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)