中性细胞外细胞陷通过损害Fundc1依赖的线粒细胞衰变来驱动肠道微血管内皮铁
Chengnan Chu1, Xinyu Wang1, Chao Yang1
1Division of Trauma and Acute Care Surgery, Department of Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China.
Redox biology
|October 9, 2023
概括
中性粒细胞外细胞陷 (NETs) 通过抑制细胞分裂并引起内皮铁亡,驱动肠道缺血-再输液 (II/R) 中的微血管损伤. 抑制NET可以改善微循环,并为II/R损伤提供潜在的治疗方法.
科学领域:
- 血管生物学 血管生物学
- 免疫学 免疫学 免疫学
- 胃肠病学 胃肠病学
背景情况:
- 肠道缺血-再输液 (II/R) 损伤会导致微血管内皮损伤,导致功能障碍和感染.
- 以前的研究集中在中性粒细胞外细胞陷 (NETs) 和铁亡的上皮损伤上,忽视了内皮细胞的影响.
- NETs在II/R诱导的肠微血管功能障碍中的作用需要进一步阐明.
研究的目的:
- 调查NETs在II/R期间导致肠道微血管功能障碍的机制.
- 探索针对NET的潜在治疗策略,以减轻II/R引起的损害.
主要方法:
- 在人类和动物II/R模型中分析NET透和内皮细胞铁亡.
- 对铁灭抑制剂 (ferrostatin-1) 和NET抑制 (Pad4缺乏症) 的治疗效果的评估.
- 用NETs处理的HUVECs的RNA-seq分析以确定受影响的信号通路.
- 调查Fundc1酸化,线粒体和线粒体ROS在内皮铁亡中的作用.
- 在改善微血管损伤方面,对线粒细胞活化剂 (urolithin A) 和基因疗法 (AAV-Fundc1) 的评估.
主要成果:
- 在II / R模型中观察到升高的NET和内皮铁,与微循环功能障碍相关.
- 抑制铁亡或NETs可以减少内皮损伤和改善微血管功能.
- 在内皮细胞中,NETs诱导了线粒体的抑制和线粒体功能障碍,导致铁亡.
- 激活线粒或恢复Fundc1功能可以逆转NET诱导的内皮损伤.
结论:
- 增加的NET形成通过内皮铁灭症加剧了肠道微循环功能障碍.
- 抑制的NET形成通过增强Fundc1-依赖的线粒细胞衰变来缓解内皮铁.
- 针对NETs为II/R诱导的肠道微血管损伤提供了一个有希望的治疗策略.
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