Dexmedetomidine alleviates pulmonary edema through epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS- induced acute lung injury

Abstract

Abstract Background: Pulmonary edema is a hallmark in acute lung injury(ALI). Researchers have also revealed that dexmedetomidine (Dex) alleviate pulmonary edema following ALI, but the mechanism is unclear.The alveolar epithelial sodium channel (ENaC)-mediated alveolar fluid clearance (AFC) plays an important role in reducing pulmonary edema. In this study, we attempted to investigate the effect of Dex on ENaC in modulating AFC and its mechanism. Methods: LipopolysacchAride (LPS) was used to induce ALI in rat and alveolar epithelial cell injury in A549 cell. The rats were randomly allotted into the following groups: control, LPS, LPS+Dex, LPS+Dex+LY294002 (n = 6 per group). In vitro, cells (1×10 6 cells/cm 2 ) were subcultured in six-well plates, then cells were allotted into the following groups: control, LPS, LPS+Dex, LPS+Dex+LY294002. Results: In vivo, Dex markedly reduced pulmonary edema induced by LPS through promoting AFC.Moreover, Dex prevented LPS-induced downregulation of α-, β- and γ-ENaC expression. In A549 cells stimulated with LPS, Dex attanuated LPS-mediated cell injury and the downregulation of α-, β- and γ-ENaC expression. Howere, all of which was blocked by PI3K inhibitor LY294002,suggesting that the protective role of Dex is PI3K dependent. Additionaly, Dex increases the expression of phosphorylated Akt and reduces the expression of Need4-2 in vivo and vitro, while the LY294002 reverses the effect of Dex, indicating that Dex activates the PI3K/Akt/Nedd4-2 signaling pathway. C onclusio ns: Dex alleviates pulmonary edema by promoting AFC, and the mechanism is partly related to up-regulation of ENaC expression via PI3K/Akt/Nedd4-2 signaling pathway.