EICOSANOIDS MODULATE HYPERPNEA-INDUCED BRONCHOCONSTRICTION IN CANINE PERIPHERAL AIRWAYS

We examined the role of leukotrienes (LTs) in the development of dry a ir-induced bronchoconstriction (AIB) in canine peripheral airways. Air way reactivity to exogenous LTs was first tested by using an LTD(4) ae rosol challenge: peripheral airway resistance increased similar to 130 +/- 51% (n = 4) above baseline when compared with its vehicle control . AIB was then assessed by measuring peripheral airway resistance afte r, and airway wall temperature during, a dry air challenge (DAC). Trea tment with a peptidoleukotriene biosynthesis inhibitor (MK-0591) atten uated AIB by similar to 65% without altering airway wall temperature. The fact that MK-0591 did not alter airway reactivity to aerosolized a cetylcholine and completely inhibited Ca2+ ionophore-induced LTB(4) ge neration in canine whole blood attests to the specificity of the drug. Treatment with MK-0591 did not affect the increased number of epithel ial cells recovered in bronchoalveolar lavage fluid 5 min after DAC. C oncentrations of LTs and other eicosanoids in bronchoalveolar lavage f luid from vehicle-treated DAC airways were increased above baseline va lues; only LTs were reduced by MK-0591. Before MK-0591, AIB was signif icantly correlated with the dry air-induced generation of LTC(4), LTD( 4), and LTE(4). After treatment with MK-0591, AIB was correlated with thromboxane B-2, prostaglandin (PG) F-2 alpha, and PGE(2). We conclude that hyperpnea with dry air stimulates local production and release o f LTs in canine bronchi and, along with the generation of bronchoconst ricting and bronchodilating PGs, plays a central role in the modulatio n of AIB.