title: Increased leukotriene E4 excretion during antigen-induced bronchoconstriction in allergic sheep.
abstract: 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.
authors.affiliation: Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Point-Claire, Quebec, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Tagari
authors.forename: W M
authors.initials: WM
authors.lastname: Abraham
authors.forename: J
authors.initials: J
authors.lastname: McGolrick
authors.forename: S
authors.initials: S
authors.lastname: Charleson
authors.forename: M
authors.initials: M
authors.lastname: Soler
authors.forename: A
authors.initials: A
authors.lastname: Ahmed
authors.forename: A
authors.initials: A
authors.lastname: Cortez
authors.forename: A W
authors.initials: AW
authors.lastname: Ford-Hutchinson
mesh_terms: 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
chemical_list: D000947:Antigens, Helminth; D013189:SRS-A; D017999:Leukotriene E4