A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings

• Published in: Journal of allergy and clinical immunology Vol. 97; no. 2; pp. 646 - 654
• Main Authors: Kane, Gregory C., Pollice, Mary, Kim, Chang-Jong, Cohn, Judith, Dworski, Ryszard T., Murray, John J., Sheller, James R., Fish, James E., Peters, Stephen P.
• Format: Journal Article
• Language: English
• Published: United States Mosby, Inc 1996
• Subjects: 5-lipoxygenase; Adult; Antigens - immunology; bronchoalveolar lavage; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Cell Count - drug effects; cysteinyl leukotrienes; Double-Blind Method; eosinophil; Eosinophils - pathology; Female; Humans; Hydroxyurea - analogs & derivatives; Hydroxyurea - therapeutic use; Hypersensitivity - immunology; IgE-mediated inflammation; leukotriene B 4; Leukotriene E4 - urine; Lipoxygenase Inhibitors - therapeutic use; Male; neutrophil; Pneumonia - drug therapy; Pneumonia - immunology; Pneumonia - pathology; Pollen; SAC of the lung; zileuton; SAC of the lung; 5-LO; PT; leukotriene B 4; LT; zileuton; neutrophil; BAL; IgE-mediated inflammation; ECP; SAC; ANOVA; cysteinyl leukotrienes; 5-lipoxygenase; eosinophil; bronchoalveolar lavage
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/S0091-6749(96)70310-X

BACKGROUND: Segmental antigen challenge (SAC) and bronchoalveolar lavage (BAL) have been proven useful for investigating IgE-mediated lung inflammation in volunteers with allergies. OBJECTIVE: This model was used to evaluate the pulmonary antiinflammatory effects of an experimental 5-lipoxygenase inhibitor (zileuton) in subjects allergic to ragweed. We hypothesized that decreased generation of leukotrienes by inhibition of the 5-lipoxygenase pathway of arachidonic acid metabolism would diminish the subsequent inflammatory response resulting from antigen challenge. METHODS: Ten subjects with allergies received zileuton or placebo, 600 mg administered orally four times a day for 8 days, and then underwent bronchoscopy, BAL of a control segment, and SAC in the contralateral lung followed by BAL of the challenged segment 24 hours later in a double-blind, placebo-controlled, crossover protocol. Urinary excretion of leukotriene E 4 induced by antigen challenge plus total and differential cell counts and the amount of total protein, albumin, urea, and eosinophil cationic protein in BAL fluid were determined. RESULTS: A significant inhibition of leukotriene production (approximately 86%) was observed in subjects receiving zileuton. In addition, there was a statistically significant increase in eosinophils after antigen challenge (0.6 ± 0.2 × 10 4 eosinophils/ml increasing to 49.0 ± 25.0 × 10 4) in subjects receiving placebo, whereas the influx of eosinophils in subjects receiving zileuton was not statistically different from baseline (1.1 ± 0.7 × 10 4 eosinophils/ml increasing to 16.5 ± 4.1 × 10 4; analysis of variance for repeated measures with post hoc comparisons). CONCLUSION: Treatment with zileuton altered the inflammatory response after antigen challenge. Products of the 5-lipoxygenase pathway appear to be important in recruiting eosinophils to the lung after SAC. (J A LLERGY C LIN I MMUNOL 1996;97:646-54.)