Am. J. Respir. Crit. Care Med.,
Volume 157, Number 5, May 1998, 1559-1564
The Effects of 5-Lipoxygenase Inhibition by Zileuton
on Platelet-activating-factor-induced Pulmonary
Abnormalities in Mild Asthma
FEDERICO P.
GÓMEZ,
RAQUEL
IGLESIA,
JOSEP
ROCA,
JOAN A.
BARBERÁ,
K.
FAN CHUNG,
and
ROBERT
RODRIGUEZ-ROISIN
Servei de Pneumologia i Al.lèrgia Respiratoria, Departament de Medicina, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain;
and National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom
Platelet-activating factor (PAF) has been implicated in the pathogenesis of asthma. We investigated
whether PAF-induced neutropenia and lung function disturbances are secondary to activation of the
5-lipoxygenase (5-LO) pathway with the consequent liberation of leukotrienes. The effect of a selective 5-LO inhibitor (zileuton) was examined in 10 mildly asthmatic patients (24 ± 1 [mean ± SE] yr;
FEV1 = 94 ± 4% predicted) before and after PAF inhalation, in a randomized, double-blind, placebo-controlled, crossover fashion. Patients were studied at baseline, 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 µg) inhalation. Compared with vehicle, premedication with zileuton reduced both PAF-induced neutropenia at 5 min (by 43%) (p < 0.005) and the subsequent rebound 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 PO2 difference (A-a)PO2 (by 40%) (p < 0.05), and the decrease in PaO2 (by 27%) (p < 0.005). The protective
effect of zileuton against PAF-induced ventilation-perfusion (
A/
) defects was shown by a parallel
improvement (decrease) in an overall marker of A/ inequality (dispersion of retention minus excretion of inert gases corrected for dead space; DISP R-E *) (by 43%) 5 min after administration of PAF
(p < 0.01). These findings indicate that PAF-induced systemic and pulmonary effects in patients with
mild asthma are effectively mediated by the ongoing release of leukotrienes.
