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| 治疗性低温调控p53/SLC7A11/GPX4通路减轻大鼠心肺复苏后脑损伤 |
| Mild therapeutic hypothermia attenuates brain injury after cardiopulmonary resuscitation in rats by regulating the p53/SLC7A11/GPX4 pathway |
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| DOI：10.12089/jca.2026.07.010 |
| 中文关键词: 心搏骤停 心肺复苏 再灌注损伤 肿瘤抑制蛋白p53 治疗性低温 |
| 英文关键词: Cardiac arrest Cardiopulmonary resuscitation Reperfusion injury Tumor suppressor protein p53 Mild therapeutic hypothermia |
| 基金项目:皖南医学院中青年科研基金项目（WK2019F32，WK2021F29）；安徽省临床重点专科建设项目（皖卫传〔2020〕243号） |
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| 中文摘要: |
目的：探讨治疗性低温(MTH)对大鼠心肺复苏(CPR)后脑损伤中p53及铁死亡相关蛋白的影响，阐明其减轻脑损伤的机制。
方法：选择健康雄性SD大鼠，7～8周龄，体重270～310 g。采用随机数字表法将大鼠分为六组：假手术组（S组）、心搏骤停(CA)/CPR组、DMSO溶剂组（DMSO组）、p53抑制剂组（pifithrin-μ，PFT-μ组）、MTH组和MTH+PFT-μ组。S组行气管插管和股动、静脉穿刺术，不进行电刺激和CPR；其余各组建立CA/CPR模型。MTH组和MTH+PFT-μ组在CPR即刻行体表降温，于体表涂擦酒精，使直肠温度15 min内降至32～34 ℃，自制变温箱维持6 h；其余组维持体温37～38 ℃。PFT-μ组和MTH+PFT-μ组自主循环恢复(再灌注)即刻给予pifithrin-μ 8 mg/kg；DMSO组注射等容积(按ml/kg计算，与给药组相同)的DMSO，其余组注射等容积的生理盐水。于再灌注后24、72 h进行神经功能评分（NFS）。于再灌注72 h采用Western blot法测定p53、胱氨酸/谷氨酸逆向转运蛋白溶质载体家族7成员11（SLC7A11）、谷胱甘肽过氧化物酶4（GPX4）、酰基辅酶A合成酶长链家族成员4（ACSL4）蛋白含量，采用HE染色观察海马组织CA1区病理学改变，并记录锥体细胞数量。
结果：与S组比较，CA/CPR组、DMSO组、PFT-μ组、MTH组和MTH+PFT-μ组再灌注后24、72 h NFS明显降低，p53和ACSL4蛋白含量明显升高，SLC7A11和GPX4蛋白含量明显降低，海马组织CA1区锥体细胞数量明显减少（P<0.05）。与CA/CPR组比较，PFT-μ组、MTH组和MTH+PFT-μ组再灌注后24、72 h NFS明显升高，p53和ACSL4蛋白含量明显降低，SLC7A11和GPX4蛋白含量明显升高，海马组织CA1区锥体细胞数量明显增加（P<0.05）。与DMSO组比较，PFT-μ组、MTH组和MTH+PFT-μ组再灌注后24、72 h NFS明显升高，p53和ACSL4蛋白含量明显降低，SLC7A11和GPX4蛋白含量明显升高，海马组织CA1区锥体细胞数量明显增加（P<0.05）。与PFT-μ组比较，MTH组p53蛋白含量明显降低，MTH+PFT-μ组再灌注后24 h NFS明显升高、p53和ACSL4蛋白含量明显降低、SLC7A11和GPX4蛋白含量明显升高，MTH组和MTH+PFT-μ组再灌注后72 h NFS明显升高、海马组织CA1区锥体细胞数量明显增加（P<0.05）。与MTH组比较，MTH+PFT-μ组再灌注后24 h NFS明显升高，p53和ACSL4蛋白含量明显降低、SLC7A11和GPX4蛋白含量明显升高，海马组织CA1区锥体细胞数量明显增加（P<0.05）。
结论：MTH可调控p53/SLC7A11/GPX4信号轴，减轻大鼠CPR后的脑损伤，发挥神经保护作用。 |
| 英文摘要: |
Objective: To investigate the effects of mild therapeutic hypothermia (MTH) on p53 and ferroptosis-related proteins in brain injury after cardiopulmonary resuscitation (CPR) in rats, and to elucidate the underlying mechanisms of its neuroprotective effects.
Methods: Healthy male Sprague-Dawley rats, aged 7-8 weeks, weighing 270-310 g, were selected. The rats were randomly divided into 6 groups using a random number table method: the sham group (group S), the cardiac arrest/cardiopulmonary resuscitation group (group CA/CPR), the DMSO solvent control group (group DMSO), the p53 inhibitor group (group PFT-μ), the mild therapeutic hypothermia group (group MTH), and the MTH + PFT-μ group (group MTH + PFT-μ). Group S only underwent tracheal intubation and femoral artery/vein cannulation without electrical stimulation or CPR. CA/CPR models were established in all other groups. For groups MTH and MTH + PFT-μ, surface cooling was initiated immediately after resuscitation by applying alcohol to the body surface to lower the rectal temperature to 32 - 34 ℃ within 15 minutes, which was maintained for 6 hours using a self-made temperature control box, the other groups maintained normal body temperature (37-38 ℃). Groups PFT-μ and MTH + PFT-μ received pifithrin-μ 8 mg/kg immediately upon return of spontaneous circulation (reperfusion). Group DMSO received an equivalent volume (ml/kg) of DMSO solution, matching that administered to the treatment groups, and the remaining groups received an equivalent volume of normal saline. Neurological function score (NFS) was assessed 24 and 72 hours after reperfusion. Western blot analysis was performed to determine the protein levels of p53, solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and acyl-CoA synthetase long-chain family member 4 (ACSL4) 72 hours after reperfusion. Hippocampal CA1 region pathology was observed using hematoxylin-eosin (HE) staining, and the number of pyramidal neurons was recorded.
Results: Compared with group S, groups CA/CPR, DMSO, PFT-μ, MTH, and MTH + PFT-μ showed significantly lower NFS 24 and 72 hours after reperfusion, significantly higher protein levels of p53 and ACSL4, significantly lower protein levels of SLC7A11 and GPX4, and a significant reduction in the number of pyramidal neurons in the hippocampal CA1 region (P < 0.05). Compared with group CA/CPR, groups PFT-μ, MTH, and MTH + PFT-μ exhibited significantly higher NFS 24 and 72 hours after reperfusion, significantly lower protein levels of p53 and ACSL4, significantly higher protein levels of SLC7A11 and GPX4, and a significant increase in the number of pyramidal neurons in the hippocampal CA1 region (P < 0.05). Compared with group DMSO, groups PFT-μ, MTH, and MTH + PFT-μ demonstrated significantly higher NFS 24 and 72 hours after reperfusion, significantly lower protein levels of p53 and ACSL4, significantly higher protein levels of SLC7A11 and GPX4, and significant increase in the number of pyramidal neurons in the hippocampal CA1 region (P < 0.05). Compared with group PFT-μ, group MTH showed significantly lower p53 protein levels, group MTH + PFT-μ exhibited significantly higher NFS 24 hours after reperfusion, significantly lower protein levels of p53 and ACSL4, and significantly higher protein levels of SLC7A11 and GPX4, groups MTH and MTH + PFT-μ showed significantly higher NFS 72 hours after reperfusion and a significant increase in the number of pyramidal neurons in the hippocampal CA1 region (P < 0.05). Compared with group MTH, group MTH + PFT-μ had significantly higher NFS 24 hours after reperfusion, significantly lower protein levels of p53 and ACSL4, significantly higher protein levels of SLC7A11 and GPX4, and a significant increase in the number of pyramidal neurons in the hippocampal CA1 region (P < 0.05).
Conclusion: MTH attenuates cerebral injury following CPR in rats and exerts neuroprotective effects, which may be mediated by the regulation of the p53/SLC7A11/GPX4 signaling axis. |
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