HIF-1alpha inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium.

摘要

Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a critical role in immune and inflammatory responses. One of the HIF-1alpha 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-1alpha activation and the role of HIF-1alpha in the pathogenesis of allergic airway disease were investigated. Transfection of airway epithelial cells with HIF-1alpha siRNA suppressed VEGF expression. In addition, the increased levels of HIF-1alpha and VEGF in lung tissues after OVA inhalation were substantially decreased by an HIF-1alpha 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 p110delta isoform (PI3K-delta) or HIF-1alpha reduced OVA-induced HIF-1alpha activation in airway epithelial cells. These findings indicate that HIF-1alpha 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-1alpha activation.