Mechanism of leukotriene D 4-induced bronchoconstriction in normal subjects

Abstract

Leukotriene (LT) D 4 is a potent constrictor of human airways and a putative mediator of asthma. However, its mechanism of action in man has not been established. In the present study we sought to determine the role of upper airway reflexes, cholinergic pathways, and cyclooxygenase products of arachidonic acid metabolism in mediating LTD 4-induced bronchoconstriction in man. Six normal subjects underwent bronchoprovocation testing with LTD 4 after pretreatment with either aerosolized phosphate-buffered saline, aerosolized atropine (1.5 mg), aerosolized lidocaine (80 to 160 mg), or oral indomethacin (50 mg three times daily for 10 doses). Specific airway conductance (SG aw), the flow rate at 30% of vital capacity from a partial forced expiratory maneuver (V30P), and the FEV 1 were measured at each concentration of LTD 4. We calculated the provocative concentration of LTD 4 required to produce a 35% fall in SG aw (PC 35SG aw) or a 30% fall in V30P (PC 30V30P) and the slope of the LTD 4 dose-response curve. Atropine increased baseline SG aw 49% (p < 0.01) and V30P 43% (p < 0.005). Atropine also increased the PC 35SG aw and PC 30V30P and increased the slope of the LTD 4 dose-response curve. However, neither of these opposing effects was significant. Lidocaine had no effect on either baseline function or the airway response to LTD 4. Indomethacin produced small decreases in baseline V30P (12%) and FEV 1 (3%) (p < 0:05 for both), but it too had no effect on the airway response to LTD 4. These results indicate that the bronchoconstriction produced by aerosolized LTD 4 in normal subjects is not mediated by cyclooxygenase products of arachidonic acid metabolism or irritant receptors in the upper airways. Although cholinergic pathways may play some role, the data suggest that bronchoconstriction results, at least in part, from a direct effect of LTD 4 on airway smooth muscle.