THE EFFECTS OF A CYSTEINYL LEUKOTRIENE ANTAGONIST (ONO-1078) ON ANTIGEN-INDUCED RESPONSES IN ALLERGIC SHEEP

The cysteinyl leukotrienes (LTC4/D4/E4) are putative mediators of asthma. In this study we used sheep allergic to Ascaris suum antigen to examine the effects of a novel orally active cysteinyl LT antagonist, ONO-1078, on antigen-induced early and late responses, airway inflammation, post challenge (24 h) airway hyperresponsiveness (AHR) and mucociliary clearance. Airway responses to antigen were determined by measuring specific lung resistance (SR(L)) before and for 8 h after challenge, bronchoalveolar lavage (BAL) was used to estimate airway inflammation, and airway responsiveness was measured by determining the carbachol dose that increased SR(L) by 400% (PC400). We also used a radiographic technique to measure the antigen-induced change in tracheal mucus velocity (TMV), a marker of mucociliary clearance. In two trials separated by at least 21 days, sheep were treated once with ONO-1078 (30 mg/kg, p.o.) and once with placebo (0.5% methylcellulose), 2 h before and 4 h after antigen challenge. Treatment with ONO-1078 (n = 7) provided 40% protection (p < 0.10) against the peak early increase in SR(L), resulted in a more rapid reversal of the early response, and provided 96% protection against the peak late (6-8 h) increase in SR(L). ONO-1078 also inhibited the AHR 24 h after challenge. In the drug trial, PC400 was unchanged as compared to pre-challenge, whereas in the placebo trial, PC400 was decreased 1.4-fold (p < 0.05). Treatment however, did not affect BAL cell numbers or differential. Antigen challenge caused a reduction in TMV (n = 7) which was less severe in the drug trial as compared to the placebo trial, but this difference was not significant. These results confirm our previous findings that the cysteinyl LT contribute to the antigen-induced early and late bronchial responses and the AHR that follows on the days after antigen challenge in allergic sheep. Our results do not support a major role for the cysteinyl LT in the airway inflammatory cell influx or the antigen-induced changes in TMV in this animal model.