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

Jiang, Yuanxu1,2; Xia, Mingzhu4; Xu, Jing3; Huang, Qiang1,2; Dai, Zhongliang1,2; Zhang, Xueping1,2

2021-02-01

10.1007/s12026-021-09176-6

IMMUNOLOGIC RESEARCH   影响因子和分区

0257-277X

1559-0755

Dexmedetomidine (Dex), a highly selective alpha(2)-adrenergic receptor (alpha(2)AR) 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 alpha-, beta-, and gamma-ENaC expression, attenuated inflammatory cell infiltration in lung tissue, reduced the concentrations of TNF-alpha, IL-1 beta, 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 alpha-, beta-, and gamma-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.

Pulmonary edema Dexmedetomidine ENaC AFC PI3K Akt Nedd4-2 signaling pathway

SCI

英语

第一 ; 通讯

Technical Research and Development Fund of Shenzhen[JCYJ20160422142317026] ; Scientific Research Project of Shenzhen Health and Family Planning System[SZFZ2018032] ; Shenzhen Key Medical Discipline Construction Fund[SZXK044] ; Sanming Project of Medicine in Shenzhen[SZSM202011021]

Immunology

Immunology

WOS:000622666200001

HUMANA PRESS INC

IMMUNOLOGY

Web of Science

1.Southern Univ Sci & Technol, Affiliated Hosp 1, Jinan Univ,Dept Anesthesiol, Clin Med Coll 2,Shenzhen Peoples Hosp, Shenzhen 518020, Peoples R China
2.Shenzhen Anesthesiol Engn Ctr, Shenzhen 518020, Peoples R China
3.Southern Univ Sci & Technol, Affiliated Hosp 1, Jinan Univ, Shenzhen Peoples Hosp,Clin Med Coll 2,Dept Pathol, Shenzhen 518020, Peoples R China
4.Luohu Peoples Hosp, Luohu Hosp Grp, Hubei Community Hlth Serv Ctr, Shenzhen 518020, Peoples R China

Jiang, Yuanxu,Xia, Mingzhu,Xu, Jing,et al. Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS-induced acute lung injury[J]. IMMUNOLOGIC RESEARCH,2021.

Jiang, Yuanxu,Xia, Mingzhu,Xu, Jing,Huang, Qiang,Dai, Zhongliang,&Zhang, Xueping.(2021).Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS-induced acute lung injury.IMMUNOLOGIC RESEARCH.

Jiang, Yuanxu,et al."Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS-induced acute lung injury".IMMUNOLOGIC RESEARCH (2021).