Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor
Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor
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DOI：
10.1016/j.jaci.2018.02.024
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发表时间：
2018-10-01
影响因子：
14.2
通讯作者：
Dahlen, Barbro
中科院分区：
文献类型：
--
作者：
Lazarinis, Nikolaos;Bood, Johan;Dahlen, Barbro
背景：白三烯（LT） E-4是半胱氨酸白三烯（CysLTs）的最终活性代谢物。动物研究已经发现了一种独特的LTE4受体，这表明目前的半胱氨酸白三烯1型（CysLT(1)）受体拮抗剂可以提供不完全抑制CysLT反应。目的：我们通过评估CysLT(1)拮抗剂孟鲁司特对哮喘患者吸入LTE4诱导的反应的影响来验证这一假设。方法：在一项随机、双盲、交叉研究（NCT01841164）中，14例轻度间歇性哮喘患者和2例阿斯匹林加重呼吸系统疾病患者接受20 mg孟鲁司特治疗，每日2次，联合安慰剂治疗5 - 7天。在每个治疗期结束时，根据不断增加的剂量挑战确定PD20值。测量包括LTE4刺激后4小时尿液和痰细胞中的脂质介质。结果：孟鲁司特完全阻断lte4诱导的支气管收缩。尽管在孟鲁司特治疗后耐受了至少10倍的LTE4剂量，但痰中嗜酸性粒细胞的百分比没有差异。吸入LTE4后，尿中所有主要脂质介质的排泄均增加。孟鲁司特阻断肥大细胞产物前列腺素（PG） D-2的释放，以及PGF（2 α）和血栓素（Tx） A的释放(2)，但不增加PGE(2)及其代谢物或异前列腺素的排泄。结论：LTE4通过CysLT(1)受体诱导气流阻塞和肥大细胞活化。
Background: Leukotriene (LT) E-4 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 (CysLT(1)) receptor antagonists can provide incomplete inhibition of CysLT responses.Objective: We tested this hypothesis by assessing the influence of the CysLT(1) 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) D-2, as well as release of PGF(2 alpha) and thromboxane (Tx) A(2), but not increased excretion of PGE(2) and its metabolites or isoprostanes.Conclusion: LTE4 induces airflow obstruction and mast cell activation through the CysLT(1) receptor.