Diminished lipoxin biosynthesis in severe asthma

Rationale and Objectives: Severe asthma is characterized by increased airway inflammation that persists despite therapy with corticosteroids. It is not, however, merely an exaggeration of the eosinophilic inflammation that characterizes mild to moderate asthma; rather, severe asthma presents unique features. Although arachidonic acid metabolism is well appreciated to regulate airway inflammation and reactivity, alterations in the biosynthetic capacity for both pro- and antiinflammatory eicosanoids in severe asthma have not been determined. Methods: Patients with severe asthma were identified according to National Heart, Lung, and Blood Institute Severe Asthma Research Program criteria. Samples of whole blood from individuals with severe or moderate asthma were assayed for biosynthesis of lipoxygenase-derived eicosanoids. Measurements and Main Results: The counterregulatory mediator lipoxin A(4) was detectable in low picogram amounts, using a novel fluorescence-based detection system. In activated whole blood, mean lipoxin A(4) levels were decreased in severe compared with moderate asthma (0.4 [SD 0.4] ng/ml vs. 1.8 [SD 0.8] ng/ml, p = 0.001). In sharp contrast, mean levels of prophlogistic cysteinyl leukotrienes were increased in samples from severe compared with moderate asthma (112.5 [SD 53.7] pg/ml vs. 64.4 [SD 24.8] pg/ml, p = 0.03). Basal circulating levels of lipoxin A(4) were also decreased in severe relative to moderate asthma. The marked imbalance in lipoxygenase-derived eicosanoid biosynthesis correlated with the degree of airflow obstruction. Conclusions: Mechanisms underlying airway responses in severe asthma include underproduction of lipoxins. This is the first report of a defect in lipoxin biosynthesis in severe asthma, and suggests an alternative therapeutic strategy that emphasizes natural counterregulatory pathways in the airways.