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Am. J. Respir. Crit. Care Med., Volume 161, Number 4, April 2000, 1229-1236

Anti-inflammatory Effects of Zileuton in a Subpopulation of Allergic Asthmatics

JEFFREY D. HASDAY, SUSAN S. MELTZER, WENDY C. MOORE, PETER WISNIEWSKI, J. RICHARD HEBEL, CARMINE LANNI, LOUISE M. DUBÉ, and EUGENE R. BLEECKER

Pulmonary and Critical Care Division of the Department of Medicine, Center for Genetics of Asthma and Complex Diseases, University of Maryland Medical School, The Medical Service of the Baltimore VA Medical Center, The UMAB Cytokine Core Laboratory, Baltimore, Maryland; and Abbott Laboratories, Abbott Park, Illinois

The objective of this study was to determine the effects of allergen exposure on leukotriene generation and inflammation within the airways of allergic asthmatics and evaluate the effects of the 5-lipoxygenase inhibitor zileuton on these responses. We measured leukotriene-B4 (LTB4) and LTC4/D4/E4, inflammatory cytokine mediators, and cellular responses in bronchoalveolar lavage fluid (BALF) before and 24 h after segmental ragweed antigen challenge in 18 asthmatic subjects at baseline. Before initiating therapy with the 5-lipoxygenase inhibitor or placebo, only nine of 18 asthmatic subjects had a significant increase (234 ± 102-fold, mean ± SE) in BALF LTC4/D4/E4 levels 24 h after segmental antigen challenge, whereas leukotriene levels were essentially unchanged (1.14 ± 0.22-fold) in the other nine subjects. The high LT producers also had higher postantigen BALF levels of LTB4, total protein, IL-5, IL-6, TNF-alpha , and recovery of more eosinophils than the low LT producers. Treatment with the 5-lipoxygenase inhibitor zileuton reduced postantigen BALF eosinophil count by 68% in the high LT producers, but had no detectable effect on BALF composition in the low LT producers. These data suggest that leukotriene inhibition may be more effective in a subset of asthmatics in whom leukotrienes are a major contributory factor in causing allergic inflammation.




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