Increased leukotriene E4 excretion during antigen-induced bronchoconstriction in allergic sheep.
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.
Tagari
P
P
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Point-Claire, Quebec, Canada.
Abraham
W M
WM
McGolrick
J
J
Charleson
S
S
Soler
M
M
Ahmed
A
A
Cortez
A
A
Ford-Hutchinson
A W
AW
D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D001200:Ascaris / Q000276:immunology; D001980:Bronchi / Q000503:physiopathology*; D002851:Chromatography, High Pressure Liquid; D003251:Constriction, Pathologic / Q000276:immunology / Q000652:urine; D007700:Kinetics; D017999:Leukotriene E4; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000652:urine*; D013189:SRS-A / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D012756:Sheep
D000947:Antigens, Helminth; D013189:SRS-A; D017999:Leukotriene E4