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首页> 外文期刊>Clinical and experimental allergy : >Blockade of cysteinyl leukotriene-1 receptors suppresses airway remodelling in mice overexpressing GATA-3.
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Blockade of cysteinyl leukotriene-1 receptors suppresses airway remodelling in mice overexpressing GATA-3.

机译：半胱氨酰白三烯1受体的阻滞抑制了过表达GATA-3的小鼠的气道重塑。

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BACKGROUND: We demonstrated previously that GATA-3 overexpression markedly enhanced allergen-induced airway inflammation and airway remodelling, including subepithelial fibrosis, and smooth muscle cell hyperplasia, in transgenic mice. OBJECTIVE: Because cysteinyl leukotrienes (cysLTs) have been shown to be involved in such structural changes, the effects of a specific cysLT1 receptor antagonist, montelukast, were evaluated in a mouse model of chronic asthma. METHODS: GATA-3-overexpressing mice and wild-type Balb/c mice were sensitized and repeatedly challenged by ovalbumin (OVA) or saline. The effects of montelukast on the development of airway remodelling were compared between the two mouse genotypes. RESULTS: CysLTs in the lung were increased after repeated allergen challenges, and significantly enhanced in GATA-3-overexpressing mice. The enhanced cysLT levels were accompanied by the development of eosinophilia, smooth muscle cell hyperplasia, and increased stromal cell-derived factor-1 gene expression with a small increase in pro-collagen gene expression in OVA-challenged GATA-3-overexpressing mice, but not in wild-type mice. Montelukast significantly decreased lung cysLT levels and inhibited the GATA-3-overexpression-related airway remodelling, potently preventing smooth muscle cell hyperplasia, but partially suppressed the increased pro-collagen gene expression and eosinophilic inflammation. Increases in the levels of IL-4, IL-5, IL-13, and eotaxin in bronchial lavage and TGF-beta gene expression in the lungs were induced by OVA in both mouse genotypes. Montelukast treatment also significantly reduced these levels to the levels seen after saline challenges in GATA-3-overexpressing mice. CONCLUSION: Montelukast efficaciously prevented airway inflammation and remodelling in a GATA-3-overexpression antigen challenge mouse model by decreasing the cysLT-driven Th2 cytokine cycle of amplification of airway pathologies.
机译：背景：我们先前证明，GATA-3的过表达在转基因小鼠中显着增强了变应原诱导的气道炎症和气道重塑，包括上皮下纤维化和平滑肌细胞增生。目的：由于半胱氨酰白三烯（cysLTs）已被证明参与这种结构变化，因此在慢性哮喘小鼠模型中评估了一种特定的cysLT1受体拮抗剂孟鲁司特的作用。方法：过表达GATA-3的小鼠和野生型Balb / c小鼠被卵清蛋白（OVA）或生理盐水反复刺激。在两种小鼠基因型之间比较了孟鲁司特对气道重塑发展的影响。结果：反复过敏原攻击后，肺中的CysLTs升高，并且在GATA-3过表达的小鼠中显着增强。增强的cysLT水平伴随着嗜酸性粒细胞增多，平滑肌细胞增生和基质细胞衍生的factor-1基因表达增加，而在OVA攻击的GATA-3过表达小鼠中，胶原蛋白基因表达的增加很小，但是不在野生型小鼠中。孟鲁司特显着降低肺cysLT水平并抑制GATA-3过表达相关的气道重塑，有效预防平滑肌细胞增生，但部分抑制了促胶原基因表达的增加和嗜酸性粒细胞的炎症。两种基因型的OVA均可诱导支气管灌洗中IL-4，IL-5，IL-13和嗜酸细胞活化趋化因子水平的升高以及肺中TGF-β基因的表达。孟鲁司特治疗还可以将这些水平显着降低至在过表达GATA-3的小鼠中加生理盐水后所见的水平。结论：孟鲁司特通过减少cysLT驱动的Th2细胞因子循环的放大，有效地预防了GATA-3过表达抗原攻击小鼠模型中的气道炎症和重塑。

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