Corticosteroid suppression of lipoxin A4 and leukotriene B4 from alveolar macrophages in severe asthma

Background: An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B-4 (LTB4), 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(-6)M). LTB4 and LXA(4) were measured by enzyme immunoassay. Results: LXA4 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 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 LXA(4), with lesser suppression of LTB4 in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA(4) and FEV1 (% predicted) (r(s) = 0.60; p < 0.01). Conclusions: Decreased LXA(4) and increased LTB4 generation plus impaired corticosteroid sensitivity of LPS-induced LTB4 but not of LXA(4) support a role for AMs in establishing a pro-inflammatory balance in severe asthma.