ic-87114 and Airway-Remodeling

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.

Topics: 2-Methoxyestradiol; Adenine; Airway Remodeling; Animals; Asthma; Bronchoalveolar Lavage Fluid; Endothelial Growth Factors; Epithelial Cells; Estradiol; Female; Histocytochemistry; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred C57BL; Ovalbumin; Peptides, Cyclic; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Quinazolines; Respiratory Function Tests; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Small Interfering; Signal Transduction; Specific Pathogen-Free Organisms; Vascular Endothelial Growth Factor A