Corticosteroid suppression of lipoxin A(4 )and leukotriene B(4)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 )(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 μg/ml) with or without dexamethasone (10(-6)M). 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; p < 0.01). CONCLUSIONS: Decreased LXA(4 )and increased LTB(4 )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.