Leukotriene E4 induces airflow obstruction and mast cell activation via the CysLT1 receptor

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Nikolaos Lazarinis, Johan Bood, Cristina Gomez, Johan Kolmert, Ann-Sofie Lantz, Pär Gyllfors, Andy Davis, Craig E. Wheelock, Sven-Erik Dahlén, Barbro Dahlén
BackgroundLeukotriene E4 (LTE4) is the final active metabolite among the cysteinyl leukotrienes (CysLTs). Animal studies have identified a distinct LTE4 receptor, suggesting that current CysLT1 receptor antagonists may provide incomplete inhibition of CysLT responses.ObjectiveWe tested this hypothesis by assessing the influence of the CysLT1 antagonist montelukast on responses induced by inhalation of LTE4 in asthmatic subjects.MethodsFourteen subjects with mild intermittent asthma and two subjects with aspirin exacerbated respiratory disease (AERD) received montelukast 20 mg bid and placebo for 5-7 days in a randomized, double blind, crossover study (NCT01841164). The provocative dose of LTE4 causing 20% fall in FEV1 (PD20) was determined at the end of each treatment period by a rising dose challenge. Measurements included lipid mediators in urine and sputum cells 4 hours post LTE4 challenge.ResultsMontelukast completely blocked the LTE4 induced bronchoconstriction. Despite tolerating at least 10 times higher dose of LTE4 after montelukast, there was no difference in the percentage of eosinophils in sputum. The urinary excretion of all major lipid mediators increased after the LTE4 inhalation. Montelukast blocked the release of the mast cell product prostaglandin (PG) D2, as well as the release of PGF2α, and thromboxane, but not the increased excretion of PGE2 and its metabolites nor isoprostanes.ConclusionLeukotriene E4 induces airflow obstruction and mast cell activation via the CysLT1 receptor.CLINICAL IMPLICATIONSClinically available leukotriene antagonists protect against the airway obstruction and the pro-inflammatory effects of the terminal cysteinyl-leukotriene LTE4.

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Teaser

Animal experiments have found a specific LTE4 receptor. This study demonstrated that LTE4-induced bronchoconstriction in asthmatics was blocked by montelukast, and discovered that LTE4 also mediated activation of mast cells via the CysLT1 receptor.


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