Effects of inhaled leukotriene D₄ and platelet-activating factor on airway reactivity in normal subjects

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 μg/ml), or LTD₄ (1 to 500 μg/ml) on separate days, a least 1 wk apart, until specific airway conductance (SGaw) decreased 50% or he 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 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. Afer 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. Although PAF produced less bronchoconstriction than did LTD₄, both mediators increased airway reactivity to MCh to the same degree. These data indicate that both LTD₄ and PAF increase airway reactivity in normal subjects and suggest that both mediators play a role in the pathogenesis of asthma.