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

¹ Dept of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, and Depts of ³ Pharmacy and ⁴ Pharmacology, University of Sydney, Sydney, Australia² Division of Physiology, Unit for Experimental Asthma & Allergy Research, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, ⁵ Both authors contributed equally to this study.

CORRESPONDENCE: J. D. Brannan, Dept of Respiratory Medicine, 11 West, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia. Fax: 61 295158196. E-mail: johnb{at}med.usyd.edu.au

Keywords: Cromoglycate, formoterol, leukotriene E₄, mannitol, 9, 11ß-prostaglandin F₂

Received: July 4, 2005
Accepted December 16, 2005

Mannitol inhalation increases urinary excretion of 9,11ß-prostaglandin F₂ (a metabolite of prostaglandin D₂ and marker of mast cell activation) and leukotriene E₄. The present study tested the hypothesis that ß₂-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 µg), SCG (40 mg) or placebo. Pre- and post-challenge urine samples were analysed by enzyme immunoassay for 9,11ß-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 9,11ß-prostaglandin F₂ concentration from 61 to 92 ng·mmol creatinine^–1, but no significant increase in 9,11ß-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.

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