Effect of indomethacin on leukotriene₄-induced histamine hyperresponsiveness in asthmatic subjects

The effect of indomethacin on the capacity of LTE₄ to enhance airway histamine responsiveness was evaluated in eight mild asthmatic subjects. Subjects attended the laboratory on three separate pairs of study days when inhalation challenges with methacholine or LTE₄ were performed and the airway responses to histamine were measured 4 and 7 h later. An open pair of study days was followed by a pair of study days during ingestion of either placebo or indomethacin capsules. The dose of agonist that produced a 35% fall in specific airways conductance (PD₃₅ SGaw) was obtained by linear interpolation from the logarithmic dose-response curve. Indomethacin treatment did not affect baseline SGaw or methacholine airway responsiveness. However, indomethacin significantly inhibited LTE₄-induced histamine hyperresponsiveness. Maximum enhancement of histamine responsiveness by LTE₄ on the open and placebo study days was 4.1 ± 0.9- (mean ± SEM) and 5.7 ± 1.2-fold, respectively (p = 0.36). Maximal enhancement on the indomethacin day was 1.68 ± 0.46, and this was significantly decreased compared with that on the placebo day (p = 0.02). This suggests that LTE₄-induced enhanced responsiveness to histamine is mediated in part by cyclooxygenase pathway- derived products.