Corticosteroid Suppression of Lipoxin A\(_4\) and Leukotriene B\(_4\) from Alveolar Macrophages in Severe Asthma

Abstract

Background: An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B(_4) (LTB(_4)), and lipoxin A(_4) (LXA(_4)) production by alveolar macrophages (AMs) and studied the impact of corticosteroids. Methods: AMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 (\mu)g/ml) with or without dexamethasone (10-6M). LTB(_4) and LXA(_4) were measured by enzyme immunoassay. Results: LXA(_4) biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA(_4) induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB(_4) were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB(_4) was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB(_4) and LXA(_4), with lesser suppression of LTB(_4) in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA(_4) and FEV(_1) (% predicted) (r(_s) = 0.60; < 0.01). Conclusions: Decreased LXA(_4) and increased LTB4 generation plus impaired corticosteroid sensitivity of LPS-induced LTB(_4) but not of LXA(_4) support a role for AMs in establishing a pro-inflammatory balance in severe asthma.