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Previous studies have shown that the experimental models of hypoxia-reoxygenation (H/R) mimics the physiological conditions of ischemia-reperfusion and induce oxidative stress and injury in various types of organs, tissues, and cells, both  in vivo  and  in vitro , including human lung adenocarcinoma epithelial cells. Nonetheless, it had not been reported whether H/R affected proliferation, apoptosis, and expression of stem/progenitor cell markers in the bronchial epithelial cells. In this study, we investigated differential effects of consecutive hypoxia and intermittent 24/24-h cycles of H/R on human bronchial epithelial (HBE) cells derived from the same-race and age-matched healthy subjects (i.e., NHBE) and subjects with chronic obstructive pulmonary disease (COPD) (i.e., DHBE). To analyze gene/protein expression during differentiation, both the NHBE and DHBE cells at the 2nd passage were cultured at the air-liquid interface (ALI) in the differentiation medium under normoxia for 3 days, followed by either culturing under hypoxia (1% O 2 ) for consecutively 9 days and then returning to normoxia for another 9 days, or culturing under 24/24-h cycles of H/R (i.e., 24 h of 1% O 2  followed by 24 h of 21% O 2 , repetitively) for 18 days in total, so that all differentiating HBE cells were exposed to hypoxia for a total of 9 days. In both the normal and diseased HBE cells, intermittent H/R significantly increased  HIF1A ,  BMP4 ,  NOTCH1 ,  MKI67 ,  OCT4 , and  MUC5AC  expression, while consecutive hypoxia significantly decreased  NKX2-1 ,  NOTCH3 ,  HEY1 ,  CC10 , and  FOXJ1  expression. Inhibition of  HIF1A  or  NKX2-1  expression by siRNA transfection respectively decreased  BMP4 / NOTCH1 / MKI67 / OCT4 / MUC5AC  and  NOTCH3 / HEY1/CC10/FOXJ1  expression in the HBE cells cultured under intermittent H/R to the same levels under normoxia. Overexpression of  NKX2-1  via cDNA transfection caused more than 2.8-fold increases in  NOTCH3 ,  HEY1 , and  FOXJ1  mRNA levels in the HBE cells cultured under consecutive hypoxia compared to the levels under normoxia. Taken together, our results show for the first time that consecutive hypoxia decreased expression of the co-regulated gene module  NOTCH3/HEY1/CC10  and the ciliogenesis-inducing transcription factor gene  FOXJ1  via  NKX2-1  mRNA downregulation, while intermittent H/R increased expression of the co-regulated gene module  BMP4/NOTCH1/MKI67/OCT4  and the predominant airway mucin gene  MUC5AC  via  HIF1A  mRNA upregulation.

frontiers in cell and developmental biology

Consecutive Hypoxia Decreases Expression of NOTCH3, HEY1, CC10, and FOXJ1 via NKX2-1 Downregulation and Intermittent Hypoxia-Reoxygenation Increases Expression of BMP4, NOTCH1, MKI67, OCT4, and MUC5AC via HIF1A Upregulation in Human Bronchial Epithelial Cells