, Respirology; 2000: 5: Suppl.). In this study salmeterol was associated with an increased number of vessels positive for cNOS. Salmeterol was not associated with either an increase or a decrease in inflammation with regard to iNOS staining or nitrite production. Conclusion: Salmeterol was not pro-inflammatory in this study, indeed the increased vessel cNOS positiviry following salmeterol is anti-inflammatory, since endogenous NO production by cNOS would modulate inflammation by reducing cell migration through the vascular endothelium (Kubes P. Proc Natl Acad Sci USA. 1991; 88: 4651-55)