Abstract
BackgroundAn imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B4 (LTB4), and lipoxin A4 (LXA4) production by alveolar macrophages (AMs) and studied the impact of corticosteroids.MethodsAMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 μg/ml) with or without dexamethasone (10-6M). LTB4 and LXA4 were measured by enzyme immunoassay.ResultsLXA4 biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA4 induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB4 were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB4 was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB4 and LXA4, with lesser suppression of LTB4 in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA4 and FEV1 (% predicted) (rs = 0.60; p < 0.01).ConclusionsDecreased LXA4 and increased LTB4 generation plus impaired corticosteroid sensitivity of LPS-induced LTB4 but not of LXA4 support a role for AMs in establishing a pro-inflammatory balance in severe asthma.
Highlights
Patients with asthma are usually well-controlled with inhaled corticosteroids (CS) and long-acting β2-agonists, but a minority of patients described as severe asthma continues to experience uncontrolled asthma in spite of these treatments
The possibility that dysregulation of the balance among these arachidonic acid products might contribute to the persistent inflammation in severe asthma has been supported by the demonstration of an increased generation of cysteinyl-leukotrienes with impaired biosynthesis of lipoxin A4 (LXA4) from whole blood of patients with severe asthma compared to non-severe asthma patients[9]
broncho-alveolar lavage (BAL) yielded fewer cells from severe asthmatics compared to non-severe asthmatics (p = 0.06), but there were proportionately more eosinophils (p < 0.05) and neutrophils (p < 0.05) with fewer macrophages (p < 0.01) in severe asthma compared to non-severe asthma
Summary
Patients with asthma are usually well-controlled with inhaled corticosteroids (CS) and long-acting β2-agonists, but a minority of patients described as severe asthma continues to experience uncontrolled asthma in spite of these treatments. One feature of severe asthma is the presence of airway inflammation despite corticosteroid therapy, often characterised by the persistence of eosinophilic inflammation and the pres-. Lipid mediators of the 5-lipoxygenase pathway such as cysteinyl-leukotrienes are implicated as mediators of airway bronchoconstriction and eosinophilic inflammation in asthma; another product, leukotriene B4 (LTB4), has been implicated, in view of its chemoattractant and activating properties for neutrophils [7]. The possibility that dysregulation of the balance among these arachidonic acid products might contribute to the persistent inflammation in severe asthma has been supported by the demonstration of an increased generation of cysteinyl-leukotrienes with impaired biosynthesis of lipoxin A4 (LXA4) from whole blood of patients with severe asthma compared to non-severe asthma patients[9]. An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B4 (LTB4), and lipoxin A4 (LXA4) production by alveolar macrophages (AMs) and studied the impact of corticosteroids
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