Inhibition of mast cell PGD2 release protects against mannitol-induced airway narrowing

Mannitol inhalation increases urinary excretion of 9 alpha,11 beta-prostaglandin F-2 (a metabolite of prostaglandin D-2 and marker of mast cell activation) and leukotriene E-4. The present study tested the hypothesis that beta(2)-adrenoreceptor agonists and disodium cromoglycate (SCG) protect against mannitol-induced bronchoconstriction by inhibition of mast cell mediator release. Fourteen asthmatic subjects inhaled mannitol (mean dose 252 +/- 213 mg) in order to induce a fall in forced expiratory volume in one second (FEV1) of >= 25%. The same dose was given 15 min after inhalation of formoterol fumarate (24 mu g), SCG (40 mg) or placebo. Pre- and post-challenge urine samples were analysed by enzyme immunoassay for 9 alpha,11 beta-prostaglandin F-2 and leukotriene E-4. The maximum fall in FEV1 of 32 +/- 10% on placebo was reduced by 95% following formoterol and 63% following SCG. Following placebo, there was an increase in median urinary 9 alpha,11 beta-prostaglandin F-2 concentration from 61 to 92 ng.mmol creatinine(-1), but no significant increase in 9 alpha,11 beta-prostaglandin F-2 concentration in the presence of either formoterol (69 versus 67 ng.mmol creatinine(-1)) or SCG (66 versus 60 ng.mmol creatinine(-1)). The increase in urinary leukotriene E-4 following placebo (from 19 to 31 ng.mmol creatinine(-1)) was unaffected by the drugs. These results support the hypothesis that the drug effect on airway response to mannitol is due to inhibition of mast cell prostaglandin D-2 release.