Prostaglandin E(2) (PGE(2)) inhibits the early and late bronchoconstrictor response to inhaled allergen. The mechanisms of action, however, are not understood. We investigated the effect of inhaled PGE(2) on the release of prostaglandin D(2) (PGD(2)), preformed mast cell mediators, and other products of arachidonic acid metabolism. We compared inhaled PGE(2) (100 microgram) to placebo in a randomized double-blind crossover study. Ten atopic asthmatics underwent bronchoscopy immediately after inhalation of PGE(2) or placebo. Bronchoalveolar lavage (BAL) was performed at baseline, and in a separate segment 4 min after allergen instillation. Nebulized PGE(2) was well tolerated. PGE(2) concentrations in baseline lavage fluid were significantly greater after PGE(2) inhalation than after placebo. PGD(2) concentrations after allergen challenge were significantly reduced in those subjects receiving nebulized PGE(2) compared with control subjects. We conclude that PGE(2) can be safely delivered by inhalation. Nebulized PGE(2) administered before to segmental allergen challenge reduced PGD(2) in BAL fluid (BALF). PGE(2) also decreased the production of other mediators of the arachidonic acid pathway, although not significantly. The reduction of PGD(2) may be part of the mechanism by which PGE(2) blocks the early asthmatic response.