Inhibition of mast cell PGD2 release protects against mannitol-induced airway narrowing.
Mannitol inhalation increases urinary excretion of 9alpha,11beta-prostaglandin F2 (a metabolite of prostaglandin D2 and marker of mast cell activation) and leukotriene E4. The present study tested the hypothesis that beta2-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 > or = 25%. The same dose was given 15 min after inhalation of formoterol fumarate (24 microg), SCG (40 mg) or placebo. Pre- and post-challenge urine samples were analysed by enzyme immunoassay for 9alpha,11beta-prostaglandin F2 and leukotriene E4. 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 9alpha,11beta-prostaglandin F2 concentration from 61 to 92 ng.mmol creatinine(-1), but no significant increase in 9alpha,11beta-prostaglandin F2 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 E4 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 D2 release.
Brannan
J D
JD
Dept of Respiratory Medicine, 11 West, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia. johnb@med.usyd.edu.au
Gulliksson
M
M
Anderson
S D
SD
Chew
N
N
Seale
J P
JP
Kumlin
M
M
D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000187:drug effects*; D004205:Cromolyn Sodium / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D008353:Mannitol / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000652:urine
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D008353:Mannitol; D004205:Cromolyn Sodium; D015230:Prostaglandin D2; D000068759:Formoterol Fumarate