The effect of an orally active leukotriene D 4/E 4 antagonist, LY171883, on antigen-induced airway responses in allergic sheep

Abstract

Leukotriene (LT) D 4 is a putative mediator of allergic asthma: inhaled LTD 4 produces early and late increases in specific lung resistance (SR L) and slows tracheal mucus velocity (TMV) similat to inhaled antigen. In this study we examined the effects of an orally active LTD 4/LTE 4 antagonist, LY171883 [1-<2-Hydroxy-3-propyl-4-<4-(1H-Tetra-zol-5-yl) Butoxy>Phenyl>Ethanonel], on early and late changes in SR L and TMV following airway challenge with Ascaris suum antigen in conscious allergic sheep. SR L and TMV were measured before and up to 8 h and 24 h after antigen challenge after either LY171883 (30 mg/kg, p.o. 2 h before challenge) or placebo pretreatment. After placebo pretreatment antigen challenge resulted in significant early (483% over baseline) and late (221% over baseline) increases in SR L (n=9). LY171883 pretreatment, however, significantly reduced the early increase in SR L (163% over baseline) and blocked the late response. LY171883 did not prevent the antigen-induced fall in TMV from 5–8 h post challenge (n=6), but TMV recovered more rapidly in the drug trial returning to baseline values by 24 h. These results suggest that the generation of LTD 4, and its metabolite LTE 4, during airway anaphylaxis contributes to the early increase in SR L and is important for eliciting the late increase in SR L as well as contributing to the fall in TMV.