Dexmedetomidine (Dex), a highly selective α₂-adrenergic receptor (α₂AR) agonist, has an anti-inflammatory property and can alleviate pulmonary edema in lipopolysaccharide (LPS)-induced acute lung injury (ALI), but the mechanism is still unclear. In this study, we attempted to investigate the effect of Dex on alveolar epithelial sodium channel (ENaC) in the modulation of alveolar fluid clearance (AFC) and the underlying mechanism. Lipopolysaccharide (LPS) was used to induce acute lung injury (ALI) in rats and alveolar epithelial cell injury in A549 cells. In vivo, Dex markedly reduced pulmonary edema induced by LPS through promoting AFC, prevented LPS-induced downregulation of α-, β-, and γ-ENaC expression, attenuated inflammatory cell infiltration in lung tissue, reduced the concentrations of TNF-α, IL-1β, and IL-6, and increased concentrations of IL-10 in bronchoalveolar lavage fluid (BALF). In A549 cells stimulated with LPS, Dex attenuated LPS-mediated cell injury and the downregulation of α-, β-, and γ-ENaC expression. However, all of these effects were blocked by the PI3K inhibitor LY294002, suggesting that the protective role of Dex is PI3K-dependent. Additionally, Dex increased the expression of phosphorylated Akt and reduced the expression of Nedd4-2, while LY294002 reversed the effect of Dex in vivo and in vitro. Furthermore, insulin-like growth factor (IGF)-1, a PI3K agonists, promoted the expression of phosphorylated Akt and reduced the expression of Nedd4-2 in LPS-stimulated A549 cells, indicating that Dex worked through PI3K, and Akt and Nedd4-2 are downstream of PI3K. In conclusion, Dex alleviates pulmonary edema by suppressing inflammatory response in LPS-induced ALI, and the mechanism is partly related to the upregulation of ENaC expression via the PI3K/Akt/Nedd4-2 signaling pathway.

右美托咪定（Dex）是一种高选择性α ₂ -肾上腺素能受体（α ₂ AR）激动剂，具有抗炎特性，可以减轻脂多糖（LPS）引起的急性肺损伤（ALI）中的肺水肿，但其机制仍不清楚不清楚。在本研究中，我们试图探讨 Dex 对肺泡上皮钠通道 (ENaC) 在肺泡液清除率 (AFC) 调节中的影响及其潜在机制。脂多糖（LPS）用于诱导大鼠急性肺损伤（ALI）和A549细胞的肺泡上皮细胞损伤。在体内，Dex通过促进AFC显着减轻LPS引起的肺水肿，阻止LPS诱导的α-、β-和γ-ENaC表达下调，减弱肺组织炎症细胞浸润，降低TNF-α、IL浓度-1β、IL-6 以及支气管肺泡灌洗液 (BALF) 中 IL-10 浓度增加。在用 LPS 刺激的 A549 细胞中，Dex 减轻了 LPS 介导的细胞损伤以及 α-、β- 和 γ-ENaC 表达的下调。然而，所有这些作用均被 PI3K 抑制剂 LY294002 阻断，表明 Dex 的保护作用是 PI3K 依赖性的。此外，Dex 增加了磷酸化 Akt 的表达并减少了 Nedd4-2 的表达，而 LY294002 在体内和体外逆转了 Dex 的作用。此外，胰岛素样生长因子（IGF）-1（一种 PI3K 激动剂）在 LPS 刺激的 A549 细胞中促进磷酸化 Akt 的表达并减少 Nedd4-2 的表达，表明 Dex 通过 PI3K 发挥作用，而 Akt 和 Nedd4- 2是PI3K的下游。 总之，Dex通过抑制LPS诱导的ALI中的炎症反应来减轻肺水肿，其机制部分与通过PI3K/Akt/Nedd4-2信号通路上调ENaC表达有关。