LEUKOTRIENES MEDIATE ANTIGEN-INDUCED AIRWAY HYPERREACTIVITY IN GUINEARIGS

The involvement of leukotrienes (LTs) in antigen-induced airway hyper- reactivity (AHR) was characterized pharmacologically by using several 5-lipoxygenase (5-LO) inhibitors and LTD(4) antagonists in guinea pigs . AHR was evidenced by consistent and significant increases in sensiti vity to bronchoconstriction induced by i.v. methacholine in anesthetiz ed and ventilated animals 24 hr after a single ovalbumin aerosol chall enge, but maximum methacholine-induced bronchoconstriction did not inc rease. Animals were pretreated with maximum doses of WY-50,295 trometh amine (WY-50,295), LY-171,883, MK-886 or zileuton, based upon inhibiti on of antigen-induced LT-dependent bronchoconstriction. WY-50,295, hav ing a long duration of action, was the only compound that prevented AH R when given once before antigen challenge. However, LY-171,883 and MK -886 prevented AHR when a second dose was given 4 hr after challenge. Zileuton, having a short duration of action, failed to prevent AHR whe n given before and after challenge. The prevention of AHR did not resu lt from functional antagonism (bronchodilation) by any compound. In br onchoalveolar lavage studies, neither WY-50,295 nor MK-886 inhibited t he influx of eosinophils into the airways 24 hr after antigen challeng e. The results provide pharmacological evidence that LTs play an impor tant role in the pathogenesis of antigen-induced AHR in guinea pigs. F urthermore, the effectiveness of 5-LO inhibitors and LTD(4) antagonist s in this model depends upon a long duration of drug action and appear s to result from inhibition of a direct airway effect of LTs rather th an inhibition of eosinophil influx into the airways. These findings su ggest that 5-LO inhibitors and LT antagonists may be useful for invest igating mechanisms of, and possibly reducing, AHR in asthmatics.