scholarly journals Rosuvastatin Enhances Alveolar Fluid Clearance in Lipopolysaccharide-Induced Acute Lung Injury by Activating the Expression of Sodium Channel and Na,K-ATPase via the PI3K/AKT/Nedd4-2 Pathway

2021 ◽  
Vol Volume 14 ◽  
pp. 1537-1549
Author(s):  
Hao-Ran Xu ◽  
Qian Yang ◽  
Shu-Yang Xiang ◽  
Pu-Hong Zhang ◽  
Yang Ye ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Sodium Channel ◽  
Alveolar Fluid Clearance

scholarly journals Melatonin Attenuates Sepsis-Induced Acute Lung Injury Through Improvement of Epithelial Sodium Channel-Mediated Alveolar Fluid Clearance Via Activation of SIRT1/SGK1/Nedd4-2 Signaling Pathway

2020 ◽  
Vol 11 ◽  
Author(s):  
Jing Li ◽  
Longfei Liu ◽  
Xiaojun Zhou ◽  
Xianzhou Lu ◽  
Xianrong Liu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Sodium Channel ◽  
Signaling Pathway ◽  
Cecal Ligation ◽  
Weight Ratio ◽  
Epithelial Sodium Channel ◽  
Enzyme Linked Immunosorbent Assay ◽  
Alveolar Fluid Clearance ◽  
Protein Expressions

Acute lung injury is characterized by alveolar vascular barrier injury, and protein-rich pulmonary oedema. Alveolar fluid clearance is closely related to the prognosis of patients with acute lung injury. Melatonin has been shown to have a protective effect on multiple organ injury induced by sepsis. In this study we investigated the effect of melatonin on alveolar fluid clearance (AFC) and explored its potential mechanisms in sepsis-induced acute lung injury. The cecal ligation and puncture was adopted to establish mouse sepsis model. Morphological changes of lung tissues with the hematoxylin staining were observed. AFC and lung wet/dry weight ratio were measured to assess pulmonary edema. Inflammatory mediators in bronchoalveolar lavage fluid were analyzed via enzyme-linked immunosorbent assay. NAD+/NADH and SIRT1 activity were measured by colorimetric assay kit. The protein expressions of epithelial sodium channel (ENaC), silent information regulator1 (SIRT1), SGK1 and Nedd4-2 were immunoblotted by western blot in vivo and in vitro. The distribution of α-ENaC and SIRT1 was detected by immunofluorescence. We found that melatonin attenuated sepsis induced lung injury, improved survival rate, enhanced alveolar fluid clearance, improved SIRT1 activity, increased protein expressions of SIRT1 and ENaC, and activated SGK1/Nedd4-2 pathway. Furthermore, SIRT1 inhibitor EX527 counteracted the effects of melatonin on alveolar fluid clearance and ENaC. These results revealed that melatonin enhanced ENaC-mediated AFC via the SIRT1/SGK1/Nedd4-2 signaling pathway. Our study demonstrated that melatonin might provide a novel therapeutic strategy for sepsis-induced acute lung injury.

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

2021 ◽  
Author(s):  
Yuanxu Jiang ◽  
Mingzhu Xia ◽  
Jing Xu ◽  
Qiang Huang ◽  
Zhongliang Dai ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Sodium Channel ◽  
Pulmonary Edema ◽  
Cell Injury ◽  
A549 Cells ◽  
Alveolar Epithelial ◽  
Phosphorylated Akt ◽  
Epithelial Sodium Channel Enac

AbstractDexmedetomidine (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.

scholarly journals Lipopolysaccharide Inhibits Alpha Epithelial Sodium Channel Expression via MiR-124-5p in Alveolar Type 2  Epithelial Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Yan Ding ◽  
Yong Cui ◽  
Zhiyu Zhou ◽  
Yapeng Hou ◽  
Xining Pang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Sodium Channel ◽  
Target Genes ◽  
Cell Model ◽  
Epithelial Sodium Channel ◽  
Alveolar Epithelial Cells ◽  
Luciferase Assay ◽  
Alveolar Type

Mesenchymal stem cells (MSCs) have been a potential strategy in the pretreatment of pulmonary diseases, while the mechanisms of MSCs-conditioned medium (MSCs-CM) involved with microRNAs on the regulation of lung ion transport are seldom reported. We investigated the role of miR-124-5p in lipopolysaccharide-involved epithelial sodium channel (ENaC) dysfunction and explored the potential target of miR-124-5p. We observed the lower expression of miR-124-5p after the administration of MSCs-CM, and the overexpression or inhibition of miR-124-5p regulated epithelial sodium channel α-subunit (α-ENaC) expression at protein levels in mouse alveolar type 2 epithelial (AT2) cells. We confirmed that α-ENaC is one of the target genes of miR-124-5p through dual luciferase assay and Ussing chamber assay revealed that miR-124-5p inhibited amiloride-sensitive currents associated with ENaC activity in intact H441 monolayers. Our results demonstrate that miR-124-5p can decrease the expression and function of α-ENaC in alveolar epithelial cells by targeting the 3′-UTR. The involvement of MSCs-CM in lipopolysaccharide-induced acute lung injury cell model could be related to the downregulation of miR-124-5p on α-ENaC, which may provide a new target for the treatment of acute lung injury.

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