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J Allergy Clin Immunol. 2018 Oct;142(4):1080-1089. doi: 10.1016/j.jaci.2018.02.024. Epub 2018 Mar 5.

Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor.

Author information

1
Division of Respiratory Medicine and Allergy, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden. Electronic address: nikolaos.lazarinis@ki.se.
2
Division of Respiratory Medicine and Allergy, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden; Unit of Experimental Asthma and Allergy Research, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
3
Unit of Experimental Asthma and Allergy Research, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
4
Division of Respiratory Medicine and Allergy, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
5
Stockholm Asthma and Allergy Clinic, Stockholm, Sweden.
6
AstraZeneca Pharmaceuticals, Mölndal, Sweden.
7
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
8
Unit of Experimental Asthma and Allergy Research, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

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 PGF 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.

KEYWORDS:

Asthma; bronchoconstriction; cysteinyl leukotrienes; leukotrienes; lipid mediators in urine; mass spectrometry; mast cells; receptors; sputum cells

PMID:
29518425
DOI:
10.1016/j.jaci.2018.02.024
[Indexed for MEDLINE]

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