Xu B, Li M, Wang J W, Li W H, Gao R, Hu H L
Emergency Department, Wuhan NO.4 Hospital, Wuhan 430034, China.
Cardiothoracic Surgery Department, Wuhan NO.4 Hospital, Wuhan 430034, China.
Zhonghua Jie He He Hu Xi Za Zhi. 2023 Oct 12;46(10):993-1001. doi: 10.3760/cma.j.cn112147-20230423-00195.
To study the effect and mechanism of post-ischemic treatment of nalmefene in alleviating the lung ischemia-reperfusion injury by inhibiting ferroptosis through activation of the Sirt 1/Nrf 2/HO-1 axis. A total of 60 rats were randomly divided into six groups equally (=10): the sham group, the model group(I/R), the nalmefene group, the nalmefene+EX527 group, the nalmefene+ML385 group, the nalmefene+Fe-citrate group (nalmefene+Fe group). The sham group without drug treatment was not treated with ischemia-reperfusion. The pulmonary ischemia-reperfusion model was established by occlusion of the left pulmonary hilum in the model group without drug treatment. After ischemic treatment, the nalmefene group was injected with nalmefene (15 μg/kg) via the tail vein at 5 minutes before reperfusion. The nalmefene+EX527 group, the nalmefene+ML385 group, and the nalmefene+Fe group were injected intraperitoneally with EX527 (5 mg/kg), ML385 (30 mg/kg), Fe-citrate(15 mg/kg), respectively, 2 h before moulding and then injected with nalmefene (15 μg/kg) via the tail vein at 5 minutes before reperfusion. All rats were sacrificed three hours after reperfusion, and the specimens from the upper lobe of the left lung tissue were preserved. The degree of lung tissue injury and the wet/dry weight ratio were assessed in each group of rats. Fe , MDA, TNF-α, and IL-6 content, GSH activity and the expression levels of Sirt1, Nrf2, HO-1, ACSL4 and GPX4 were determined. Compared with the sham group, the wet/dry weight ratio, lung tissue injury score, ACSL 4 expression level, Fe , TNF-α, IL-6 and MDA content, Sirt 1, Nrf 2, HO-1 messenger RNA and protein expression levels were significantly increased (0.01), while GPX 4 expression level and GSH activity were significantly decreased in the model group (0.01). Compared with the model group, wet/dry weight ratio, lung tissue injury score, ACSL 4 expression level, Fe , TNF-α, IL-6, and MDA content decreased significantly (0.01), Nrf 2, HO-1 messenger RNA and protein, GPX 4 expression, and GSH activity were significantly increased in the nalmefene group and the nalmefene+EX527 group (0.01). Sirt 1 messenger RNA and protein expression increased significantly in the nalmefene (<0.01) and the nalmefene+EX527 groups (>0.05). In the nalmefene+ML385 group, the wet/dry weight ratio, lung tissue injury score, TNF-α and IL-6 content were decreased significantly (<0.01), while Sirt 1 messenger RNA and protein expression levels were significantly increased (<0.01), but there were no significant changes in Nrf 2, HO-1 messenger RNA and protein expression levels, ACSL 4 and GPX 4 expression levels, Fe , MDA content, and GSH activity (>0.05). In the nalmefene+Fe group, wet/dry weight ratio, lung-injury score, TNF-α, IL-6, MDA content were decreased significantly (0.01), messenger RNA and protein expression levels of Sirt 1, Nrf 2, HO-1, and GSH activity were increased significantly (0.01), but there were no significant changes in Fe content, ACSL 4 and GPX 4 expression levels (>0.05). Compared with the nalmefene group, in the nalmefene+EX527 group, the nalmefene+ML385 group and the nalmefene+Fe group, wet/dry weight ratio, lung tissue damage score, ACSL 4 expression level, TNF-α, IL-6 and MDA content were significantly increased (<0.01), the expression level of GPX 4 and GSH activity were significantly decreased (<0.01). The expression levels of Sirt 1, Nrf 2, HO-1 messenger RNA and protein were significantly decreased in the nalmefene+EX527 group (<0.01). The expression levels of Nrf 2, HO-1 messenger RNA and protein decreased significantly in the namemefene+ML385 group (0.01), but there was no significant change in Sirt 1 messenger RNA and protein expression level (>0.05). Sirt 1, Nrf 2, HO-1 messenger RNA-protein expression levels did not change significantly in the nalmefene+Fe group (>0.05). Post-ischemic treatment with nalmefene hydrochloride may alleviate pulmonary ischemia-reperfusion injury by inhibiting ferroptosis through activation of the Sirt 1/Nrf 2/HO-1 axis.
研究盐酸纳美芬缺血后处理通过激活Sirt 1/Nrf 2/HO-1轴抑制铁死亡减轻肺缺血再灌注损伤的作用及机制。将60只大鼠随机均分为6组（n = 10）：假手术组、模型组（I/R）、纳美芬组、纳美芬+EX527组、纳美芬+ML385组、纳美芬+柠檬酸铁组（纳美芬+铁组）。假手术组不进行药物处理及缺血再灌注。模型组不进行药物处理，通过阻断左肺门建立肺缺血再灌注模型。缺血处理后，纳美芬组在再灌注前5分钟经尾静脉注射纳美芬（15 μg/kg）。纳美芬+EX527组、纳美芬+ML385组、纳美芬+铁组在造模前2小时分别腹腔注射EX527（5 mg/kg）、ML385（30 mg/kg）、柠檬酸铁（15 mg/kg），然后在再灌注前5分钟经尾静脉注射纳美芬（15 μg/kg）。再灌注3小时后处死所有大鼠，留取左肺上叶组织标本。评估每组大鼠肺组织损伤程度及湿/干重比。测定铁、丙二醛、肿瘤坏死因子-α、白细胞介素-6含量、谷胱甘肽活性以及Sirt1、Nrf2、HO-1、ACSL4和GPX4的表达水平。与假手术组比较，模型组湿/干重比、肺组织损伤评分、ACSL 4表达水平、铁、肿瘤坏死因子-α、白细胞介素-6和丙二醛含量、Sirt 1、Nrf 2、HO-1信使核糖核酸和蛋白表达水平显著升高（P < 0.01），而GPX 4表达水平和谷胱甘肽活性显著降低（P < 0.01）。与模型组比较，纳美芬组和纳美芬+EX527组湿/干重比、肺组织损伤评分、ACSL 4表达水平、铁、肿瘤坏死因子-α、白细胞介素-6和丙二醛含量显著降低（P < 0.01），Nrf 2、HO-1信使核糖核酸和蛋白、GPX 4表达及谷胱甘肽活性显著升高（P < 0.01）。纳美芬组和纳美芬+EX527组Sirt 1信使核糖核酸和蛋白表达显著增加（纳美芬组P < 0.01，纳美芬+EX527组P > 0.05）。纳美芬+ML385组湿/干重比、肺组织损伤评分、肿瘤坏死因子-α和白细胞介素-6含量显著降低（P < 0.01），Sirt 1信使核糖核酸和蛋白表达水平显著升高（P < 0.01），但Nrf 2、HO-1信使核糖核酸和蛋白表达水平、ACSL 4和GPX 4表达水平、铁、丙二醛含量及谷胱甘肽活性无显著变化（P > 0.05）。纳美芬+铁组湿/干重比、肺损伤评分、肿瘤坏死因子-α、白细胞介素-6、丙二醛含量显著降低（P < 0.01），Sirt 1、Nrf 2、HO-1信使核糖核酸和蛋白及谷胱甘肽活性显著升高（P < 0.01），但铁含量、ACSL 4和GPX 4表达水平无显著变化（P > 0.05）。与纳美芬组比较，纳美芬+EX527组、纳美芬+ML385组和纳美芬+铁组湿/干重比、肺组织损伤评分、ACSL 4表达水平、肿瘤坏死因子-α、白细胞介素-6和丙二醛含量显著升高（P < 0.01），GPX 4表达水平和谷胱甘肽活性显著降低（P < 0.01）。纳美芬+EX527组Sirt 1、Nrf 2、HO-1信使核糖核酸和蛋白表达水平显著降低（P < 0.01）。纳美芬+ML385组Nrf 2、HO-1信使核糖核酸和蛋白表达水平显著降低（P < 0.01），但Sirt 1信使核糖核酸和蛋白表达水平无显著变化（P > 0.05）。纳美芬+铁组Sirt 1、Nrf 2、HO-1信使核糖核酸-蛋白表达水平无显著变化（P > 0.05）。盐酸纳美芬缺血后处理可能通过激活Sirt 像1/Nrf 2/HO-1轴抑制铁死亡减轻肺缺血再灌注损伤。
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