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

Eur J Immunol. 2010 Oct;40(10):2858-69. doi: 10.1002/eji.200939948.

Abstract

Hypoxia-inducible factor-1α (HIF-1α) plays a critical role in immune and inflammatory responses. One of the HIF-1α 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-1α activation and the role of HIF-1α in the pathogenesis of allergic airway disease were investigated. Transfection of airway epithelial cells with HIF-1α siRNA suppressed VEGF expression. In addition, the increased levels of HIF-1α and VEGF in lung tissues after OVA inhalation were substantially decreased by an HIF-1α 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 p110δ isoform (PI3K-δ) or HIF-1α reduced OVA-induced HIF-1α activation in airway epithelial cells. These findings indicate that HIF-1α inhibition may attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular leakage mediated by VEGF, and that PI3K-δ signaling may be involved in the allergen-induced HIF-1α activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Methoxyestradiol
  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Airway Remodeling / immunology*
  • Animals
  • Asthma / immunology*
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Endothelial Growth Factors / pharmacology
  • Epithelial Cells
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Female
  • Histocytochemistry
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Ovalbumin / immunology
  • Peptides, Cyclic / pharmacology
  • Phosphatidylinositol 3-Kinases / immunology
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinazolines / pharmacology
  • RNA / chemistry
  • RNA / genetics
  • RNA, Small Interfering / pharmacology
  • Respiratory Function Tests
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology
  • Specific Pathogen-Free Organisms
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / immunology*

Substances

  • Endothelial Growth Factors
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • IC 87114
  • Peptides, Cyclic
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinazolines
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • cyclo-VEGI
  • Estradiol
  • RNA
  • 2-Methoxyestradiol
  • Ovalbumin
  • Adenine