Role of Nrf2/HO-1 signaling pathway in reduction of endotoxin-induced acute lung injury by esketamine in mice: relationship with NLRP3 inflammasome-mediated pyroptosis
10.3760/cma.j.cn131073.20230403.01017
- VernacularTitle:Nrf2/HO-1信号通路在艾司氯胺酮减轻小鼠内毒素性急性肺损伤中的作用：与NLRP3炎性小体介导细胞焦亡的关系
- Author:
Yang MA
1
;
Jingyi LIU
;
Zijian MA
;
Jixiao ZHANG
;
Xuefeng CAO
;
Yan LI
;
Zhixue WANG
Author Information
1. 承德医学院附属医院麻醉科，承德 067000
- Keywords:
Endotoxemia;
Acute lung injury;
NF-E2-related factor 2;
Heme oxygenase-1;
NLR family, pyrin domain-containing protein 3;
Pyroptosis;
Esketamine
- From:
Chinese Journal of Anesthesiology
2023;43(10):1237-1242
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To evaluate the role of NF-E2-related factor 2 (Nrf2)/heme oxygenase (HO-1) signaling pathway in reduction of endotoxin-induced acute lung injury (ALI) by esketamine and the relationship with NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis in mice.Methods:SPF male wild-type (WT) and Nrf2 knockout (KO) C57BL/6J mice, aged 6-8 weeks, weighing 20-25 g, were divided into 3 groups ( n=6 each) using a random number table method: control group (WT+ C group, KO+ C group), ALI group (WT+ ALI group, KO+ ALI group) and ALI+ esketamine group (WT+ ALI+ E group, KO+ ALI+ E group). ALI model was developed by injection of lipopolysaccharide (LPS) 15 mg/kg via the tail vein. Esketamine 10 mg/kg was intraperitoneally injected at 30 min after LPS injection, and 6 h later the medication was repeated for one time in WT+ ALI+ E and KO+ ALI+ E groups, while the equal volume of normal saline was given in the other groups. The mice were anesthetized at 12 h after LPS injection, and blood samples were obtained by cardiac puncture for determination of serum interleukin-1beta (IL-1β) and IL-18 concentrations, and bilateral lung tissues were also obtained for examination of the pathological changes of lung tissues(with the light microscope) which were scored and for determination of the content of reduced glutathione (GSH) and expression of Nrf2, HO-1 and NLRP3 inflammasome-mediated pyroptosis-related proteins (NLRP3, apoptosis-associated speck-like protein containing a CARD[ASC], pro-caspase-1, cleaved-caspase-1, gasdermin D[GSDMD]) (by Western blot). Results:Compared with the corresponding C group (WT+ C group or KO+ C group), the lung injury score and concentrations of IL-1β and IL-18 were significantly increased, the content of GSH in lung tissues was decreased, and the expression of NLRP3, ASC, pro-caspase-1, cleved-caspase-1 and GSDMD was up-regulated in WT+ ALI group and KO+ ALI group ( P<0.05), and the expression of Nrf2 and HO-1 was significantly up-regulated in WT+ ALI group( P<0.05). Compared with the corresponding ALI group (WT+ ALI group or KO+ ALI group), the lung injury score and concentrations of IL-1β and IL-18 were significantly decreased, the content of GSH in lung tissues was increased, and the expression of NLRP3, ASC, pro-caspase-1, cleved-caspase-1 and GSDMD was down-regulated in WT+ ALI+ E group and KO+ ALI+ E group ( P<0.05), and Nrf2 and HO-1 expression was significantly up-regulated in WT+ ALI+ E group( P<0.05). Compared with WT+ ALI+ E group, the lung injury score and concentrations of IL-1β and IL-18 were significantly increased, the content of GSH in lung tissues was decreased, the expression of Nrf2 and HO-1 was down-regulated, and the expression of NLRP3, ASC, pro-caspase-1, cleved-caspase-1 and GSDMD was up-regulated in KO+ ALI+ E group ( P<0.05). Conclusions:The mechanism by which esketamine reduces endotoxin-induced ALI may be related to activation of Nrf2/HO-1 signaling pathway, thus inhibiting NLRP3 inflammasome-mediated pyroptosis in mice.
