Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor - 06/08/18
, Johan Bood, MD, PhD a, b, ∗, Cristina Gomez, PhD b, c, ∗, Johan Kolmert, MSc b, c, ∗, Ann-Sofie Lantz, RN a, ∗, Pär Gyllfors, MD, PhD d, Andy Davis, PhD e, Craig E. Wheelock, PhD c, ∗, Sven-Erik Dahlén, MD, PhD b, ∗, Barbro Dahlén, MD, PhD a, ∗Cet article a été publié dans un numéro de la revue, cliquez ici pour y accéder
Abstract |
Background |
Leukotriene (LT) E4 is the final active metabolite among the cysteinyl leukotrienes (CysLTs). Animal studies have identified a distinct LTE4 receptor, suggesting that current cysteinyl leukotriene type 1 (CysLT1) receptor antagonists can provide incomplete inhibition of CysLT responses.
Objective |
We tested this hypothesis by assessing the influence of the CysLT1 antagonist montelukast on responses induced by means of inhalation of LTE4 in asthmatic patients.
Methods |
Fourteen patients with mild intermittent asthma and 2 patients with aspirin-exacerbated respiratory disease received 20 mg of montelukast twice daily and placebo for 5 to 7 days in a randomized, double-blind, crossover study (NCT01841164). The PD20 value was determined at the end of each treatment period based on an increasing dose challenge. Measurements included lipid mediators in urine and sputum cells 4 hours after LTE4 challenge.
Results |
Montelukast completely blocked LTE4-induced bronchoconstriction. Despite tolerating an at least 10 times higher dose of LTE4 after montelukast, there was no difference in the percentage of eosinophils in sputum. Urinary excretion of all major lipid mediators increased after LTE4 inhalation. Montelukast blocked release of the mast cell product prostaglandin (PG) D2, as well as release of PGF2α and thromboxane (Tx) A2, but not increased excretion of PGE2 and its metabolites or isoprostanes.
Conclusion |
LTE4 induces airflow obstruction and mast cell activation through the CysLT1 receptor.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Asthma, cysteinyl leukotrienes, receptors, bronchoconstriction, mast cells, sputum cells, leukotrienes, mass spectrometry, lipid mediators in urine
Abbreviations used : AERD, CysLT, CysLT1, Feno, IOS, LT, PG, TX
Plan
| Supported by the Swedish Heart-Lung Foundation, MRC, Stockholm County Council Research Funds (ALF), and the Asthma and Allergy Research Foundation. The ChAMP (Centre for Allergy Research Highlights Asthma Markers of Phenotype) consortium is funded by the Swedish Foundation for Strategic Research, the Karolinska Institutet, AstraZeneca & Science for Life Laboratory Joint Research Collaboration, and the Vårdal Foundation. C.G. and J.K. were supported by U-BIOPRED (IMI initiative for severe asthma). C.E.W. was supported by the Swedish Heart-Lung Foundation (HLF 20150640). |
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| Disclosure of potential conflict of interest: A. Davis reports employment from AstraZeneca AB. S.-E. Dahlén reports personal fees from Merck, GlaxoSmithKline, Regeneron-Sanofi, Teva, and RSPR Pharma and grants and personal fees from AstraZeneca. B. Dahlén reports personal fees from AstraZeneca and Teva. The rest of the authors declare that they have no relevant conflicts of interest. |
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