Increased urinary excretion of the prostaglandin D2 metabolite 9α,11β-prostaglandin F2 after aspirin challenge supports mast cell activation in aspirin-induced airway obstruction,☆☆,,★★

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Abstract

Prostaglandin (PG)D2 is a major product of arachidonic acid metabolism in pulmonary mast cells. We therefore attempted to determine whether measurement of the stable urinary metabolite of PGD2, 9α,11β-PGF2, could serve as a marker of mast cell activation in the lungs. A commercially available enzyme immunoassay was validated and found to be specific and sensitive when applied to unpurified urine. There was no diurnal variation in the levels of 9α,11β-PGF2 in healthy volunteers. Morning baseline values of urinary 9α,11β-PGF2 were measured in three groups—healthy volunteers (n = 9), patients with atopic asthma (n = 14), and aspirin-intolerant patients with asthma (n = 12)—and found to be very similar, 54 ± 9, 62 ± 6, and 71 ± 15 ng/mmol creatinine, respectively (means ± SEM). Urinary excretion of 9α,11β-PGF2 was increased threefold immediately after allergen-induced bronchoconstriction in nine patients with atopic asthma. Bronchial challenge with inhaled lysine aspirin in eight aspirin-intolerant patients with asthma produced bronchoconstriction without extrapulmonary symptoms and was also followed by a significant increase in the urinary excretion of 9α,11β-PGF2. In addition, challenge with a higher dose of aspirin produced an even greater increase in urinary 9α,11β-PGF2, supporting dose-dependent release of PGD2 during aspirin-induced bronchoconstriction. In contrast, the postchallenge levels of urinary 9α,11β-PGF2 were not increased when bronchoconstriction was induced by histamine challenge in the aspirin-intolerant patients with asthma. The study confirms mast cell involvement in allergen-induced bronchoconstriction and provides novel data, which strongly support the hypothesis that pulmonary mast cells are activated during aspirin-induced airway obstruction. It is finally suggested that measurement of urinary 9α,11β-PGF2 with enzyme immunoassay may be used as a new noninvasive strategy to monitor mast cell activation in vivo. (J ALLERGY CLIN IMMUNOL 1996;98:421-32.)

Section snippets

Materials

Synthetic PGD2, PGF, 8-epi-PGF, 11-dehydro-thromboxane B2 and 13,14-dihydro-15-keto-PGF were obtained from Cayman Chemical Company (Ann Arbor, Mich.). Tritiated PGF ([5,6,8,9,11,12,14,15-3H]PGF, 168 Ci/mmol) was purchased from New England Nuclear (Boston, Mass.). Stock solutions of histamine diphosphate for the bronchoprovocations were prepared under good laboratory practice conditions by the hospital pharmacy and kept in the refrigerator until use. Crystalline lysine aspirin

Characteristics of the EIA for 9α,11β-PGF2

The specificity of the 9α,11β-PGF2 antibody was assessed in a series of cross-reactivity studies (Table I). The antibody proved to be highly specific for 9α,11β-PGF2, and neither PGF nor 8-epi-PGF caused any significant displacement of the tracer. The accuracy of the EIA for 9α,11β-PGF2 was assessed in both buffer and urine and was excellent (r2 = 0.99) (Fig. 1). The EIA was linear from 15.6 up to 200 pg/ml (Fig. 1). Samples exceeding this concentration were subsequently diluted to ensure

DISCUSSION

It is known that PGD2 is released in disorders involving mast cell activation, such as mastocytosis,21 but also in association with bronchoconstriction after allergen challenge in patients with atopic asthma. The levels of PGD2 in bronchoalveolar lavage fluid were found to be significantly increased after inhalation of 29 or endobronchial challenge with allergen.30 Furthermore, a recent study showed increases in the levels of PGD2, as well as its metabolite 9α,11β-PGF2, in bronchoalveolar

Acknowledgements

We thank the nurses, Heléne Blomqvist and Christina Larsson, at the Asthma and Allergy Research Unit, Division of Thoracic Medicine, Department of Internal Medicine, Karolinska Hospital and the technicians, Fatima Stensvad and Lilian Larsson, at the Department of Physiology and Pharmacology for excellent and dedicated assistance.

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      Citation Excerpt :

      Prostaglandins D2 (PGD2) and metabolites (11 β prostaglandin F2α) are released by lung mast cells and are major product of cyclooxygenase pathway that causes bronchoconstriction and vasodilation in the airways. Increased urinary PGD2 and 11βPGF2 were seen in asthmatic patients undergoing allergen or aspirin challenges [69]. The utility of these urinary biomarkers is limited to research and deserve further evaluation especially with the development of novel therapies that target PGD2 receptors (DP2 antagonists).

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    From aInstitute of Environmental Medicine, Karolinska Institutet; and the Departments of bMedical Biochemistry and Biophysics, cMedicine, and dPhysiology and Pharmacology at Karolinska Hospital, Stockholm.

    ☆☆

    Supported by grants from the Swedish Medical Research Council (projects 14X-09071, 03X-217), the Swedish Association Against Asthma and Allergy (RmA), the Swedish Heart Lung Foundation, the Swedish Society of Medicine, Stiftelsen Lars Hiertas minne, the Institute of Environmental Medicine, the Swedish Environmental Protection Board (312049), and Karolinska Institutet.

    Reprint requests: Siobhán O’Sullivan, Asthma and Allergy Research Group, Institute of Environmental Medicine, Karolinska Institutet, S-171 77, Stockholm, Sweden.

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