Inflammatory mediators such as platelet-activating factor (PAF) and the sulfidopeptide leukotrienes (LT) may contribute to airway hyperreactivity and asthma. PAF has been reported to produce bronchoconstriction and a sustained increase in airway reactivity when inhaled by normal subjects. Leukotrienes produce bronchoconstriction in both normal and asthmatic subjects, but whether they increase airway reactivity is unclear. Before initiating studies to determine how these bioactive mediators influence airway function, we sought to confirm that PAF increases airway reactivity and identify whether one of the sulfidopeptide leukotrienes, LTD4, has a similar effect. Eight normal male subjects inhaled saline and increasing concentrations of either histamine (0.1 to 50 mg/ml), PAF (1 to 1,000 micrograms/ml), or LTD4 (1 to 500 micrograms/ml) on separate days, at least 1 wk apart, until specific airway conductance (SGaw) decreased 50% or the maximal concentration was reached. After inhaling the test substance, methacholine (MCh) challenges were performed at 6 h, at 1, 3, and 7 days, and weekly thereafter until airway reactivity (measured as the MCh concentration that decreased SGaw 35% [PC35SGaw]) normalized. The four postsaline MCh challenges (6 h to 7 days) were used to determine the 95% confidence interval for PC35SGaw (in each subject) and identify significant changes in airway reactivity after inhaling each test substance. Airway reactivity did not change after inhaling histamine. After inhaling PAF, six of eight subjects developed increased airway reactivity, which was maximal at 1 day and persisted for 14 days in three. After inhaling LTD4, six of eight subjects also developed increased airway reactivity, which was maximal at 7 days and persisted for 14 days in two.(ABSTRACT TRUNCATED AT 250 WORDS)