Cystic fibrosis airway epithelial cells have an exaggerated response to hypoxia that is partially reversible through transmembrane receptor modulation.

The pathophysiology of cystic fibrosis (CF) leads to epithelial cell hypoxia, which directly affects epithelial cells. CF is caused by genetic disruption of the CF transmembrane receptor that has important direct impacts on cell signaling and proteotoxic stress, and indirect impacts through microbiome alterations. How these alterations impact hypoxia signaling is not known. We collected primary human airway cells from explanted lungs of individuals with or without CF, differentiated them at air-liquid interface, and subjected them to short-term hypoxia. Differential gene expression was assessed by RNAseq, with findings validated by flow cytometry. We also assessed the impacts of modulator therapies on CF epithelial cells. While there was overlap in the transcriptomic response to hypoxia between CF and referent epithelial cells, CF cells activated additional pathways. In CF cells under hypoxia, activation of the hypoxia pathway was associated with HIF1α, EMT, and immune-related pathways, the latter not seen in referent cells. Among HIF1α related genes, VEGF was uniquely increased in cells from CF, and its expression was modulated through HIF1α signaling. We show that correction of CFTR blunts exaggerated response to hypoxia in CF cells. These results suggest CF airway cells have an exacerbated response to hypoxia, which may be alleviated through the correction of misfolded CFTR.