2-Methoxyestradiol (2-ME) reduces the airway inflammation and remodeling in an experimental mouse model
2-Methoxyestradiol (2-ME) reduces the airway inflammation and remodeling in an experimental mouse model
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DOI：
10.1016/j.clim.2008.07.023
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发表时间：
2008-11-01
影响因子：
8.6
通讯作者：
Bonavida, B.
中科院分区：
文献类型：
--
作者：
Huerta-Yepez, S.;Baay-Guzman, G. J.;Bonavida, B.
哮喘患者在持续的炎症反应中会经历呼吸道结构的改变，称为气道重塑。2-甲氧基雌二醇(2-ME)是一种抗血管生成剂，可下调缺氧诱导因子1(HIF-1)的表达，抑制HIF-1α诱导的血管内皮生长因子(VEGF)的转录激活。我们推测2-ME可能干扰哮喘临床表现的发展。我们使用了BALB/c小鼠过敏性呼吸道炎症伴上皮下纤维化的慢性小鼠模型。用卵白蛋白(OVA)致敏小鼠，OVA在0-5天给小鼠腹腔注射，12-22天用OVA气管内激发(IT)。小鼠分别于第24、26、28天接受2-MEIT，第32天处死。致敏/挑战的小鼠出现了广泛的呼吸道细胞炎症反应。2-ME可明显减少血管周围和支气管周围肺组织的细胞浸润，减少杯状粘液的产生，减轻气道纤维化，减少血管和平滑肌厚度，减少嗜酸性粒细胞的浸润。经2-ME处理的小鼠肺组织血管周围、支气管周围和间质中HIF-1和VEGF的表达显著减少。与未处理的小鼠相比，2-ME处理的小鼠的IV型胶原表达也显著减少。2-ME治疗与OVA特异性IgE抗体显著降低有关。这些发现首次表明，IT注射2-ME在预防和逆转抗原诱导的OVA过敏原炎症小鼠模型中的气道重构方面是有效的。对2-ME在患者中的潜在作用进行了讨论。(C)2008 Elsevier Inc.保留所有权利。
Patients with asthma experience airway structural changes, termed airway remodeling, in response to persistent inflammation. 2-Methoxyestradiol (2-ME) is an anti-angiogenic agent and downregulates hypoxia-inducible factor 1 (HIF-1) and inhibits HIF-1 alpha-induced transcriptional activation of vascular endothelial growth factor (VEGF) expression. We hypothesized that 2-ME may interfere with the development of the clinical manifestations of asthma. We used a chronic murine model of allergic airway inflammation with subepithelial fibrosis in BALB/c mice. Mice were sensitized with ovalbumin (OVA) that was administered intraperitoneally at days 0-5 and challenged intratracheally (IT) with OVA on days 12-22. The mice received 2-ME IT at days 24, 26 and 28 and sacrificed at day 32. The sensitized/challenged mice developed an extensive cell inflammatory response of the airways. 2-ME administration significantly reduced the cellular infiltrate in the perivascular and peribronchial lung tissues, reduced goblet mucous production, reduced airway fibrosis and thickness of smooth muscle and blood vessels, and reduced eosinophil infiltration. Mice treated with 2-ME had a significant decrease of HIF-1 and VEGF expression in the perivascular, peribronchial, and interstitium of lung tissues. Collagen IV expression was also significantly reduced in 2-ME treated mice compared to untreated mice. The 2-ME treatment was associated with a significant decrease of OVA-specific IgE antibodies. These findings provide the first indication that IT administration of 2-ME is effective in preventing and reversing antigen-induced airway remodeling in the OVA allergen inflammatory murine model. The potential rote of 2-ME in patients is discussed. (C) 2008 Elsevier Inc. All rights reserved.