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 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 microg) 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 (VA/Q) defects was shown by a parallel improvement (decrease) in an overall marker of VA/Q 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.
Gómez
F P
FP
Departament de Medicina, Hospital Clinic, Universitat de Barcelona, Spain.
Iglesia
R
R
Roca
J
J
Barberà
J A
JA
Chung
K F
KF
Rodriguez-Roisin
R
R
D000328:Adult; D000403:Airway Resistance / Q000187:drug effects; D001249:Asthma / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D008297:Male; D009503:Neutropenia / Q000139:chemically induced; D010100:Oxygen / Q000097:blood; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects*; D014692:Ventilation-Perfusion Ratio / Q000187:drug effects
D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D010100:Oxygen; C063449:zileuton; D006918:Hydroxyurea