THE EFFECTS OF 5-LIPOXYGENASE INHIBITION BY ZILEUTON ON PLATELET-ACTIVATING-FACTOR-INDUCED PULMONARY ABNORMALITIES IN MILD ASTHMA

Platelet-activating factor (PAF) has been implicated in the pathogenes is of asthma. We investigated whether PAF-induced neutropenia and lung function disturbances are secondary to activation of the 5-lipoxygena se (5-LO) pathway with the consequent liberation of teukotrienes. The effect of a selective 5-LO inhibitor (zileuton) was examined in 10 mil dly asthmatic patients (24 +/- 1 [mean +/- SE] yr; FEV1 = 94 +/- 4% pr edicted) before and after PAF inhalation, in a randomized, double-blin d, placebo-controlled, crossover fashion. Patients were studied at bas eline, 3 h after an oral single dose of zileuton (600 mg) or placebo, and then at 5 min, 15 min, and 45 min after PAF (18 mu g) inhalation. Compared with vehicle, premedication with zileuton reduced both PAF-in duced neutropenia at 5 min (by 43%) (p < 0.005) and the subsequent reb ound neutrophilia at 15 min and 45 min (by 50% and 47%, respectively) (p < 0.025 each). In addition, at 5 min after PAF inhalation, zileuton attenuated increases in respiratory system resistance (Rrs) (by 39%) (p < 0.01) and in the alveolar-arterial Pot difference (A-a)PO2 (by 40 %) (p < 0.05), and the decrease in Pa-O2 (by 27%) (p < 0.005). The pro tective effect of zileuton against PAF-induced ventilation-perfusion ( (V) over dot A/(Q) over dot) defects was shown by a parallel improveme nt (decrease) in an overall marker of (V)over dot A/(Q) over dot inequ ality (dispersion of retention minus excretion of inert gases correcte d for dead space; DISP R-E) (by 43%) 5 min after administration of PA F (p < 0.01). These findings indicate that PAF-induced systemic and pu lmonary effects in patients with mild asthma are effectively mediated by the ongoing release of leukotrienes.