背景:脓毒症相关性脑病(SAE)是指由脓毒症介导的非中枢神经系统感染引起的广泛的脑功能损害。脂质过氧化诱导的铁死亡有助于SAE的发生和过程。本研究旨在探讨SAE中脂质过氧化诱导的铁凋亡与神经元损伤的关系。
方法:收集儿科患者入院时的基线数据,监测SAE患者和SAE模型小鼠的血清和外周血单个核细胞(PBMC)中与脂质过氧化和铁凋亡相关的各种标志物的表达水平。评估了海马磷脂酰乙醇胺结合蛋白(PEBP)-1/15-赖氨酸氧化酶(LOX)/谷胱甘肽过氧化物酶4(GPX4)途径对SAE治疗中铁凋亡抑制作用的作用。
结果:结果显示S100钙结合蛋白β(S-100β)水平升高,胶质纤维酸性蛋白,SAE患者血清中的丙二醛,而超氧化物歧化酶水平降低。此外,PBMC分析显示PEBP1、LOX、和SAE患者的长链脂酰辅酶A合成酶家族成员4(ACSL4),而GPX4和胱氨酸/谷氨酸转运体xCT(SLC7A11)的转录水平降低。与对照组相比,SAE小鼠海马中S-100β和神经元特异性烯醇化酶(NSE)的表达增加,而去铁胺(DFO)小鼠中S-100β和NSE的表达降低。此外,在SAE小鼠的海马中观察到铁积累,而DFO小鼠的铁离子水平降低。铁凋亡的抑制减轻了线粒体损伤(通过透射电子显微镜评估,海马线粒体ATP检测,和海马中JC-1聚合物与单体的比例)和SAE诱导的氧化应激反应以及减弱的神经炎性反应。进一步的研究表明,SAE治疗中铁死亡抑制作用的潜在机制与海马PEBP-1/15-LOX/GPX4途径有关。
结论:这些结果为SAE中神经元损伤的管理提供了潜在的治疗靶点,并对神经系统疾病中铁死亡的潜在机制提供了有价值的见解。
BACKGROUND: Sepsis-associated encephalopathy (SAE) refers to the widespread impairment of brain function caused by noncentral nervous system infection mediated by sepsis. Lipid peroxidation-induced ferroptosis contributes to the occurrence and course of SAE. This study aimed to investigate the relationship between neuronal injury and lipid peroxidation-induced ferroptosis in SAE.
METHODS: Baseline data were collected from pediatric patients upon admission, and the expression levels of various markers related to lipid peroxidation and ferroptosis were monitored in the serum and peripheral blood mononuclear cells (PBMCs) of patients with SAE as well as SAE model mice. The hippocampal phosphatidylethanolamine-binding protein (PEBP)-1/15-lysine oxidase (LOX)/ glutathione peroxidase 4 (GPX4) pathway was assessed for its role on the inhibitory effect of ferroptosis in SAE treatment.
RESULTS: The results showed elevated levels of S100 calcium-binding protein beta (S-100β), glial fibrillary acidic protein, and malondialdehyde in the serum of SAE patients, while superoxide dismutase levels were reduced. Furthermore, analysis of PBMCs revealed increased transcription levels of PEBP1, LOX, and long-chain fatty acyl-CoA synthetase family member 4 (ACSL4) in SAE patients, while the transcription levels of GPX4 and cystine/glutamate transporter xCT (SLC7A11) were decreased. In comparison to the control group, the SAE mice exhibited increased expression of S-100β and neuron-specific enolase (NSE) in the hippocampus, whereas the expression of S-100β and NSE were reduced in deferoxamine (DFO) mice. Additionally, iron accumulation was observed in the hippocampus of SAE mice, while the iron ion levels were reduced in the DFO mice. Inhibition of ferroptosis alleviated the mitochondrial damage (as assessed by transmission electron microscopy, hippocampal mitochondrial ATP detection, and the JC-1 polymer-to-monomer ratio in the hippocampus) and the oxidative stress response induced by SAE as well as attenuated neuroinflammatory reactions. Further investigations revealed that the mechanism underlying the inhibitory effect of ferroptosis in SAE treatment is associated with the hippocampal PEBP-1/15-LOX/GPX4 pathway.
CONCLUSIONS: These results offer potential therapeutic targets for the management of neuronal injury in SAE and valuable insights into the potential mechanisms of ferroptosis in neurological disorders.