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)

Possible anti-inflammatory effect of salmeterol against interleukin-8 and neutrophil activation in asthma in vivo

In-vitro data suggest that long-acting β-agonists may have a neutrophil-stabilising effect. A reduction in airway wall eosinophil number following introduction of salmeterol in persistent asthma has previously been described. There is currently interest in the "neutrophil system" in asthma, and thus the aim of the present study was to investigate the effect of salmeterol on interleukin (IL)-8, neutrophils and myeloperoxidase (MPO) in persistent asthma. In the same 12-week double-blind parallel-group placebo-controlled study as described previously, the effects on bronchoalveolar lavage fluid (BALF) IL-8, neutrophils and MPO of introducing salmeterol (50 μg b.i.d.) or giving additional inhaled corticosteroid (fluticasone 100 μg b.i.d.) in 45 subjects with persistent asthma already on low/moderate doses of inhaled corticosteroids were further investigated. At baseline, BALF IL-8 but not neutrophil or MPO levels were significantly raised in the asthmatic subjects compared to normal controls. MPO levels correlated strongly with IL-8 levels, and weakly with BALF neutrophil numbers in the asthmatics. Fluticasone treatment resulted in significantly elevated neutrophil numbers, but not MPO or IL-8 levels. In contrast, introducing salmeterol significantly reduced IL-8 and MPO levels, but did not affect BALF neutrophil numbers. Interestingly, salmeterol and fluticasone showed significantly contrasting effects on MPO and neutrophils, and there was a divergent effect on IL-8 levels that almost reached significance. Excessive interleukin-8 levels may be relevant to asthma pathogenesis, even in the setting of moderate-dose inhaled corticosteroid therapy. Reduction in interleukin-8 production and possibly stabilisation of airway neutrophil numbers may explain the greater clinical benefit of adding a long-acting β-agonist rather than merely increasing inhaled corticosteroid doses. Indeed, high-dose inhaled corticosteroid therapy alone may promote airway neutrophilia

Inter-relationships between airway inflammation, reticular basement membrane thickening and bronchial hyper-reactivity to methacholine in asthma: A systematic bronchoalveolar lavage and airway biopsy analysis

Background: Asthma is accepted as a disease characterized by airway inflammation, with evidence that airway structural changes, or ‘remodelling’ occurs. There are few studies relating airway physiology, inflammation and remodelling, however. We have carried out a study of inter-relationships between airway inflammation, airway remodelling, reticular basement membrane (RBM) thickening, and bronchial hyper-reactivity (BHR), before and after high-dose inhaled corticosteroid (fluticasone propionate 750 μg b.d.), in a group of relatively mild but symptomatic, steroid naïve asthma patients. Methods: Double-blind, randomized, placebo-controlled, parallel group study of inhaled corticosteroid (ICS) in 35 asthmatics, with bronchoalveolar lavage (BAL) and airway endobronchial biopsy (EBB) for inflammatory cell profiles and EBB for airway remodelling carried out at baseline, 3 and 12 months. Results: At baseline RBM thickening was related to BAL mast cells and EBB eosinophil counts. In turn baseline log EBB EG2 eosinophil count, log%BAL epithelial cells and log RBM thickness explained 55% of the variability in BHR. Conclusion: We provide new information that airway inflammation, remodelling, and BHR in asthma are inter-related and improved by ICS therapy. Our data potentially support the need for early and long-term intervention with ICS even in relatively mild asthmatics, and the need to further assess the potential merit of longitudinal BHR testing in management of some patients, as this may reflect both airway inflammation and remodelling

The dynamics and associations of airway neutrophilia post lung transplantation

Bronchoalveolar lavage (BAL) neutrophilia has been repeatedly observed in lung transplant recipients with established bronchiolitis obliterans syndrome (BOS). Little is known of the fluctuations in BAL and airway neutrophilic inflammation post-transplant. This prospective longitudinal study aimed to evaluate the dynamic changes of lung allograft neutrophils with time, immunosuppression, infection and BOS. A total of 28, initially healthy, BOS 0, lung transplant recipients underwent 134 bronchoscopic assessments, including BAL and endobronchial biopsies (EBB) (with immunohistochemistry) over 3-year follow up. Subsequently, 21 developed BOS 0p and 16 ultimately BOS. Compared to controls, there was early and persistent BAL neutrophilia (p \u3c 0.05), contrasting with an initially normal EBB that shows a progressive increased airway wall neutrophil infiltrate. BAL neutrophilia (but not airway wall neutrophilia) was most striking when there was concomitant bronchopulmonary infection, particularly in the patients with BOS. Univariate and multivariate analyses suggested that BAL neutrophilia was linked to markers of infection while EBB neutrophilia was linked with coexistent inflammation with macrophages and lymphocytes. In conclusion: (i) BAL neutrophilia is predominantly associated with infection; (ii) Airway wall neutrophilia (as monitored by EBB) increases with time post-transplant and is not associated with infection; (iii) By itself, BOS is not the major contributor to BAL and EBB neutrophilia

Atrioventricular Interval Extension Is Highly Efficient in Preventing Unnecessary Right Ventricular Pacing in Sinus Node Disease: A Randomized Cross-Over Study Versus Dual- to Atrial Single-Chamber Mode Switch

Objectives This study sought to compare the Intrinsic Rhythm Support (IRSplus) and Ventricular Pace Suppress (VpS) in terms of right ventricular pacing percentage (VP %), mean atrioventricular interval (MAVI), atrial fibrillation, and cardiac volumes. Background Modern pacemakers are provided with algorithms for reducing unnecessary ventricular pacing. These may be classified as: periodic search for intrinsic atrioventricular (AV) conduction prolonging the AV delay accordingly; or DDD-ADI mode switch. The IRSplus and VpS algorithms belong to the former and latter classes, respectively. Methods Patients with sick sinus dysfunction without evidence of II/III degree AV block were 1:1 randomized to 6-month periods of either IRSplus or VpS, and then crossed over. Subsequent follow-ups were at the 12th month after randomization for device data retrieving, and at the 18th month with the same device programming for echocardiographic assessment. Results A total of 230 patients (62% males, median age 75 years [interquartile range: 69 to 79 years]) were enrolled. At a linear mixed-model analysis with order of treatment and investigational sites as nested random effects, differences in VP% and MAVI reached statistical significance: VP% was 1% (0% to 11%) during IRSplus and 3% (0% to 26%) during VpS (p = 0.029); MAVI was 225 ms (198 to 253 ms) during IRSplus and 214 ms (188 to 240 ms) during VpS (p = 0.014). No differences were observed in atrial fibrillation burden and incidence, ejection fraction, and cardiac volumes. Conclusions Both IRSplus and VpS algorithms ensured VP% ≤3% in most patients with sinus node dysfunction and preserved AV conduction. The IRSplus was slightly more efficient in reducing VP% at the expense of a small MAVI increase, with statistical but clinically insignificant differences. (Ventricular Pace Suppression Versus Intrinsic Rhythm Support Study; NCT01528657