中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (11): 2537-2543.doi: 10.4103/1673-5374.339000

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

睡眠呼吸暂停加重蛛网膜下腔出血后早期脑损伤中的神经炎症和细胞焦亡

  

  • 出版日期:2022-11-15 发布日期:2022-04-23
  • 基金资助:
    江苏省自然科学基金项目(青年计划项目)(BK20190129);江苏省高校国家自然科学基金项目(19KJB320012)

Obstructive sleep apnea aggravates neuroinflammation and pyroptosis in early brain injury following subarachnoid hemorrhage via ASC/HIF-1α pathway

Jun Xu1, #, Qian Li1, #, Chen-Yu Xu1, Shan Mao1, Jia-Jia Jin1, Wei Gu1, Ying Shi1, *, Chun-Fang Zou1, 2, *, Liang Ye1, *   

  1. 1Department of Respiration, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China; 2Department of Respiration, Nanjing Yuhua Hospital, Yuhua Branch of Nanjing First Hospital, Nanjing, Jiangsu Province, China
  • Online:2022-11-15 Published:2022-04-23
  • Contact: Ying Shi, PhD, 1339189844@qq.com; Chun-Fang Zou, MD, zouchunfang78@sohu.com; Liang Ye, MD, njyeliang@163.com or yeliang0988@163.com.
  • Supported by:
    This study was supported by the Natural Science Foundation of Jiangsu Province (Youth Program), No. BK20190129, and National Scientific Program of Jiangsu Colleges and Universities of China, No. 19KJB320012 (both to LY).

摘要:

睡眠呼吸暂停可恶化蛛网膜下腔出血的预后,但其机制尚不明确。(1)实验首先通过血管内穿孔方法构建了蛛网膜下腔出血小鼠模型,然后以连续2d每天暴露于8h间歇性缺氧环境以模拟睡眠呼吸暂停,结果发现,睡眠呼吸暂停可加重蛛网膜下腔出血小鼠脑水肿,增加海马神经元凋亡,降低小鼠的神经功能。(2)然后以血红素诱导HT-22 细胞构建了体外蛛网膜下腔出血/间歇性缺氧模型,发现48h后的细胞死亡和乳酸脱氢酶释放增加。(3)进一步机制研究发现,睡眠呼吸暂停增加蛛网膜下腔出血小鼠海马神经炎症因子白细胞介素1β、白细胞介素18、白细胞介素6和核因子κB以及细胞焦亡相关蛋白caspase-1、pro-caspase-1和NLRP3的水平,促进星形胶质细胞增殖,并增加缺氧诱导因子1α/凋亡相关斑点样蛋白信号通路关键蛋白缺氧诱导因子1α和凋亡相关斑点样蛋白的表达。(4)最后在体外敲低缺氧诱导因子1α,结果显示HT22细胞模型的损伤明显减轻。(5)提示睡眠呼吸暂停通过加剧神经炎症和细胞焦亡而加重蛛网膜下腔出血后早期脑损伤,且其作用部分依赖于缺氧诱导因子1α/凋亡相关斑点样蛋白信号通路。

https://orcid.org/0000-0002-4648-4448 (Liang Ye)

关键词: 睡眠呼吸暂停, 蛛网膜下腔出血, 细胞焦亡, 神经炎症, 早期脑损伤, 凋亡相关斑点样蛋白信号, NOD样受体蛋白3, 缺氧诱导因子1α

Abstract: Obstructive sleep apnea can worsen the prognosis of subarachnoid hemorrhage. However, the underlying mechanism remains unclear. In this study, we established a mouse model of subarachnoid hemorrhage using the endovascular perforation method and exposed the mice to intermittent hypoxia for 8 hours daily for 2 consecutive days to simulate sleep apnea. We found that sleep apnea aggravated brain edema, increased hippocampal neuron apoptosis, and worsened neurological function in this mouse model of subarachnoid hemorrhage. Then, we established an in vitro HT-22 cell model of hemin-induced subarachnoid hemorrhage/intermittent hypoxia and found that the cells died, and lactate dehydrogenase release increased, after 48 hours. We further investigated the underlying mechanism and found that sleep apnea increased the expression of hippocampal neuroinflammatory factors interleukin-1β, interleukin-18, interleukin-6, nuclear factor κB, pyroptosis-related protein caspase-1, pro-caspase-1, and NLRP3, promoted the proliferation of astrocytes, and increased the expression of hypoxia-inducible factor 1α and apoptosis-associated speck-like protein containing a CARD, which are the key proteins in the hypoxia-inducible factor 1α/apoptosis-associated speck-like protein containing a CARD signaling pathway. We also found that knockdown of hypoxia-inducible factor 1α expression in vitro greatly reduced the damage to HY22 cells. These findings suggest that sleep apnea aggravates early brain injury after subarachnoid hemorrhage by aggravating neuroinflammation and pyroptosis, at least in part through the hypoxia-inducible factor 1α/apoptosis-associated speck-like protein containing a CARD signaling pathway.

Key words: apoptosis associated speck like protein containing a CARD, early brain injury, hypoxia-inducible factor 1α, nucleotide-binding domain and leucine-rich repeat protein 3, obstructive sleep apnea, pyroptosis, neuroinflammation, subarachnoid hemorrhage