Do neutrophils play a role in the bronchiolitis obliterans syndrome post-lung transplant?

published_or_final_versio

The role of the bronchial microvasculature in the airway remodelling in asthma and COPD

In recent years, there has been increased interest in the vascular component of airway remodelling in chronic bronchial inflammation, such as asthma and COPD, and in its role in the progression of disease. In particular, the bronchial mucosa in asthmatics is more vascularised, showing a higher number and dimension of vessels and vascular area. Recently, insight has been obtained regarding the pivotal role of vascular endothelial growth factor (VEGF) in promoting vascular remodelling and angiogenesis. Many studies, conducted on biopsies, induced sputum or BAL, have shown the involvement of VEGF and its receptors in the vascular remodelling processes. Presumably, the vascular component of airway remodelling is a complex multi-step phenomenon involving several mediators. Among the common asthma and COPD medications, only inhaled corticosteroids have demonstrated a real ability to reverse all aspects of vascular remodelling. The aim of this review was to analyze the morphological aspects of the vascular component of airway remodelling and the possible mechanisms involved in asthma and COPD. We also focused on the functional and therapeutic implications of the bronchial microvascular changes in asthma and COPD

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

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)

Endobronchial Biopsy and Bronchoalveolar Lavage in Stable Lung Transplant Recipients and Chronic Rejection

We have obtained endobronchial biopsies (EBB), bronchoalveolar lavage (BAL), and transbronchial biopsies (TBB) in 17 stable lung transplant recipients (sLTR), 8 subjects with physiologic evidence of chronic rejection (BOS), and 9 normal subjects. A striking finding was the marked neutrophilia in BAL samples from patients with BOS, in the carefully screened absence of infection. A statistically higher neutrophil count was also present in the sLTR group relative to the normal group. Median BAL neutrophil count in BOS was 100 × 103/ml, range 13–1,661 103/ml (p < 0.001 relative to normal subjects and sLTR). Median BAL neutrophil count in sLTR was 7 × 103/ml, range 1–81 103/ml (p < 0.01 relative to normal subjects). Normal subjects had a median BAL neutrophil count of 3 × 103/ml, range 1–7 103/ml. There was evidence of a predominance of CD8 lymphocytes in BAL from sLTR and BOS with a lower CD4/CD8 ratio in both compared to normal subjects (p < 0.05). EBB mononuclear cell counts, class II major histocompatibility complex expression, and T-cell activation markers were normal in BOS, in contrast to the sLTR group. Our data may be consistent with BOS, representing a relative resolution of an active mononuclear cell chronic inflammation, perhaps at the expense of airway fibrosis. The relevance of the BAL neutrophilia and its role in BOS pathogenesis need further longitudinal investigation