Hyperoxia can lead to a myriad of deleterious effects in the lung including epithelial damage and diffuse
inflammation. The specific mechanisms by which
hyperoxia promotes these pathological changes are not completely understood. Activation of
ion channels has been proposed as one of the mechanisms required for cell activation and mediator secretion. The two-pore-domain K(+) channel (K2P)
Trek-1 has recently been described in lung epithelial cells, but its function remains elusive. In this study we hypothesized that
hyperoxia affects expression of
Trek-1 in alveolar epithelial cells and that
Trek-1 is involved in regulation of cell proliferation and
cytokine secretion. We found gene expression of several K2P channels in mouse alveolar epithelial cells (MLE-12), and expression of
Trek-1 was significantly downregulated in cultured cells and lungs of mice exposed to
hyperoxia. Similarly, proliferation cell
nuclear antigen (
PCNA) and
Cyclin D1 expression were downregulated by exposure to
hyperoxia. We developed an MLE-12 cell line deficient in
Trek-1 expression using
shRNA and found that
Trek-1 deficiency resulted in increased cell proliferation and upregulation of
PCNA but not
Cyclin D1. Furthermore,
IL-6 and regulated on activation normal T-expressed and presumably secreted (
RANTES) secretion was decreased in Trek-1-deficient cells, whereas release of
monocyte chemoattractant protein-1 was increased. Release of KC/IL-8 was not affected by
Trek-1 deficiency. Overall, deficiency of
Trek-1 had a more pronounced effect on mediator secretion than exposure to
hyperoxia. This is the first report suggesting that the K(+) channel
Trek-1 could be involved in regulation of alveolar epithelial cell proliferation and
cytokine secretion, but a direct association with
hyperoxia-induced changes in
Trek-1 levels remains elusive.