title: Urinary excretion of lipid mediators in response to repeated eucapnic voluntary hyperpnea in asthmatic subjects.
abstract: Exercise-induced bronchoconstriction displays refractoriness manifested as a decreased response to repeated exercise challenge within hours. The refractoriness may be attenuated by inhibition of the biosynthesis of prostaglandins (PG). The aim of the study was to determine which PGs and other lipid mediators are excreted during the refractory period. First, 16 subjects with mild stable asthma performed two repeated 4-min challenges with eucapnic voluntary hyperpnea (EVH) 1 and 3 h apart. There was a similar degree of refractoriness in both protocols (∼15% protection). The 1-h interval was too short to study mediator excretion because the urinary levels did not return to baseline before the second challenge. With the 3-h protocol, there was increased urinary excretion of cysteinyl-leukotrienes and metabolites of the mast cell product PGD2 after both challenges. Next, another eight subjects performed two 6-min challenges with EVH 3 h apart, which produced a greater bronchoconstrictor response than the 4-min protocol (30.0 ± 5.4 vs. 17.7 ± 1.5%; P = 0.0029) and a greater degree of refractoriness (∼30%). Analysis by ultra-performance liquid chromatography triple quadrupole mass spectrometry confirmed excretion of the bronchoconstrictor cysteinyl-leukotrienes and PGD2 during both challenges. In addition, there was increased excretion of the bronchoprotective PGE2, and also of the main metabolite of PGI2. This is the first report of excretion of PGE2 and PGI2 during the refractory period to EVH challenge, suggesting that they may mediate the refractoriness. Maintained excretion of PGD2 and leukotriene E4 following the repeat challenge argues against mast cell mediator depletion as the mechanism of refractoriness.
authors.affiliation: Lung and Allergy Research, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden; Experimental Asthma and Allergy Research, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Johan.Bood@ki.se.
authors.forename: Johan R
authors.initials: JR
authors.lastname: Bood
authors.affiliation: Lung and Allergy Research, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Sundblad
authors.affiliation: Experimental Asthma and Allergy Research, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Ingrid
authors.initials: I
authors.lastname: Delin
authors.affiliation: Experimental Asthma and Allergy Research, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Marcus
authors.initials: M
authors.lastname: Sjödin
authors.affiliation: Lung and Allergy Research, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Kjell
authors.initials: K
authors.lastname: Larsson
authors.affiliation: Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Anderson
authors.affiliation: The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
authors.affiliation: Experimental Asthma and Allergy Research, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlén
authors.affiliation: Lung and Allergy Research, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden; The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Barbro
authors.initials: B
authors.lastname: Dahlén
mesh_terms: D000328:Adult; D001249:Asthma / Q000652:urine*; D015415:Biomarkers / Q000652:urine; D001985:Bronchial Provocation Tests / Q000379:methods; D016084:Bronchoconstriction; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000652:urine*; D008297:Male; D008875:Middle Aged; D011453:Prostaglandins / Q000652:urine*; D015656:Respiratory Mechanics; D014554:Urination; D055815:Young Adult
chemical_list: D015415:Biomarkers; D008055:Lipids; D011453:Prostaglandins
keywords: asthma; exercise-induced bronchoconstriction; leukotrienes; prostaglandins; refractoriness