Leukotriene E(4)-induced persistent eosinophilia and airway obstruction are reversed by zafirlukast in patients with asthma.

Abstract

We have shown that inhalation of leukotriene (LT) E 4 contributes to specific recruitment of eosinophils to the airway mucosa in patients with asthma at the time of maximal decrease in airway-specific conductance. We examined the ability of the cysteinyl LT 1 receptor antagonist, zafirlukast, to improve or prevent LT-mediated eosinophilia and airway obstruction in asthma. Bronchial biopsies were taken and pulmonary function was measured before and 4 to 6 hours after the dose of inhaled LTE 4 causing a > or =15% fall in FEV 1 at baseline both at week 0 and after 6-week randomly assigned treatment with a high dose of zafirlukast, 80 mg twice daily. Leukotriene E 4 inhalation at week 0 doubled the number of eosinophils in the airway mucosa in 21 of 25 patients with mild asthma, increased the numbers of neutrophils and lymphocytes, and decreased FEV 1 (-17%). Zafirlukast reduced both airway eosinophilia and obstruction in FEV 1 , whereas with a double-blind placebo treatment, the effect of LTE 4 on both parameters persisted for 6 weeks. On repeat LTE 4 inhalation challenge after 6 weeks, zafirlukast treatment prevented further airway eosinophilia and decrease in FEV 1 seen in the placebo group. Persistent LTE 4 -induced airway eosinophilia may form the basis of an amplification mechanism for further eosinophil recruitment. Zafirlukast prevents LTE 4 -induced eosinophilic airway inflammation in mild asthma.