title: Sulfidopeptide leukotrienes mediate acrolein-induced bronchial hyperresponsiveness.
abstract: The sulfidopeptide leukotrienes are bronchoconstrictive lipid mediators thought to have an important role in the pathophysiology of asthma. The objective of this study was to determine if treatment with a leukotriene receptor antagonist and 5-lipoxygenase inhibitors could diminish acrolein-induced bronchial hyperresponsiveness and to determine whether leukotriene (LT) C4 generation is augmented by acrolein exposure. Guinea pigs (groups of 6-7) were exposed to 1.3 ppm acrolein for 2 h and bronchial responsiveness to intravenous acetylcholine determined twice before, and once 1, 2, 6, and 24 h after exposure. Immediately after acrolein exposure (5 min) specific total airway resistance (sRt) increased from 0.86 +/- 0.01 to 1.29 +/- 0.07 ml.cmH2O.ml-1.s. Within 1 h after exposure, the effective dose of acetylcholine sufficient to double sRt (ED200) decreased from 114.0 +/- 6.6 to 58.5 +/- 6.5 micrograms.kg-1.min-1. Bronchial hyperresponsiveness became maximal at 2 h with ED200 = 44.7 +/- 4.2 and persisted for up to 24 h after exposure (24 h ED200 = 60.2 +/- 11.6 micrograms.kg-1.min). A LTC4/LTD4 receptor antagonist, L-649,923 (10 mg/kg iv), and two putative inhibitors of 5-lipoxygenase, L-651,392 (10 mg/kg po) and U-60,257 (5 mg/kg i.v.), diminished the immediate bronchoconstriction and markedly inhibited bronchial hyperresponsiveness. Analysis of bronchoalveolar lavage fluid obtained from guinea pigs after acrolein exposure revealed a significant increase in immunoreactive LTC4 concentrations (control LTC4 = 8.8 +/- 0.3, n = 7; exposed LTC4 = 15.9 +/- 2.4 pg/ml, n = 6). Treatment with L-651,392 inhibited this response (acrolein exposed = 9.4 +/- 2.4 pg/ml, n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Environmental Health, University of Cincinnati Medical Center, Ohio 45267-0182.
authors.forename: G D
authors.initials: GD
authors.lastname: Leikauf
authors.forename: C A
authors.initials: CA
authors.lastname: Doupnik
authors.forename: L M
authors.initials: LM
authors.lastname: Leming
authors.forename: H E
authors.initials: HE
authors.lastname: Wey
mesh_terms: D000171:Acrolein / Q000494:pharmacology*; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001980:Bronchi / Q000187:drug effects*; D011464:Epoprostenol / Q000494:pharmacology / Q000031:analogs & derivatives; D006168:Guinea Pigs; D015289:Leukotrienes / Q000502:physiology*; D016859:Lipoxygenase Inhibitors; D010640:Phenothiazines / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000187:drug effects*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors
chemical_list: D000447:Aldehydes; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010640:Phenothiazines; D010654:Phenylbutyrates; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D000171:Acrolein; C050033:L 649923; C053726:4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one; D011464:Epoprostenol; D001091:Arachidonate Lipoxygenases; C035296:piriprost