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摘要:
目的 探讨氨基胍对急性肝损伤小鼠的作用及其机制,为烧伤急性肝损伤和研究奠定理论基础。 方法 该研究采用成组设计为实验研究。取60只6~8周龄雄性C57BL/6J小鼠,按随机数字表法分为空白对照组、模型组、氨基胍对照组、氨基胍干预组,每组15只。模型组和氨基胍干预组小鼠均通过腹腔注射内毒素/脂多糖+D-氨基半乳糖诱导急性肝损伤进行造模,其中氨基胍干预组小鼠在造模12 h前经腹腔注射氨基胍；氨基胍对照组小鼠仅经腹腔注射氨基胍；空白对照组小鼠经腹腔注射的磷酸盐缓冲液。造模后6 h,采用苏木精-伊红染色检测空白对照组、模型组、氨基胍干预组小鼠肝组织的病理情况；按照试剂盒说明书,采用酶标仪检测空白对照组、模型组、氨基胍干预组小鼠血清中天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）水平及肝组织中丙二醛、谷胱甘肽和铁离子含量；采用原位末端标记染色法检测空白对照组、模型组、氨基胍干预组小鼠肝组织中细胞凋亡情况；采用实时荧光定量反转录PCR法检测空白对照组、模型组、氨基胍对照组、氨基胍干预组小鼠肝组织中一氧化氮合酶2（NOS2）、白细胞介素（IL）-18、IL-1β、NOD样受体热蛋白结构域相关蛋白3（NLRP3）等炎症基因的mRNA水平；采用蛋白质印迹法检测空白对照组、模型组、氨基胍对照组、氨基胍干预组小鼠肝组织中铁死亡标志蛋白酰基辅酶A合成酶长链家族成员4（ACSL4）、谷胱甘肽过氧化物酶4（GPX4）及炎症相关通路蛋白NLRP3的相对表达量及磷酸化P65（p-P65）与P65比值。 结果 造模后6 h,空白对照组小鼠肝小叶结构完整,肝细胞索排列规整,无炎症细胞浸润及肝细胞坏死现象；模型组小鼠肝小叶结构异常,肝细胞索排列紊乱,肝细胞坏死,炎症细胞大量浸润,肝窦扩张充血；氨基胍干预组小鼠病理损伤程度介于空白对照组与模型组之间。造模后6 h,与空白对照组相比,模型组小鼠血清中AST、ALT水平均明显升高（P<0.05）；与模型组相比,氨基胍干预组小鼠血清中AST、ALT水平均明显下降（P<0.05）。造模后6 h,与空白对照组相比,模型组小鼠肝组织中丙二醛、铁离子含量均明显升高（P<0.05）,谷胱甘肽含量明显降低（P<0.05）；与模型组相比,氨基胍干预组小鼠肝组织中丙二醛含量明显降低（P<0.05）,谷胱甘肽含量明显升高（P<0.05）。造模后6 h,模型组小鼠肝组织中凋亡细胞占比为26.93%,明显高于空白对照组的0.43%（P<0.05）和氨基胍干预组的0.37%（P<0.05）。造模后6 h,空白对照组与氨基胍对照组小鼠肝组织中NOS2、IL-18、IL-1β、NLRP3的mRNA水平比较,差异均无统计学意义（P>0.05）；与空白对照组相比,模型组小鼠肝组织中前述基因的mRNA水平均明显升高（P<0.05）；与模型组相比,氨基胍干预组小鼠肝组织中前述基因的mRNA水平均明显降低（P<0.05）。造模后6 h,空白对照组与氨基胍对照组小鼠肝组织中ACSL4、NLRP3、GPX4的相对表达量及p-P65与P65比值比较,差异均无统计学意义（P>0.05）；与空白对照组相比,模型组小鼠肝组织中ACSL4、NLRP3的相对表达量及p-P65与P65比值均明显升高（P<0.05）,GPX4的相对表达量明显降低（P<0.05）；与模型组相比,氨基胍干预组小鼠肝组织中ACSL4、NLRP3的相对表达量及p-P65与P65比值均明显下降（P<0.05）,GPX4的相对表达量明显升高（P<0.05）。 结论 氨基胍能够通过下调炎症反应和抑制铁死亡,改善肝功能,减轻内毒素/脂多糖+D-氨基半乳糖诱导的小鼠急性肝损伤。 Abstract:Objective To explore the effect and mechanism of aminoguanidine on acute liver injury in mice. Methods This was an experimental study. Sixty 6-8-week-old male C57BL/6J mice were randomly divided into blank control group, model group, aminoguanidine control group, and aminoguanidine intervention group, with 15 mice in each group. Mice in model group and aminoguanidine intervention group were induced to acute liver injury by intraperitoneal injection of lipopolysaccharide+D-galactosamine, and mice in aminoguanidine intervention group were intraperitoneally injected with aminoguanidine 12 hours before modeling; mice in aminoguanidine control group were only intraperitoneally injected with an equal amount of aminoguanidine; mice in blank control group were intraperitoneally injected with an equal volume of phosphate buffered saline. At 6 hours after modeling, hematoxylin-eosin staining was used to detect the pathological conditions of liver tissues in blank control group, model group, and aminoguanidine intervention group. According to the kit instructions, a microplate reader was used to determine the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of mice in blank control group, model group and aminoguanidine intervention group, as well as the contents of malondialdehyde (MDA), glutathione (GSH) and iron ions in the liver tissues. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the cell apoptosis in liver tissues of mice in blank control group, model group, and aminoguanidine intervention group. Reverse transcription polymerase chain reaction was used to detect the mRNA levels of inflammatory factors such as nitric oxide synthase 2 (NOS2), interleukin (IL)-18, IL-1β, and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) in liver tissues of mice in blank control group, model group, aminoguanidine control group, and aminoguanidine intervention group. Western blotting was used to detect the relative expression levels of ferroptosis marker proteins acyl-CoA synthetase long-chain family member 4 (ACSL4), GSH peroxidase 4 (GPX4), and inflammation-related pathway protein NLRP3 and Phosphorylated P65 (p-P65)/P65 ratio in liver tissues of mice in blank control group, model group, aminoguanidine control group, and aminoguanidine intervention group. Results At 6 hours after modeling, the liver lobule structure of mice in blank control group was intact, the arrangement of hepatocyte cords was regular, and there was no inflammatory cell infiltration or hepatocyte necrosis. The liver lobule structure of mice in model group was abnormal, the arrangement of hepatocyte cords was disordered, hepatocytes were necrotic, and there was a large amount of inflammatory cell infiltration and liver sinus dilation and congestion. The degree of pathological damage in aminoguanidine intervention group was between that of blank control group and model group. At 6 hours after modeling, compared with that in blank control group, the levels of AST and ALT in the serum of mice in model group were significantly increased (P<0.05); compared with that in model group, the levels of AST and ALT in the serum of mice in aminoguanidine intervention group were significantly decreased (P<0.05). At 6 hours after modeling, compared with that in blank control group, the contents of MDA and iron ions in liver tissues of mice in model group were significantly increased (P<0.05), and the content of GSH was significantly decreased (P<0.05); compared with that in model group, the content of MDA in liver tissues of mice in aminoguanidine intervention group was significantly decreased (P<0.05), and the level of GSH was significantly increased (P<0.05). At 6 hours after modeling, the proportion of TUNEL-positive cells in liver tissues of mice in model group was 26.93%, which was significantly higher than 0.43% in blank control group (P<0.05); the proportion of TUNEL-positive cells in liver tissues of mice in aminoguanidine intervention group was 0.37%, which was significantly lower than that in model group (P<0.05). At 6 hours after modeling, compared with that in blank control group, the aminoguanidine control group of mice showed no statistically significant differences in the mRNA levels of NOS2, IL-18, IL-1β, and NLRP3 in the liver tissues (P>0.05); compared with that in blank control group, the mRNA levels of aforementioned genes in liver tissues of mice in model group were significantly increased (P<0.05); compared with that in model group, the mRNA levels of aforementioned genes in liver tissues of mice in aminoguanidine intervention group were significantly decreased (P<0.05). At 6 hours after modeling, Compared with that in blank control group, the aminoguanidine control group of mice showed no statistically significant differences in the relative expression levels of ACSL4, NLRP3, and GPX4 or p-P65/P65 ratio in liver tissues (P > 0.05); compared with that in blank control group, the relative expression levels of ACSL4 and NLRP3 or p-P65/P65 ratio in the liver tissues of mice in model group were significantly increased (P<0.05), while the relative expression level of GPX4 was significantly decreased (P<0.05). Compared with that in model group, the relative expression levels of ACSL4 and NLRP3 or p-P65/P65 ratio in aminoguanidine intervention group were significantly decreased (P<0.05), and the relative expression level of GPX4 protein was significantly increased (P<0.05). Conclusions Aminoguanidine can improve liver function and alleviate acute liver injury induced by lipopolysaccharide+D-galactosamine in mice by down-regulating inflammatory response and inhibiting ferroptosis. -
Key words:
- Ferroptosis /
- Inflammation /
- Aminoguanidine /
- Liver injury /
- Lipopolysaccharide /
- D-(+)-galactosamine
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参考文献
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图 1 2组小鼠造模后24 h内的生存比例比较
注：模型组（12只）和氨基胍干预组（8只）小鼠均通过腹腔注射内毒素/脂多糖+D-氨基半乳糖诱导急性肝损伤,其中氨基胍干预组小鼠在造模12 h前经腹腔注射氨基胍；与模型组相比,aP<0.05
图 2 3组小鼠造模后6 h时肝脏大体形态及肝组织病理情况。2A、2B、2C.分别为空白对照组、模型组、氨基胍干预组肝脏大体形态,图2B中的肝脏颜色呈暗红色,形态异常；2D、2E、2F.分别为空白对照组、模型组、氨基胍干预组肝组织病理情况,图2E中肝组织病理损伤严重,干细胞大量坏死（箭头所示） 苏木精-伊红 ×400
注：模型组和氨基胍干预组小鼠均通过腹腔注射内毒素/脂多糖+D-氨基半乳糖诱导急性肝损伤进行造模,其中氨基胍干预组小鼠在造模12 h前经腹腔注射氨基胍；空白对照组小鼠经腹腔注射磷酸盐缓冲液
图 3 3组小鼠造模后6 h时肝组织中细胞凋亡情况 藻红蛋白-4',6-二脒基-2-苯基吲哚 ×200。3A、3B、3C.分别为空白对照组、模型组、氨基胍干预组,图3B中凋亡细胞占比明显高于图3A,3C中凋亡细胞占比明显低于图3B
注：模型组和氨基胍干预组小鼠均通过腹腔注射内毒素/脂多糖+D-氨基半乳糖诱导急性肝损伤,其中氨基胍干预组小鼠在造模12 h前经腹腔注射氨基胍；空白对照组小鼠经腹腔注射等体积的磷酸盐缓冲液；活细胞阳性染色为蓝色,凋亡细胞阳性颜色为红色
图 4 3组小鼠造模后6 h时肝组织中4-HNE阳性细胞情况 辣根过氧化物酶-苏木精×400。4A、4B、4C.分别为空白对照组、模型组、氨基胍干预组,图4B中凋亡细胞占比明显高于图4A,4C中凋亡细胞占比明显低于图4B
注：模型组和氨基胍干预组小鼠均通过腹腔注射内毒素/脂多糖+D-氨基半乳糖诱导急性肝损伤,其中氨基胍干预组小鼠在造模12 h前经腹腔注射氨基胍；空白对照组小鼠经腹腔注射等体积的磷酸盐缓冲液；4-HNE为4-羟基壬烯醛；目标细胞阳性染色为棕褐色,细胞核阳性染色为蓝色
图 5 蛋白质印迹法检测的4组小鼠造模后6 h时肝组织中炎症相关通路蛋白的表达
注：模型组和氨基胍干预组小鼠均通过腹腔注射内毒素/脂多糖+D-氨基半乳糖诱导急性肝损伤,其中氨基胍干预组小鼠在造模12 h前经腹腔注射氨基胍；氨基胍对照组小鼠仅经腹腔注射等量氨基胍；空白对照组小鼠经腹腔注射等体积的磷酸盐缓冲液；条带图上方的1、2、3、4分别指空白对照组、氨基胍对照组、模型组和氨基胍干预组；NLRP3为NOD样受体热蛋白结构域相关蛋白3
图 6 蛋白质印迹法检测的4组小鼠造模后6 h时肝组织中铁死亡标志蛋白的表达
注：模型组和氨基胍干预组小鼠均通过腹腔注射内毒素/脂多糖+D-氨基半乳糖诱导急性肝损伤,其中氨基胍干预组小鼠在造模12 h前经腹腔注射氨基胍；氨基胍对照组小鼠仅经腹腔注射等量氨基胍；空白对照组小鼠经腹腔注射等体积的磷酸盐缓冲液；条带图上方的1、2、3、4分别指空白对照组、氨基胍对照组、模型组和氨基胍干预组；ACSL4为酰基辅酶A合成酶长链家族成员4,GPX4为谷胱甘肽过氧化物酶4
Table 1. 3组小鼠造模后6 h时肝组织的氧化应激水平及铁离子含量比较（
组别 样本数 丙二醛（nmol/g） 谷胱甘肽（μg/g） 铁离子（μmol/L） 空白对照组 3 7.1±2.0 16.3±0.5 8.9±3.6 模型组 3 19.0±4.4 7.4±0.4 25.8±8.4 氨基胍干预组 3 5.9±1.8 16.4±5.3 14.4±0.4 F值 17.63 12.86 7.959 P值 0.003 <0.001 0.020 P1值 0.007 0.036 0.018 P2值 0.004 0.001 0.085 注：模型组和氨基胍干预组小鼠均通过腹腔注射内毒素/脂多糖+D-氨基半乳糖诱导急性肝损伤进行造模,其中氨基胍干预组小鼠在造模12 h前经腹腔注射氨基胍；空白对照组小鼠经腹腔注射等体积的磷酸盐缓冲液；F值、P值为3组间各指标总体比较所得；P1值为模型组与空白对照组各指标比较所得；P2值为氨基胍干预组与模型组各指标比较所得 
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Table 2. 4组小鼠造模后6 h时肝组织中炎症基因的mRNA水平比较（
组别 样本数 NOS2 IL-18 IL-1β NLRP3 空白对照组 3 0.001 14±0.000 42 0.796±0.022 0.028 0±0.001 3 0.111 1±0.004 3 氨基胍对照组 3 0.001 84±0.000 24 0.786±0.224 0.029 4±0.002 0 0.083 0±0.001 7 模型组 3 1.818 00±0.086 00 1.603±0.202 1.848 0±0.401 8 1.974 0±0.148 5 氨基胍干预组 3 0.450 60±0.293 20 0.991±0.065 0.620 7±0.131 4 0.805 1±0.342 1 F值 95.01 15.46 49.28 67.56 P值 <0.001 0.002 <0.001 <0.001 P1值 >0.999 >0.999 >0.999 0.998 P2值 <0.001 0.004 <0.001 <0.001 P3值 <0.001 0.011 <0.001 0.006 注：NOS2为诱导型一氧化氮合酶2,IL为白细胞介素,NLRP3为NOD样受体热蛋白结构域相关蛋白3；模型组和氨基胍干预组小鼠均通过腹腔注射内毒素/脂多糖+D-氨基半乳糖诱导急性肝损伤,其中氨基胍干预组小鼠在造模12 h前经腹腔注射氨基胍；氨基胍对照组小鼠仅经腹腔注射等量氨基胍；空白对照组小鼠经腹腔注射等体积的磷酸盐缓冲液；F值、P值为3组间各指标总体比较所得；P1值为空白对照组与氨基胍对照组各指标比较所得；P2值为模型组与空白对照组各指标比较所得；P3值为氨基胍干预组与模型组各指标比较所得
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