中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (11): 2474-2481.doi: 10.4103/1673-5374.371377

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

抑制铁死亡可保护脊髓损伤后血管内皮细胞和维持血脊髓屏障的完整性

  

  • 出版日期:2023-11-15 发布日期:2023-05-05
  • 基金资助:
    国家自然科学基金(81972074)、天津市自然科学基金(19JCZDJC34900)和国家重点研发计划干细胞与转化研究重点专项(2019YFA0112100)

Ferroptosis inhibition protects vascular endothelial cells and maintains integrity of the blood-spinal cord barrier after spinal cord injury

Wenxiang Li1, #, Xiaoqing Zhao1, #, Rong Zhang1, #, Xinjie Liu2, Zhangyang Qi1, Yang Zhang1, Weiqi Yang1, Yilin Pang2, Chenxi Zhao1, Baoyou Fan2, Ning Ran1, Jiawei Zhang2, Xiaohong Kong1, Shiqing Feng1, 2, *, Xue Yao1, 2, *   

  1. 1Shandong University Center for Orthopedics, Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; 2Tianjin Key Laboratory of Spine and Spinal Cord, National Spinal Cord Injury International Cooperation Base, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
  • Online:2023-11-15 Published:2023-05-05
  • Contact: Xue Yao, PhD, yaoxue@sdu.edu.cn; Shiqing Feng, PhD, shiqingfeng@sdu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 81972074 (to XY), the Natural Science Foundation of Tianjin, No. 19JCZDJC34900 (to XY), and National Key Research and Development Project of Stem Cell and Transformation Research, No. 2019YFA0112100 (to SF).

摘要:

维持血脊髓屏障完整性对脊髓损伤的恢复至关重要。铁死亡参与了脊髓损伤的病理改变,而铁死亡是否参与了脊髓损伤后血脊髓屏障的破坏尚无定论。实验在大鼠挫伤性脊髓损伤后腹腔注射铁死亡抑制剂liproxstatin-1(Lip-1)。发现Lip-1可以:(1)改善脊髓损伤大鼠的运动功能和电生理表现;(2)通过上调紧密连接蛋白的表达来维持血脊髓屏障的完整性;(3)抑制脊髓损伤后的内皮细胞铁中毒,这表现在内皮细胞标志物大鼠内皮细胞抗原1和铁死亡标志物酯酰辅酶A合成酶长链家族成员4和15-脂氧合酶的免疫荧光结果上。此外,由于Lip-1对血脊髓屏障完整性的保护,炎症细胞的招募以及星形胶质细胞出现减少。体外实验结果显示,Lip-1可通过上调谷胱甘肽过氧化物酶4和下调酯酰辅酶A合成酶长链家族成员4和15-脂氧合酶减轻体外大脑内皮细胞铁中毒。总之,Lip-1通过抑制内皮细胞的铁死亡和维持血脊髓屏障来促进脊髓损伤的恢复。

https://orcid.org/0000-0003-4904-7697 (Xue Yao); https://orcid.org/0000-0001-9437-7674 (Shiqing Feng)

Abstract: Maintaining the integrity of the blood-spinal cord barrier is critical for the recovery of spinal cord injury. Ferroptosis contributes to the pathogenesis of spinal cord injury. We hypothesized that ferroptosis is involved in disruption of the blood-spinal cord barrier. In this study, we administered the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal cord injury in rats. Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord injury. Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein. Liproxstatin-1 inhibited ferroptosis of endothelial cell after spinal cord injury, as shown by the immunofluorescence of an endothelial cell marker (rat endothelium cell antigen-1, RECA-1) and ferroptosis markers Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase. Liproxstatin-1 reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase. Furthermore, inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment. In summary, liproxstatin-1 improved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-spinal cord barrier integrity.

Key words: blood-spinal cord barrier, ferroptosis, liproxstatin-1, neuroinflammation, spinal cord injury, vascular endothelial cells