A CONTROLLED TRIAL OF THE EFFECT OF THE 5-LIPOXYGENASE INHIBITOR, ZILEUTON, ON LUNG INFLAMMATION PRODUCED BY SEGMENTAL ANTIGEN CHALLENGE INHUMAN-BEINGS

Background: Segmental antigen challenge (SAC) and bronchoalveolar lava ge (BAL) have been proven useful for investigating IgE-mediated lung i nflammation in volunteers with allergies. Objective: This model was us ed to evaluate the pulmonary antiinflammatory effects of an experiment al 5-lipoxygenase inhibitor (zileuton) in subjects allergic to ragweed . We hypothesized that decreased generation of leukotrienes by inhibit ion of the 5-lipoxygenase pathway of arachidonic acid metabolism would diminish the subsequent inflammatory response resulting from antigen challenge. Methods: Ten subjects with allergies received zileuton or p lacebo, 600 mg administered orally four times a day for 8 days, and th en underwent bronchoscopy, BAL of a control segment, and SAC in the co ntralateral lung followed by BAL of the challenged segment 24 hours la ter in a double-blind, placebo-controlled, crossover protocol. Urinary excretion of leukotriene E(4) induced by antigen challenge plus total and differential cell counts and the amount of total protein, albumin , urea, and eosinophil cationic protein in BAL fluid were determined. Results: A significant inhibition of leukotriene production (approxima tely 86%) was observed in subjects receiving zileuton. In addition, th ere was a statistically significant increase in eosinophils after anti gen challenge (0.6 +/- 0.2 x 10(4) eosinophils/ml increasing to 49.0 /- 25.0 x 10(4)) in subjects receiving placebo, whereas the influx of eosinophils in subjects receiving zileuton was not statistically diffe rent from baseline (1.1 +/- 0.7 x 10(4) eosinophils/ml increasing to 1 6.5 +/- 4.1 x 10(4); analysis of variance for repeated measures with p ost hoc comparisons). Conclusion: Treatment with zileuton altered the inflammatory response after antigen challenge. Products of the 5-lipox ygenase pathway appear to be important in recruiting eosinophils to th e lung after SAC.