摘要
目的探讨红系衍生的核因子2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf-2)激动剂特丁基对苯二酚(tert-butylhydroquinone,tBHQ)对氮芥(nitrogen mustard,HN2)诱导急性肝损伤的保护作用及其机制。方法给予C57BL/6小鼠腹腔单次注射盐酸HN2(2 mg/kg)构建HN2诱导急性肝损伤模型,染毒前0.5 h、染毒后1h和6h分别给予tBHQ(20 mg/kg)进行干预,HN2染毒3天后处死小鼠并取材检测,进而探讨tBHQ对HN2诱导的小鼠急性肝损伤是否具有保护作用并研究其保护机制。检测指标如下:肝组织大体改变和苏木精-伊红(hematoxylin-eosin,HE)染色病理变化;血清谷氨酸氨基转移酶(alanine aminotransferase,ALT)和天门冬氨酸氨基转移酶(aspartate aminotransferase,AST)活性;肝组织活性氧(reactive oxygen species,ROS)水平,丙二醛(malondialdehyde,MDA)含量,还原型谷胱甘肽(reduced glutathione,GSH)含量;肝组织髓过氧化物酶(myeloperoxidase,MPO)活性,血清炎症因子肿瘤坏死因子α(tumor necrosis factor alpha,TNF-α)、白细胞介素6(interleukin 6,IL-6)含量;肝组织氧化还原调控分子Nrf-2的mRNA和蛋白表达水平。结果2 mg/kg的HN2单次腹腔暴露可以成功诱导小鼠肝组织氧化损伤和炎症反应。与HN2染毒组小鼠相比,tBHQ干预显著减轻小鼠肝组织病理损伤程度,血清ALT和AST活性降低(P均<0.05)。同时tBHQ显著抑制了HN2染毒导致的肝组织ROS水平和MDA含量升高及GSH含量降低(P均<0.05)。此外,HN2+tBHQ治疗组小鼠的肝组织MPO活性及血清TNF-α、IL-6含量较HN2染毒组均显著降低(P均<0.05)。最后,tBHQ干预上调了HN2染毒后Nrf-2的mRNA和蛋白表达水平(P均<0.05)。结论tBHQ通过激活Nrf-2发挥抗氧化和抗炎作用,能够有效减轻HN2染毒诱导的急性肝损伤,tBHQ可能是一种HN2中毒临床救治的有效候选药物。
Objective To investigate the protective effects and machanisms of erythroid-derived nuclear factor erythroid 2-related factor 2(Nrf-2) agonist tert-butylhydroquinone(tBHQ) against nitrogen mustard(HN2) induced acute liver injury.Methods C57 BL/6 mice were given a single intraperitoneal injection of hydrochloride HN2(2 mg/kg) to establish the HN2-induced acute liver injury model, and these mice were given tBHQ(20 mg/kg) for intervention 0.5 h before, 1 h and 6 h after exposure of HN2, mice were sacrificed 3 days after exposure to HN2 and the samples were collected for detection, and then to explore whether tBHQ had a protective effect on HN2-induced acute liver injury in mice and to study its protective mechanisms. The following indicators were detected: general changes in liver tissue and pathological changes by hematoxylin-eosin(HE) staining;serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) activities;reactive oxygen species(ROS) level of liver tissue, malondialdehyde(MDA) content, reduced glutathione(GSH) content;myeloperoxidase(MPO) activities of liver tissue, serum inflammatory factor of tumor necrosis factor alpha(TNF-α) and interleukin 6(IL-6) content;mRNA and protein expression levels of redox regulatory molecule Nrf-2 in liver tissue.Results A single intraperitoneal exposure of 2 mg/kg HN2 could successfully induce oxidative damage and inflammatory response in liver tissue in mice. Compared with HN2-exposed mice, tBHQ intervention significantly reduced the degree of pathological damage in the liver tissue of mice, and decreased the activities of serum ALT and AST(all P<0.05). At the same time, tBHQ treatment significantly inhibited the increase of ROS level and MDA content and the decrease of GSH content in liver tissue caused by HN2 exposure(all P<0.05). In addition, the MPO activities in liver tissue and the contents of serum TNF-α and IL-6 in the HN2+tBHQ treatment group were significantly lower than those in the HN2 exposure group(all P<0.05). Finally, tBHQ intervention up-regulated the mRNA and protein expression levels of Nrf-2 in the liver of mice exposed to HN2(all P<0.05).Conclusion tBHQ exerts antioxidant and anti-inflammatory effects by activating Nrf-2, which can effectively alleviate HN2 exposure-induced acute liver injury, and tBHQ may be an effective candidate drug for the clinical treatment for HN2 poisoning.
作者
徐安琦
艾多
马丞飞
刘建豪
刘思佳
赵昱舜
孔德钦
刘颖
龙子
刘江正
XU Anqi;AI Duo;MA Chengfei;LIU Jianhao;LIU Sijia;ZHAO Yushun;KONG Deqin;LIU Ying;LONG Zi;LIU Jiangzheng(School of Basic Medicine,Air Force Medical University,Xi'an Shaanxi 710032,China)
出处
《华南国防医学杂志》
CAS
2022年第11期845-852,共8页
Military Medical Journal of South China
基金
国家自然科学基金青年基金资助项目(31900892)。
关键词
特丁基对苯二酚
氮芥
肝损伤
氧化应激
炎症
保护作用
Tert-butylhydroquinone
Nitrogen mustard
Liver injury
Oxidative stress
Inflammation
Protective effect