OBJECTIVE: To investigate the influence of MCTRs on IL-13-induced airway hyperresponsiveness in isolated human and mice airways.
METHODS: Before responsiveness to contractile agonists were assessed in myographs, human small bronchi were cultured for 2 days and mouse tracheas were cultured for 1-4 days. During the culture procedure airways were exposed to interleukin (IL)-13 in the presence or absence of MCTRs. Signalling mechanisms were explored using pharmacologic agonists and antagonists, and genetically modified mice.
RESULTS: IL-13 treatment increased contractions to histamine, carbachol and leukotriene D4 (LTD4) in human small bronchi, and to 5-hydroxytryptamine (5-HT) in mouse trachea. In both preparations, co-incubation of the explanted tissues with MCTR3 reduced the IL-13 induced enhancement of contractions. In mouse trachea, this inhibitory effect of MCTR3 was blocked by three different CysLT1 receptor antagonists (montelukast, zafirlukast and pobilukast) during IL-13 exposure. Likewise, MCTR3 failed to reduce the IL-13-induced 5-HT responsiveness in mice deficient of the CysLT1 receptor. However, co-incubation with the classical CysLT1 receptor agonist LTD4 did not alter the IL-13-induced 5-HT hyperreactivity.
CONCLUSIONS: MCTR3, but not LTD4, decreased the IL-13-induced airway hyperresponsiveness by activation of the CysLT1 receptor. The distinct actions of the two lipid mediators on the CysLT1 receptor suggest an alternative signalling pathway appearing under inflammatory conditions, where this new action of MCTR3 implicates potential to inhibit airway hyperresponsiveness in asthma.
目的:研究MCTRs对IL-13诱导的人和小鼠气道高反应性的影响。
方法:在肌电图中评估对收缩激动剂的反应之前,人小支气管培养2天,小鼠气管培养1-4天。在培养过程中,在存在或不存在MCTR的情况下,将气道暴露于白介素(IL)-13。使用药理学激动剂和拮抗剂探索信号机制,和转基因小鼠。
结果:IL-13治疗增加了对组胺的收缩,人体小支气管中的卡巴胆碱和白三烯D4(LTD4),和小鼠气管中的5-羟色胺(5-HT)。在这两种准备中,外植组织与MCTR3的共孵育减少了IL-13诱导的收缩增强。在小鼠气管中,MCTR3的这种抑制作用被三种不同的CysLT1受体拮抗剂阻断(孟鲁司特,扎鲁司特和泊鲁司特)在IL-13暴露期间。同样,MCTR3未能降低缺乏CysLT1受体的小鼠中IL-13诱导的5-HT反应性。然而,与经典CysLT1受体激动剂LTD4共孵育不会改变IL-13诱导的5-HT高反应性。
结论:MCTR3,而不是LTD4,通过激活CysLT1受体降低IL-13诱导的气道高反应性。两种脂质介质对CysLT1受体的不同作用表明在炎症条件下出现的替代信号通路。MCTR3的这种新作用暗示了抑制哮喘气道高反应性的潜力。