Emergency Department, Shenzhen University General Hospital, Shenzhen, China.
Emergency Center, Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong, China.
Environ Toxicol. 2021 Sep;36(9):1742-1757. doi: 10.1002/tox.23295. Epub 2021 May 25.
Oxidative stress has been considered as an important cause of neurocyte damage induced by carbon monoxide (CO) poisoning; however, the precise mechanisms are not fully understood. The study aimed to elucidate the molecular mechanism and the neuroprotective effect of targeted regulatory nuclear factor erythroid2-related factor 2 (Nrf2) gene on acute brain injury in CO poisoning rats. An acute CO poisoning rat model was established by CO inhalation in hyperbaric oxygen chamber and followed by the administration of Nrf2 gene-loaded lentivirus. Mitochondrial membrane potential (ΔΨM), the levels of Nrf2, glutamate-cysteine ligase catalytic subunit (GCLC), catalase (CAT) and glutathione peroxidase (GSH-Px), and cell apoptosis were determined in brain tissue in rats. We found that CO poisoning could decrease ΔΨm of cells, slightly increase the expressions of Nrf2 and GCLC at mRNA and protein levels, reduce CAT and GSH-Px, and thus initiate apoptosis process. The Nrf2 gene treatment could obviously enhance the expressions of Nrf2 at mRNA and protein levels, and increase the concentrations of CAT and GSH-Px, maintain the ΔΨm of cells in brain tissue, significantly inhibit cell apoptosis as compared with the CO poisoning group (p < .05). These findings suggest that CO poisoning could induce oxidative stress and impair mitochondrial function of cells in brain tissue. The administration of Nrf2 gene could notably strengthen the antioxidant capacity of cells through regulating the downstream genes of Nrf2/antioxidant responsive element signal pathway, and positively protect cells against brain injury induced by acute severe CO poisoning.
氧化应激被认为是一氧化碳（CO）中毒引起神经细胞损伤的重要原因，但确切机制尚不完全清楚。本研究旨在阐明靶向调节核因子红细胞 2 相关因子 2（Nrf2）基因对 CO 中毒大鼠急性脑损伤的分子机制和神经保护作用。通过高压氧舱 CO 吸入建立急性 CO 中毒大鼠模型，然后给予 Nrf2 基因负载的慢病毒。测定大鼠脑组织中线粒体膜电位（ΔΨm）、Nrf2、谷氨酸-半胱氨酸连接酶催化亚基（GCLC）、过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GSH-Px）水平以及细胞凋亡情况。结果发现，CO 中毒可降低细胞 ΔΨm，轻度增加 Nrf2 和 GCLC 在 mRNA 和蛋白水平的表达，降低 CAT 和 GSH-Px，从而启动细胞凋亡过程。Nrf2 基因治疗可明显增强 Nrf2 在 mRNA 和蛋白水平的表达，增加 CAT 和 GSH-Px 的浓度，维持脑组织细胞的 ΔΨm，与 CO 中毒组相比，明显抑制细胞凋亡（p<0.05）。这些发现表明，CO 中毒可诱导氧化应激，损害脑组织细胞的线粒体功能。Nrf2 基因治疗可通过调节 Nrf2/抗氧化反应元件信号通路的下游基因，显著增强细胞的抗氧化能力，积极保护细胞免受急性重度 CO 中毒引起的脑损伤。
