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.

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 Nasal potential difference to detect Na+channel dysfunction in acute lung injury

2011 ◽  
Vol 300 (3) ◽  
pp. L305-L318 ◽  
Author(s):  
R. Mac Sweeney ◽  
H. Fischer ◽  
D. F. McAuley
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Ion Channel ◽  
Pulmonary Edema ◽  
Potential Difference ◽  
Na Channel ◽  
Alveolar Epithelial ◽  
Nasal Potential Difference ◽  
Respiratory Epithelial

Pulmonary fluid clearance is regulated by the active transport of Na+and Cl−through respiratory epithelial ion channels. Ion channel dysfunction contributes to the pathogenesis of various pulmonary fluid disorders including high-altitude pulmonary edema (HAPE) and neonatal respiratory distress syndrome (RDS). Nasal potential difference (NPD) measurement allows an in vivo investigation of the functionality of these channels. This technique has been used for the diagnosis of cystic fibrosis, the archetypal respiratory ion channel disorder, for over a quarter of a century. NPD measurements in HAPE and RDS suggest constitutive and acquired dysfunction of respiratory epithelial Na+channels. Acute lung injury (ALI) is characterized by pulmonary edema due to alveolar epithelial-interstitial-endothelial injury. NPD measurement may enable identification of critically ill ALI patients with a susceptible phenotype of dysfunctional respiratory Na+channels and allow targeted therapy toward Na+channel function.

scholarly journals Dexmedetomidine Promotes Alveolar Fluid Clearance by Upregulating Na,K-ATPase Expression in a Rat Model of Acute Lung Injury via α2 AR/PI3K/Akt Pathway

2021 ◽  
Author(s):  
Mingzhu Xia ◽  
Zhi Huang ◽  
Mingyu Xu ◽  
Chao Hai ◽  
Wenbo Diao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Molecular Mechanisms ◽  
A549 Cells ◽  
Lung Injury Score ◽  
Alveolar Fluid Clearance ◽  
Apoptosis Rate ◽  
Tnf Α

Abstract 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.

scholarly journals Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury

2009 ◽  
Vol 297 (2) ◽  
pp. L219-L227 ◽  
Author(s):  
Charlie Wray ◽  
Ying Mao ◽  
Jue Pan ◽  
Anita Chandrasena ◽  
Frank Piasta ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tight Junction ◽  
Pulmonary Edema ◽  
Barrier Function ◽  
Mapk Pathway ◽  
Paracellular Transport ◽  
Epithelial Barrier ◽  
Altered Expression ◽  
Alveolar Epithelial

Intact alveolar barrier function is associated with better outcomes in acute lung injury patients; however, the regulation of alveolar epithelial paracellular transport during lung injury has not been extensively investigated. This study was undertaken to determine whether changes in tight junction claudin expression affect alveolar epithelial barrier properties and to determine the mechanisms of altered expression. In anesthetized mice exposed to ventilator-induced lung injury, claudin-4 was specifically induced among tight junction structural proteins. Real-time PCR showed an eightfold increase in claudin-4 expression in the lung injury model. To examine the role of this protein in barrier regulation, claudin-4 function was inhibited with small interfering RNA (siRNA) and a blocking peptide derived from the binding domain of Clostridium perfringens enterotoxin (CPEBD). Inhibition of claudin-4 decreased transepithelial electrical resistance but did not alter macromolecule permeability in primary rat and human epithelial cells. In mice, CPEBD decreased air space fluid clearance >33% and resulted in pulmonary edema during moderate tidal volume ventilation that did not induce edema in control peptide-treated mice. In vitro phorbol ester induced a ninefold increase in claudin-4 expression that was dependent on PKC activation and the JNK MAPK pathway. These data establish that changes in alveolar epithelial claudin expression influence paracellular transport, alveolar fluid clearance rates, and susceptibility to pulmonary edema. We hypothesize that increased claudin-4 expression early in acute lung injury represents a mechanism to limit pulmonary edema and that the regulation of alveolar epithelial claudin expression may be a novel target for acute lung injury therapy.

scholarly journals Effects of Antibiotic Therapy on Pseudomonas aeruginosa-Induced Lung Injury in a Rat Model

1999 ◽  
Vol 43 (10) ◽  
pp. 2389-2394 ◽  
Author(s):  
Erika J. Ernst ◽  
Satoru Hashimoto ◽  
Joseph Guglielmo ◽  
Teiji Sawa ◽  
Jean-Francois Pittet ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Rat Model ◽  
In Vivo Model ◽  
Antibiotic Administration ◽  
Lung Water ◽  
Alveolar Epithelial ◽  
The Right

ABSTRACT The effect of antibiotics on the acute lung injury induced by virulent Pseudomonas aeruginosa PA103 was quantitatively analyzed in a rat model. Lung injury was induced by the instillation of PA103 directly into the right lower lobes of the lungs of anesthetized rats. The alveolar epithelial injury, extravascular lung water, and total plasma equivalents were measured as separate, independent parameters of acute lung injury. Four hours after the instillation of PA103, all the parameters were increased linearly depending on the dose of P. aeruginosa. Next, we examined the effects of intravenously administered antibiotics on the parameters of acute lung injury in d-galactosamine-sensitized rats. One hour after the rats received 107 CFU of PA103, an intravenous bolus injection of aztreonam (60 mg/kg) or imipenem-cilastatin (30 mg/kg) was administered. Despite an MIC indicating resistance, imipenem-cilastatin improved all the measurements of lung injury; in contrast, aztreonam, which had an MIC indicating sensitivity, did not improve any of the lung injury parameters. The antibiotics did not generate different quantities of plasma endotoxin; therefore, endotoxin did not appear to explain the differences in lung injury. This in vivo model is useful to quantitatively compare the efficacies of parenteral antibiotic administration on Pseudomonas airspace infections.

scholarly journals Role of LecA and LecB Lectins in Pseudomonas aeruginosa-Induced Lung Injury and Effect of Carbohydrate Ligands

2009 ◽  
Vol 77 (5) ◽  
pp. 2065-2075 ◽  
Author(s):  
Chanez Chemani ◽  
Anne Imberty ◽  
Sophie de Bentzmann ◽  
Maud Pierre ◽  
Michaela Wimmerová ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Parental Strain ◽  
A549 Cells ◽  
Carbohydrate Ligands ◽  
Vitro Model

ABSTRACT Pseudomonas aeruginosa is a frequently encountered pathogen that is involved in acute and chronic lung infections. Lectin-mediated bacterium-cell recognition and adhesion are critical steps in initiating P. aeruginosa pathogenesis. This study was designed to evaluate the contributions of LecA and LecB to the pathogenesis of P. aeruginosa-mediated acute lung injury. Using an in vitro model with A549 cells and an experimental in vivo murine model of acute lung injury, we compared the parental strain to lecA and lecB mutants. The effects of both LecA- and Lec B-specific lectin-inhibiting carbohydrates (α-methyl-galactoside and α-methyl-fucoside, respectively) were evaluated. In vitro, the parental strain was associated with increased cytotoxicity and adhesion on A549 cells compared to the lecA and lecB mutants. In vivo, the P. aeruginosa-induced increase in alveolar barrier permeability was reduced with both mutants. The bacterial burden and dissemination were decreased for both mutants compared with the parental strain. Coadministration of specific lectin inhibitors markedly reduced lung injury and mortality. Our results demonstrate that there is a relationship between lectins and the pathogenicity of P. aeruginosa. Inhibition of the lectins by specific carbohydrates may provide new therapeutic perspectives.

scholarly journals Mitochondrial peptides cause proinflammatory responses in the alveolar epithelium via FPR-1, MAPKs, and AKT: a potential mechanism involved in acute lung injury

2018 ◽  
Vol 315 (5) ◽  
pp. L775-L786 ◽  
Author(s):  
Xue Zhang ◽  
Tao Wang ◽  
Zhi-Cheng Yuan ◽  
Lu-Qi Dai ◽  
Ni Zeng ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Cell Injury ◽  
Specific Inhibitor ◽  
Alveolar Epithelium ◽  
Formyl Peptide Receptor ◽  
Potential Mechanism ◽  
Alveolar Epithelial

Acute lung injury (ALI) is characterized by alveolar epithelial damage and uncontrolled pulmonary inflammation. Mitochondrial damage-associated molecular patterns (DAMPs), including mitochondrial peptides [ N-formyl peptides (NFPs)], are released during cell injury and death and induce inflammation by unclear mechanisms. In this study, we have investigated the role of mitochondrial DAMPs (MTDs), especially NFPs, in alveolar epithelial injury and lung inflammation. In murine models of ALI, high levels of mitochondrial NADH dehydrogenase 1 in bronchoalveolar lavage fluid (BALF) were associated with lung injury scores and increased formyl peptide receptor (FPR)-1 expression in the alveolar epithelium. Cyclosporin H (CsH), a specific inhibitor of FPR1, inhibited lung inflammation in the ALI models. Both MTDs and NFPs upon intratracheal challenge caused accumulation of neutrophils into the alveolar space with elevated BALF levels of mouse chemokine KC, interleukin-1β, and nitric oxide and increased pulmonary FPR-1 levels. CsH significantly attenuated MTDs or NFP-induced inflammatory lung injury and activation of MAPK and AKT pathways. FPR1 expression was present in rat primary alveolar epithelial type II cells (AECIIs) and was increased by MTDs. CsH inhibited MTDs or NFP-induced CINC-1/IL-8 release and phosphorylation of p38, JNK, and AKT in rat AECII and human cell line A549. Inhibitors of MAPKs and AKT also suppressed MTD-induced IL-8 release and NF-κB activation. Collectively, our data indicate an important role of the alveolar epithelium in initiating immune responses to MTDs released during ALI. The potential mechanism may involve increase of IL-8 production in MTD-activated AECII through FPR-1 and its downstream MAPKs, AKT, and NF-κB pathways.

scholarly journals A2BAR activation attenuates acute lung injury by inhibiting alveolar epithelial cell apoptosis both in vivo and in vitro

2018 ◽  
Vol 315 (4) ◽  
pp. C558-C570 ◽  
Author(s):  
Xiaotao Xu ◽  
Qingwei Zhu ◽  
Fangfang Niu ◽  
Rong Zhang ◽  
Yan Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cell Apoptosis ◽  
A549 Cells ◽  
Apoptosis Pathway ◽  
Alveolar Epithelial ◽  
Exact Function ◽  
Parp 1

The epithelial barrier of the lung is destroyed during acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) due to the apoptosis of alveolar epithelial cells (AECs). Therefore, treatments that block AEC apoptosis might be a therapeutic strategy to ameliorate ALI. Based on recent evidence, A2B adenosine receptor (A2BAR) plays an important role in ALI in several different animal models, but its exact function in AECs has not been clarified. We investigated the role of A2BAR in AEC apoptosis in a mouse model of oleic acid (OA)-induced ALI and in hydrogen peroxide (H2O2)-induced AEC (A549 cells and MLE-12 cells) injury. Mice treated with BAY60-6583, a selective A2BAR agonist, showed lower AEC apoptosis rates than mice treated with OA. However, the role of BAY60-6583 in OA-induced ALI was attenuated by a specific blocker of A2BAR, PSB1115. A2BAR activation decreased H2O2-induced cell apoptosis in vitro, as characterized by the translocation of apoptotic proteins, the release of cytochrome c, and the activation of caspase-3 and poly (ADP ribose) polymerase 1 (PARP-1). In addition, apoptosis was required for the phosphorylation of ERK1/2, p38, and JNK. Importantly, compared with cells transfected with the A2BAR-siRNA, an ERK inhibitor or p38 inhibitor exhibited decreased apoptotic ratios and cleaved caspase-9 and cleaved PARP-1 levels, whereas the JNK inhibitor displayed increases in these parameters. In conclusion, A2BAR activation effectively attenuated OA-induced ALI by inhibiting AEC apoptosis and mitigated H2O2-induced AEC injury by suppressing the p38 and ERK1/2-mediated mitochondrial apoptosis pathway.

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