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Hypoxia Modulates Epithelial Permeability via Regulation of Vascular Endothelial Growth Factor in Airway Epithelia

 Hyun-Ah Song  ;  Yoo-Suk Kim  ;  Hyung-Ju Cho  ;  Soo In Kim  ;  Min Jung Kang  ;  Ji Hyun Kim  ;  Hyun Jin Min  ;  Ju-Wan Kang  ;  Joo-Heon Yoon  ;  Chang-Hoon Kim 
 American Journal of Respiratory Cell and Molecular Biology, Vol.57(5) : 527-535, 2017 
Journal Title
 American Journal of Respiratory Cell and Molecular Biology 
Issue Date
Animals ; Cell Hypoxia ; Cell Membrane Permeability ; Epithelial Cells/metabolism ; Epithelium/metabolism* ; Epithelium/physiopathology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; RNA, Small Interfering/metabolism ; Transcriptional Activation/physiology ; Up-Regulation ; Vascular Endothelial Growth Factor A/metabolism*
hypoxia ; hypoxia-inducible factor-1 ; paracellular permeability ; sinusitis ; vascular endothelial growth factor
Hypoxia resulting from occlusion of the sinus ostium is known to be one of the major pathogenic mechanisms of sinusitis. Hypoxia-inducible factor (HIF)-1 is a widely known transcription factor that induces the cellular response to hypoxic conditions and activates the transcription of several genes, including vascular endothelial growth factor (VEGF). We hypothesized that induced permeability caused by hypoxia is a major pathophysiologic mechanism of upper airway diseases, such as sinusitis. The aim of this study was to investigate the mechanism of hypoxia-induced hyperpermeability, which mediates increased paracellular permeability and enhanced microbial invasiveness in the airway epithelium. We show that expression of VEGF mRNA and protein and HIF-1α protein increased as a function of time under hypoxia in normal human nasal epithelial cells. Our results also indicate that VEGF expression was induced by transfection with a mammalian expression vector encoding HIF-1 but down-regulated by transfection with small interfering RNA specific for HIF-1α under hypoxic conditions. Results of a transepithelial permeability assay measuring transepithelial electrical resistance indicated that permeability was increased as a function of time under hypoxia and was rescued by anti-VEGF monoclonal antibody (bevacizumab) and small interfering RNA specific for HIF-1α. We detected up-regulated HIF-1α and VEGF expression in mucosal epithelium samples from patients with sinusitis compared with normal mucosal epithelium using Western blotting and immunohistochemical staining. In conclusion, we suggest that the hypoxia-HIF-1α-VEGF axis plays an important role in hyperpermeability of airway epithelial cells, implying a role in the pathophysiology of upper respiratory tract diseases, such as sinusitis.
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1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Chang Hoon(김창훈) ORCID logo https://orcid.org/0000-0003-1238-6396
Cho, Hyung Ju(조형주) ORCID logo https://orcid.org/0000-0002-2851-3225
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