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J Appl Physiol 68: 1321-1327, 1990;
8750-7587/90 $5.00
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Journal of Applied Physiology, Vol 68, Issue 4 1321-1327, Copyright © 1990 by American Physiological Society

ARTICLES

Increased leukotriene E4 excretion during antigen-induced bronchoconstriction in allergic sheep

P. Tagari, W. M. Abraham, J. McGolrick, S. Charleson, M. Soler, A. Ahmed, A. Cortez and A. W. Ford-Hutchinson
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Point-Claire, Quebec, Canada.

The metabolism of leukotrienes (LT) in the sheep was investigated to define markers of 5-lipoxygenase involvement in allergic responses, obtainable by noninvasive techniques. Intravenous administration of 14, 15-[3H]LTC4 (0.5 microCi/kg) revealed a rapid clearance from the circulation (half time = 90 s). Circulatory metabolism was apparent, with early formation (within 1 min) of LTD4 and LTE4 shown by reverse-phase high-pressure liquid chromatography (RP-HPLC). Urinary 3H excretion comprised 10% of the original dose. [3H]LTE4 (characterized by coelution with authentic standards during RP-HPLC analysis) was observed in early urine samples. By use of a sensitive and specific RP-HPLC radioimmunoassay analysis, immunoreactive material coeluting with LTE4 was detected in urine from allergic sheep. Excretion of this material was significantly increased during antigen-induced acute bronchoconstriction in eight conscious allergic sheep [preantigen, 65.70 +/- 24.27 (SE) pg; 0-1 h postantigen, 208.00 +/- 71.10 pg, P less than 0.05], but not during late responses. However, total postantigen LTE4 excretion (37.8 - 956.1 pg/8 h) was highly correlated (r = 0.976, P less than 0.001) with the severity of bronchoconstriction (445.3 - 2,409.1% specific pulmonary resistance per hour) assessed by measurement of the area under the curve of pulmonary function plotted against time. These findings represent an important demonstration of in vivo allergen-induced peptide LT generation in a physiologically characterized animal model of prolonged allergic bronchoconstriction and further substantiate an important role for LT in this model of allergic asthma.


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