期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 40, 期 10, 页码 2858-2869出版社
WILEY
DOI: 10.1002/eji.200939948
关键词
Allergic airway disease; Hypoxia-inducible factor-1 alpha; PI3K-delta; RNA interference; Vascular endothelial growth factor
类别
资金
- Ministry for Health, Welfare and Family Affairs, Republic of Korea [A084144]
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.
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