Hypoxia resulting from occlusion of the sinus ostium is known to be one of the major pathogenic mechanisms of sinusitis. Hypoxiainducible 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 ofVEGFmRNAand protein andHIF-1a 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 transfectionwith amammalian expressionvector encoding HIF-1 but down-regulated by transfection with small interfering RNA specific for HIF-1a 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-1a.We detected up-regulated HIF-1a 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-1a-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.
|Number of pages||9|
|Journal||American Journal of Respiratory Cell and Molecular Biology|
|Publication status||Published - 2017 Nov|
Bibliographical noteFunding Information:
This work was supported by the Bio and Medical Technology Development Program of the National Research Foundation (NRF) funded by the ministry of Science, ICT, and Future Planning grant NRF-2016M3A9D5A01952414 (C.-H.K.), by the Basic Science Research Program through the NRF of Korea funded by Ministry of Education grant 2015R1D1A1A02062228 (C.-H.K.), and by the NRF of Korea funded through the Korean Government (MSIP), grant 2016R1A5A2008630 (C.-H.K.).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Pulmonary and Respiratory Medicine
- Clinical Biochemistry
- Cell Biology