title: HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium.
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.
authors.affiliation: Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea.
authors.forename: So Ri
authors.initials: SR
authors.lastname: Kim
authors.forename: Kyung Sun
authors.initials: KS
authors.lastname: Lee
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Park
authors.forename: Seoung Ju
authors.initials: SJ
authors.lastname: Park
authors.forename: Kyung Hoon
authors.initials: KH
authors.lastname: Min
authors.forename: Hee
authors.initials: H
authors.lastname: Moon
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Lee
mesh_terms: D000077584:2-Methoxyestradiol; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D056151:Airway Remodeling / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004847:Epithelial Cells; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006651:Histocytochemistry; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D010456:Peptides, Cyclic / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D012129:Respiratory Function Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*
chemical_list: D000077584:2-Methoxyestradiol; D000225:Adenine; D016228:Endothelial Growth Factors; D004958:Estradiol; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010047:Ovalbumin; D010456:Peptides, Cyclic; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D012313:RNA; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C497443:Hif1a protein, mouse; C477872:IC 87114; C478485:cyclo-VEGI