EFFECT OF CHRONIC 5-LIPOXYGENASE INHIBITION ON AIRWAY HYPERRESPONSIVENESS IN ASTHMATIC SUBJECTS

The leukotrienes are known bronchoactive agonists with potential proin flammatory effects that may be involved in mediating airway hyperrespo nsiveness. We investigated the effects of zileuton, an inhibitor of 5- lipoxygenase (5-LO), on airway responsiveness to cold, dry air in pati ents with moderate asthma. A group of 10 asthmatic patients underwent cold, dry air hyperventilation challenge; challenges were performed be fore drug treatment and 1 to 10 d after the completion of treatment wi th study drugs. The cold air minute ventilation required to cause a 15 % decrease in FEV(1) (PD15 VE) increased by 58% compared with the resp onse before treatment, 1 to 10 d after the completion of 13 wk of trea tment with zileuton. The geometric mean (geometric mean/SEM and geomet ric mean x SEM) PD15 VE increased from 24.5 (20.4, 29.5) L/min to 38.8 (34.7, 43.7) L/min (p = 0.01). Zileuton treatment inhibited 5-LO as m easured ex vivo by ionophore-stimulated LTB(4) levels in whole blood. In four of seven subjects, LTB(4) levels before zileuton ingestion fel l from 110.88 +/- 25.42 to 5.40 +/- 1.95 ng/ml 2 h postzileuton dosing (p = 0.02, pre- versus 2 h postzileuton ingestion). Consistent with t he short half-life of zileuton, 6 h postzileuton dosing the ionophore- stimulated, LTB(4) levels in whole blood had increased to 89.68 +/- 35 .54 ng/ml (p = 0.41, pre- versus 6 h postzileuton ingestion). Based on the first-order kinetics of zileuton, its effect on 5-LO activity sho uld have been dissipated less than 16 h postingestion. Thus, chronic z ileuton treatment decreased airway hyperresponsiveness as determined b y reactivity to cold, dry air. These data suggest that 5-LO products o f arachidonic acid metabolism can mediate airway hyperresponsiveness s eparately from their acute effects on airway tone.