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.

Dexmedetomidine (DEX), a selective agonist of α 2 -adrenergic receptors, has anti-inflammation properties and potential beneficial effects against trauma, shock, or infection. Therefore, this study aimed to investigate whether DEX might protect against multiple-organ dysfunction in a two-hit model of hemorrhage/resuscitation (HS) and subsequent endotoxemia. Eighty Wistar rats were randomized into four groups: NS (normal saline), HS/L (HS plus lipopolysaccharide), HS/L+D (HS/L plus dexmedetomidine), and HS/L+D+Y (HS/L+D plus yohimbine). Six hours after resuscitation, blood gas (PaO 2 ) and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urine nitrogen (BUN), creatinine (Cr), TNF-α, IL-β, IL-6, IL-8, IL-10, and nitric oxide (NO) were measured. The histopathology was assayed by staining. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels and heme oxygenase-1 (HO-1) were assayed. The PaO 2 levels in HS/L rats were lower whereas the ALT, AST, BUN, Cr, TNF-α, IL-β, IL-6, IL-8, IL-10, and NO levels were higher compared to the control group. The HS/L+D increased PaO 2 and further increased IL-10 and decreased ALT, AST, BUN, Cr, TNF-α, IL-β, IL-6, IL-8, and NO levels of the HS/L groups. In addition, the MDA in the HS/L groups increased whereas SOD activity decreased compared to the control group. Moreover, the HO-1 expression levels were increased by DEX administration in lung, liver, and kidney tissues. Lungs, livers, and kidneys of the HS/L group displayed significant damage, but such damage was attenuated in the HS/L+D group. All of the above-mentioned effects of DEX were partly reversed by yohimbine. DEX reduced multiple organ injury caused by HS/L in rats, which may be mediated, at least in part, by α 2 -adrenergic receptors.

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.

Our previous studies have shown that Dexmedetomidine (Dex), α2 adrenergic receptor (α2AR) agonist, reduces pulmonary edema in LPS-induced acute lung injury (ALI), but the mechanism is not clear. The purpose of this study is to explore whether Dex promotes AFC by upregulating the expression of Na,K-ATPase in LPS-induced ALI and possible molecular mechanisms. Histology of the lungs was assayed with H-E staining, and the lung injury score was calculated. PaO2, PaO2/FiO2 , the lung index, wet/dry (W/D) ratio of the lung tissues and alveolar fluid clearance(AFC) was measured; The concentrations of TNF-α, IL-1β, IL-6 in bronchoalveolar lavage fluid (BALF) and serum were measured. Myeloperoxidase (MPO) activity in lung tissues were determined. The apoptosis rate of A549 cells and the expression of Bcl-2 and Bax were evaluated. The expression of Na,K-ATPase , p-PI3K and p-Akt in vivo and in vitro were evaluated. Dex significantly alleviated lung tissue injury induced by LPS. Dex treatment reduced the W/D, lung index and MPO activity, increased PaO2, PaO2/FiO2 and AFC in LPS-induced ALI. In addition, Dex reduced the concentrations of TNF-α, IL-β and IL-6 in BALF and serum. Dex reduced the apoptosis rate, up-regulated the expression of Bcl-2 and down-regulated the expression of Bax in LPS-stimulated A549 cells. Furthermore, Dex increased the expression of α1Na,K-ATPase, β1 Na,K-ATPase and p-PI3K , p-Akt in vivo and vitro. However, these effects of Dex were partially reversed by the α2AR inhibitor yohim-bine or PI3K inhibitor LY294002. Collectively, these results suggest that Dex attenuates pulmonary edema by stimulating AFC via upregulating the Na,K-ATPase expressi-on in LPS-induced acute lung injury by modulating the α2AR/PI3K/Akt signaling pathway.