scholarly journals Nadph oxidase regulates alveolar epithelial sodium channel (ENaC) activity and lung fluid balance in vivo via O 2 ‐ signaling

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
My N Helms ◽  
Preston Goodson ◽  
Lucky Jain ◽  
Michael Koval
Keyword(s):  
Nadph Oxidase ◽  
Sodium Channel ◽  
Fluid Balance ◽  
Epithelial Sodium Channel ◽  
Alveolar Epithelial ◽  
Lung Fluid ◽  
Lung Fluid Balance ◽  
Epithelial Sodium Channel Enac

scholarly journals Nadph oxidase regulates alveolar epithelial sodium channel activity and lung fluid balance in vivo via O2− signaling

2012 ◽  
Vol 302 (4) ◽  
pp. L410-L419 ◽  
Author(s):  
Preston Goodson ◽  
Amrita Kumar ◽  
Lucky Jain ◽  
Kousik Kundu ◽  
Niren Murthy ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Sodium Channel ◽  
Fluid Balance ◽  
Epithelial Sodium Channel ◽  
Ros Production ◽  
Open Probability ◽  
Lung Fluid ◽  
Lung Fluid Balance ◽  
Air Space

To define roles for reactive oxygen species (ROS) and epithelial sodium channel (ENaC) in maintaining lung fluid balance in vivo, we used two novel whole animal imaging approaches. Live X-ray fluoroscopy enabled quantification of air space fluid content of C57BL/6J mouse lungs challenged by intratracheal (IT) instillation of saline; results were confirmed by using conventional lung wet-to-dry weight ratios and Evans blue as measures of pulmonary edema. Visualization and quantification of ROS produced in lungs was performed in mice that had been administered a redox-sensitive dye, hydro-Cy7, by IT instillation. We found that inhibition of NADPH oxidase with a Rac-1 inhibitor, NSC23766, resulted in alveolar flooding, which correlated with a decrease in lung ROS production in vivo. Consistent with a role for Nox2 in alveolar fluid balance, Nox2−/− mice showed increased retention of air space fluid compared with wild-type controls. Interestingly, fluoroscopic analysis of C57BL/6J lungs IT instilled with LPS showed an acute stimulation of lung fluid clearance and ROS production in vivo that was abrogated by the ROS scavenger tetramethylpiperidine- N-oxyl (TEMPO). Acute application of LPS increased the activity of 20 pS nonselective ENaC channels in rat type 1 cells; the average number of channel and single-channel open probability ( NPo) increased from 0.14 ± 0.04 to 0.62 ± 0.23. Application of TEMPO to the same cell-attached recording caused an immediate significant decrease in ENaC NPo to 0.04 ± 0.03. These data demonstrate that, in vivo, ROS has the capacity to stimulate lung fluid clearance by increasing ENaC activity.

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

2020 ◽  
Author(s):  
Yuanxu Jiang ◽  
jing Xu ◽  
Qiang Huang ◽  
Wenjie Yang ◽  
Mingzhu Xia ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Sodium Channel ◽  
Pulmonary Edema ◽  
Signaling Pathway ◽  
Cell Injury ◽  
Epithelial Sodium Channel ◽  
Alveolar Epithelial ◽  
Epithelial Sodium Channel Enac

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.

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 Homocysteine Causes Endothelial Dysfunction via Inflammatory Factor-Mediated Activation of Epithelial Sodium Channel (ENaC)

2021 ◽  
Vol 9 ◽  
Author(s):  
Chen Liang ◽  
Qiu-Shi Wang ◽  
Xu Yang ◽  
Di Zhu ◽  
Yu Sun ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Nadph Oxidase ◽  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Inflammatory Factor ◽  
Aortic Endothelial Cells ◽  
Cox 2 ◽  
Epithelial Sodium Channel Enac ◽  
Aortic Endothelial

BackgroundHyperhomocysteinemia (HHcy) causes cardiovascular diseases via regulating inflammatory responses. We investigated whether and how the epithelial sodium channel (ENaC), a recently identified ion channel in endothelial cells, plays a role in HHcy-induced endothelial dysfunction.MethodsCell-attached patch-clamp recording in acute split-open aortic endothelial cells, western blot, confocal imaging, and wire myograph combined with pharmacological approaches were used to determine whether HHcy-mediated inflammatory signaling leads to endothelial dysfunction via stimulating ENaC.ResultsThe data showed that 4 weeks after L-methionine diet the levels of plasma Hcy were significantly increased and the ENaC was dramatically activated in mouse aortic endothelial cells. Administration of benzamil, a specific ENaC blocker, ameliorated L-methionine diet-induced impairment of endothelium-dependent relaxation (EDR) and reversed Hcy-induced increase in ENaC activity. Pharmacological inhibition of NADPH oxidase, reactive oxygen species (ROS), cyclooxygenase-2 (COX-2)/thromboxane B2 (TXB2), or serum/glucocorticoid regulated kinase 1 (SGK1) effectively attenuated both the Hcy-induced activation of endothelial ENaC and impairment of EDR. Our in vitro data showed that both NADPH oxidase inhibitor and an ROS scavenger reversed Hcy-induced increase in COX-2 expression in human umbilical vein endothelial cells (HUVECs). Moreover, Hcy-induced increase in expression levels of SGK-1, phosphorylated-SGK-1, and phosphorylated neural precursor cell-expressed developmentally downregulated protein 4-2 (p-Nedd4-2) in HUVECs were significantly blunted by a COX-2 inhibitor.ConclusionWe show that Hcy activates endothelial ENaC and subsequently impairs EDR of mouse aorta, via ROS/COX-2-dependent activation of SGK-1/Nedd4-2 signaling. Our study provides a rational that blockade of the endothelial ENaC could be potential method to prevent and/or to treat Hcy-induced cardiovascular disease.

scholarly journals Lung Fluid Clearance Is Mediated Via Epithelial Sodium Channel (ENaC)

1999 ◽  
Vol 45 (4, Part 2 of 2) ◽  
pp. 305A-305A
Author(s):  
Lucky Jain ◽  
Chen Xi-Juan ◽  
Joshi B ◽  
Eaton C Douglas
Keyword(s):  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Lung Fluid ◽  
Epithelial Sodium Channel Enac

scholarly journals NADPH oxidase signaling regulates Epithelial Sodium Channel (ENaC) activity

2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Michael S Park ◽  
Yoshizumi Takemura ◽  
Julie L Self ◽  
My N Helms
Keyword(s):  
Nadph Oxidase ◽  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Epithelial Sodium Channel Enac
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