HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium
HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium
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DOI：
10.1002/eji.200939948
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发表时间：
2010-10-01
影响因子：
5.4
通讯作者：
Lee, Yong Chul
中科院分区：
文献类型：
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作者：
Kim, So Ri;Lee, Kyung Sun;Lee, Yong Chul
缺氧诱导因子-1α(HIF-1α)在免疫和炎症反应中起重要作用。血管内皮生长因子(VEGF)是HIF-1α的靶基因之一，它是过敏性呼吸道疾病炎症、气道重塑和生理失调的有力刺激因子。利用卵清蛋白处理的小鼠和小鼠气管上皮细胞，研究了参与HIF-1α激活的信号网络以及HIF-1α在过敏性呼吸道疾病发病机制中的作用。转染HIF-1αsiRNA的呼吸道上皮细胞可抑制血管内皮生长因子的表达。此外，吸入OVA后肺组织中HIF-1α和VEGF水平的增加可被HIF-1α抑制剂2-甲氧基雌二醇显著降低。我们的数据还显示，吸入OVA后炎症细胞数量增加，呼吸道高反应性增加，IL-4，IL-5，IL-13水平和肺血管通透性显著降低，2-甲氧基雌二醇或血管内皮生长因子抑制剂CBO-P11显著降低。此外，我们发现抑制PI3K p110 Delta异构体(PI3K-Delta)或HIF-1α可降低OVA诱导的呼吸道上皮细胞中HIF-1α的激活。这些结果表明，抑制HIF-1α可能通过调节血管内皮生长因子介导的血管渗漏来减轻抗原诱导的气道炎症和高反应性，而PI3K-Delta信号可能参与了变应原诱导的HIF-1α的激活。
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays a critical role in immune and inflammatory responses. One of the HIF-1 alpha target genes is vascular endothelial growth factor (VEGF), which is a potent stimulator of inflammation, airway remodeling, and physiologic dysregulation in allergic airway diseases. Using OVA-treated mice and murine tracheal epithelial cells, the signaling networks involved in HIF-1 alpha activation and the role of HIF-1 alpha in the pathogenesis of allergic airway disease were investigated. Transfection of airway epithelial cells with HIF-1 alpha siRNA suppressed VEGF expression. In addition, the increased levels of HIF-1 alpha and VEGF in lung tissues after OVA inhalation were substantially decreased by an HIF-1 alpha inhibitor, 2-methoxyestradiol. Our data also show that the increased numbers of inflammatory cells, increased airway hyperresponsiveness, levels of IL-4, IL-5, IL-13, and vascular permeability in the lungs after OVA inhalation were significantly reduced by 2-methoxyestradiol or a VEGF inhibitor, CBO-P11. Moreover, we found that inhibition of the PI3K p110 delta isoform (PI3K-delta) or HIF-1 alpha reduced OVA-induced HIF-1 alpha activation in airway epithelial cells. These findings indicate that HIF-1 alpha inhibition may attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular leakage mediated by VEGF, and that PI3K-delta signaling may be involved in the allergen-induced HIF-1 alpha activation.