A leukotriene and thromboxane inhibitor (Sch 37224) blocks antigen-induced immediate and late responses and airway hyperresponsiveness in allergic sheep

Peptide leukotrienes and thromboxane A₂ are putative mediators of allergen-induced late responses and allergen-induced airway hyperresponsiveness (AHR), respectively. Sch 37224 blocks antigen-induced leukotriene D₄ and thromboxane B₂ release in guinea pig lung fragments. It also inhibits leukotriene-mediated allergic guinea pig bronchospasm. Sch 37224 was, therefore, tested in allergic sheep (n = 6) with documented immediate and late airway responses and AHR to inhaled Ascaris suum antigen. For these studies, base-line airway dose-response curves to histamine and carbachol were determined on the same day. The sheep were challenged 1 to 2 days later with Ascaris suum antigen, once after placebo treatment and once after 10 mg/kg of Sch 37224, administered orally 18 and 2 hr before challenge (total dose, 20 mg/kg). Airway dose-response curves were subsequently performed 24 hr after antigen challenge. In the placebo trial, antigen challenge caused significant peak immediate and peak late increases over base line in specific lung resistance (SR(L)) of 286 ± 51 and 196 ± 29%, respectively. SR(L) returned to baseline values 24 hr later, but the sheep had AHR to both histamine and carbachol as indicated by 2.6- and 3.1-fold increases in the slopes of the dose-response curves (P < .05). Sch 37224 treatment reduced the peak immediate and peak late increases in SR(L) to 128 ± 32 and 43 ± 17%, respectively (both P < .05 vs. placebo). Furthermore, 24 hr later, the antigen-induced AHR to both histamine and carbachol was blocked (P < .05 vs. placebo). In addition, Sch 37224 reduced basal (prechallenge) airway responsiveness to both histamine and carbachol. These results suggest that an inhibitor of leukotriene and thromboxane generation/release such as Sch 37224 may be beneficial in alleviating antigen-induced immediate and late responses, the associated AHR, as well as reducing basal airway responsiveness.