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中华妇幼临床医学杂志(电子版) ›› 2023, Vol. 19 ›› Issue (05) : 540 -549. doi: 10.3877/cma.j.issn.1673-5250.2023.05.007

论著

转录因子12过表达对脓毒症相关性脑病大鼠大脑皮质的保护作用及其机制
张晓燕, 肖东琼, 高沪, 陈琳, 唐发娟, 李熙鸿†()   
  1. 四川大学华西第二医院急诊医学科、出生缺陷与相关妇儿疾病教育部重点实验室，成都　610041
  • 收稿日期:2023-07-01 修回日期:2023-09-08 出版日期:2023-10-01
  • 通信作者: 李熙鸿

The protective effect and mechanism of overexpression of transcription factor 12 on the cerebral cortex of rats with sepsis-associated encephalopathy

Xiaoyan Zhang, Dongqiong Xiao, Hu Gao, Lin Chen, Fajuan Tang, Xihong Li†()   

  1. Department of Emergency Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
  • Received:2023-07-01 Revised:2023-09-08 Published:2023-10-01
  • Corresponding author: Xihong Li
  • Supported by:
    National Natural Science Foundation of China(82071353); Key R&D Project of Sichuan Provincial Department of Science and Technology(2021YFS0029, 2023YFS0025)
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引用本文：

张晓燕, 肖东琼, 高沪, 陈琳, 唐发娟, 李熙鸿. 转录因子12过表达对脓毒症相关性脑病大鼠大脑皮质的保护作用及其机制[J]. 中华妇幼临床医学杂志(电子版), 2023, 19(05): 540-549.

Xiaoyan Zhang, Dongqiong Xiao, Hu Gao, Lin Chen, Fajuan Tang, Xihong Li. The protective effect and mechanism of overexpression of transcription factor 12 on the cerebral cortex of rats with sepsis-associated encephalopathy[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2023, 19(05): 540-549.

目的

探讨转录因子12(Tcf12)过表达，对脓毒症相关性脑病(SAE)大鼠大脑皮质的保护作用及其机制。

方法

选择144只30 d龄Sprague Dawley(SD)雄性大鼠为研究对象。按照处理方法，将其分为盲肠结扎穿孔术(CLP)组、Tcf12阴性对照组(Veh＋CLP组)和Tcf12过表达组(AD-Tcf12 ＋CLP组)和假手术组(Sham组) 4组。对Sham组和CLP组大鼠，在其双侧侧脑室各注射5 μL生理盐水；对AD-Tcf12＋CLP组大鼠采取硬脑膜微量注射5 μL AD-Tcf12，Veh＋CLP组，则硬脑膜微量注射5 μL Veh。侧脑室注射后48 h ，对CLP组、Veh＋CLP组和AD-Tcf12＋CLP组实施CLP，对Sham组仅开腹后翻看盲肠。在造模后3、6、12、24、48 h监测4组大鼠平均动脉压(MAP)、心率和神经行为学评分；其中24 h时，采取苏木精-伊红(HE)染色，激光共聚焦扫描显微镜观察大鼠大脑皮质病理改变；采用Western blotting检测大鼠大脑皮质蛋白(Tcf12、cleaved caspase-3、Bax、Bcl2、P38、p-P38)表达；免疫荧光染色观察在大鼠大脑皮质神经细胞中Tcf12相对表达水平。本实验获得四川大学华西第二医院动物保护研究委员会批准[批准编号：2020动伦审批第(申022)号]，并且按照相应的指南和规则进行动物实验。

结果

①与Sham组比较，CLP组和Veh＋CLP组大鼠MAP、神经行为学评分在造模后不同时间点(3、6、12、24、48 h)呈下降趋势，心率呈增高趋势，均于24 h时最显著，并且差异均有统计学意义(P<0.05)。②与Veh＋CLP组比较，AD-Tcf12＋CLP组MAP、神经行为学评分增高，心率下降，于造模后24 h时最明显，并且差异有统计学意义(P<0.05)。②Western blotting检测结果显示，与Sham组相比，CLP组造模后12、24、48 h时，Tcf12相对表达水平比较，差异均有统计学意义(P＝0.045、0.019、0.030)，其中24 h时达低谷。③造模后24 h时，免疫荧光染色显示，Tcf12表达主要定位在神经元细胞质中。其中24 h时，CLP组SD大鼠Tcf12相对荧光信号为75.11±6.39，显著低于Sham组的101.79±3.89，并且差异有统计学意义(t＝8.73，P<0.001)。④与Sham组比较，CLP组和Veh＋CLP组大鼠凋亡相关cleaved caspase-3和Bax相对表达水平，以及p-P38与P38比值(p-P38/P38)明显升高，Bcl2相对表达水平明显降低，差异均有统计学意义(P<0.05)。⑤HE染色显示，与Sham组比较，Veh＋CLP组与CLP组大鼠大脑皮质组织病理学改变重度异常，可见细胞核固缩、细胞水肿、细胞数目减少、排列紊乱，而AD-Tcf12＋CLP组大鼠皮质病理学改变异常明显好转。

结论

SAE大鼠大脑皮质组织，特别是皮质神经元中Tcf12相对表达水平下调，而Tcf12过表达，对SAE大鼠具有神经保护作用，其病理生理机制可能与抑制大脑皮质神经细胞凋亡有关。

关键词: 转录因子12, 细胞凋亡, 脓毒症相关性脑病, 神经元, 作用机制, 大鼠
Objective

To investigate protective effects and mechanism of overexpressed transcription factor 12 (Tcf12) on the cortex of rats with sepsis-associated encephalopathy (SAE).

Methods

A total of 144 male Sprague Dawley (SD) rats at 30 days of age were selected into this study. They were randomly divided into four groups according to the processing method: cecal ligation and perforation (CLP) model group (CLP group), Tcf12 negative control group (Veh+ CLP group), Tcf12 overexpression group (AD-Tcf12+ CLP group), and sham surgery group (Sham group). The Sham group and CLP group received 5 μL physiological saline injected into each lateral ventricle. The AD-Tcf12+ CLP group received 5 μL AD-Tcf12, and the Veh+ CLP group received 5 μL Veh. After 48 hours of lateral ventricle injection, CLP surgery was performed. The Sham group only underwent laparotomy and examination of the cecum. The mean arterial pressure (MAP), heart rate, and neurobehavioral scores were monitored at 3, 6, 12, 24, and 48 hours after modeling. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the cerebral cortex of each group at 24 hours after modeling. Western blotting was used to detect the protein expression of Tcf12, cleaved caspase-3, Bax, Bcl2, P38, and p-P38 in the cerebral cortex of rats. Immunofluorescence staining was used to observe the expression of Tcf12 in neurons of the cerebral cortex. This experiment was approved by the Animal Protection Research Committee of West China Second University Hospital, Sichuan University [Approval No. 2020(022)], and animal experiments were carried out in accordance with corresponding guidelines and regulations.

Results

① Compared with Sham group, the MAP and neurobehavioral scores of CLP group and Veh+ CLP group showed a decreasing trend at different time points, while heart rate showed an increasing trend. The most significant changes occurred at 24 hours after modeling, and the differences were statistically significant (P<0.05). In addition, the neurobehavioral scores of CLP group and Veh+ CLP group were less than 6 points at 24 hours, consistent with the diagnosis of SAE. ② Compared with Veh+ CLP group, AD-Tcf12+ CLP group showed increased MAP and neurobehavioral scores and decreased heart rate, with the most significant changes occurring 24 hours after modeling, and the differences were statistically significant (P<0.05). ② Western blotting detection results showed that compared with Sham group, there were statistically significant differences in the relative expression levels of Tcf12 at 12, 24, and 48 h after modeling in CLP group (P=0.045, 0.019, 0.030), reaching a low point at 24 hours. ③ Immunofluorescence staining at 24 h after modeling showed that Tcf12 expression was mainly located in the cytoplasm of neurons. At 24 h after modeling, the fluorescence signal of Tcf12 (75.11±6.39) in CLP group SD rats was significantly lower than that in Sham group (101.79±3.89), and the difference was statistically significant (t=8.73, P<0.001). ④ Compared with Sham group, the expression levels of cleaved caspase-3 and Bax, as well as p-P38/P38, were significantly increased in CLP group and Veh+ CLP group rats, while the expression level of Bcl2 protein was significantly decreased, with statistically significant differences (P<0.05). ⑤ HE staining showed that compared with Sham group, there were significant pathological changes in the cerebral cortex tissue of Veh+ CLP group and CLP group rats, including nuclear condensation, cell edema, decreased cell number, and disordered arrangement. However, the pathological changes in the cerebral cortex tissue of AD-Tcf12+ CLP group rats were significantly improved.

Conclusions

The expression of Tcf12 is downregulated in the cortical tissue of rats with SAE, especially in cortical neurons. Overexpression of Tcf12 could have neuroprotective effects on rats with SAE, and its mechanism might be related to the neuronal apoptosis inhibited in the cerebral cortex.

Key words: Transcription factor 12, Apoptosis, Sepsis related encephalopathy, Neurons, Mechanism, Rats
表1 4组30 d龄雄性SD大鼠不同时间点平均动脉压比较(mmHg，±s)
组别 鼠数(只) 3 h 6 h 12 h 24 h 48 h
①CLP组 6 96.5±3.6 95.7±3.1 81.0±2.4 63.5±4.4 78.0±1.8
②AD-Tcf12＋CLP组 6 98.8±2.0 97.0±2.4 95.2±3.4 91.5±2.7 94.2±3.7
③Veh＋CLP组 6 97.0±4.3 96.0±4.7 79.8±1.3 64.5±3.1 76.2±3.1
④Sham组 6 100.0±2.1 100.0±1.7 100.3±2.6 102.5±1.6 103.8±4.0
总体比较            
F值   1.58 2.30 99.05 237.11 100.47
P值   0.225 0.109 <0.001 <0.001 <0.001
多重比较的P值            
① vs ④   0.419 0.173 <0.001 <0.001 <0.001
③ vs ④   0.698 0.252 <0.001 <0.001 <0.001
③ vs ①   >0.999 >0.999 >0.999 >0.999 >0.999
② vs ③   >0.999 >0.999 <0.001 <0.001 <0.001
表2 4组30 d龄雄性SD大鼠不同时间点心率比较(次/min，±s)
组别 鼠数(只) 3 h 6 h 12 h 24 h 48 h
①CLP组 6 334.7±8.4 336.0±7.2 375.0±4.7 415.8±9.6 392.8±8.7
②AD-Tcf12＋CLP组 6 335.8±5.3 335.8±5.1 352.7±5.0 379.5±5.2 361.0±4.5
③Veh＋CLP组 6 335.2±6.0 336.8±7.9 376.2±7.6 417.8±9.8 396.7±8.6
④Sham组 6 330.3±2.1 330.3±3.5 332.5±8.1 330.8±7.8 333.5±6.7
总体比较            
F值   1.08 1.40 60.30 144.40 98.97
P值   0.382 0.273 <0.001 <0.001 <0.001
多重比较的P值            
① vs ④   >0.999 0.764 <0.001 <0.001 <0.001
③ vs ④   >0.999 0.498 <0.001 <0.001 <0.001
③ vs ①   >0.999 >0.999 >0.999 >0.999 >0.999
② vs ③   >0.999 >0.999 <0.001 <0.001 <0.001
表3 4组30 d龄雄性SD大鼠不同时间点神经行为学评分(分，±s)
组别 鼠数(只) 3 h 6 h 12 h 24 h 48 h
①CLP组 6 9.17±0.75 8.00±1.10 6.33±0.82 4.17±0.75 5.00±0.63
②AD-Tcf12＋CLP组 6 9.17±0.75 8.83±1.17 7.67±1.21 6.83±0.75 7.50±1.05
③Veh＋CLP组 6 9.00±0.89 8.17±1.17 6.17±0.75 4.17±0.75 5.33±1.37
④Sham组 6 10.00±0.00 10.00±0.00 10.00±0.00 10.00±0.00 10.00±0.00
总体比较            
F值   2.53 5.03 27.88 108.60 38.07
P值   0.086 0.009 <0.001 <0.001 <0.001
多重比较的P值            
① vs ④   0.306 0.014 <0.001 <0.001 <0.001
③ vs ④   0.130 0.027 <0.001 <0.001 <0.001
③ vs ①   >0.999 >0.999 >0.999 >0.999 >0.999
② vs ③   >0.999 >0.999 0.029 <0.001 0.003
图1 Western blotting检测Sham组和CLP组SD大鼠不同时间点大脑皮质神经细胞中Tcf12的相对表达水平注：CLP为盲肠结扎穿孔术
表4 Sham组与CLP组SD大鼠不同时间点大脑皮质神经细胞中Tcf12的相对表达水平比较(±s)
组别 鼠数(只) Tcf12
CLP组    
①术后3 h 6 1.05±0.26
②术后6 h 6 1.01±0.19
③术后12 h 6 0.81±0.20
④术后24 h 6 0.77±0.16
⑤术后48 h 6 0.79±0.16
⑥Sham组 6 1.17±0.19
总体比较    
F值   4.37
P值   0.004
多重比较的P值    
① vs ⑥   >0.999
② vs ⑥   >0.999
③ vs ⑥   0.045
④ vs ⑥   0.019
⑤ vs ⑥   0.030
图2 Sham组及CLP组SD大鼠造模后24 h时大脑皮质神经细胞中Tcf12表达及定位[图2A～2D分别为CLP组DAPI(蓝色)、Tcf12(绿色)、NeuN(红色)、Merge；图2E～2H分别为Sham组DAPI(蓝色)、Tcf12(绿色)、NeuN(红色)、Merge](免疫荧光染色，高倍)注：CLP为盲肠结肠穿孔术
图3 Western blotting检测4组SD大鼠造模后24 h时大脑皮质神经细胞中cleaved caspase-3、Bax、Bcl2、p-P38和P38相对表达水平
表5 4组30 d龄SD大鼠造模后24 h时cleaved caspase-3、Bax、Bcl2、p-P38/P38相对表达水平比较(±s)
组别 鼠数(只) cleaved caspase-3 Bax Bcl2 p-P38/P38
①CLP组 6 1.47±0.05 1.67±0.04 0.48±0.04 1.09±0.04
②AD-Tcf12＋CLP组 6 0.71±0.05 0.88±0.04 0.81±0.04 0.53±0.04
③Veh＋CLP组 6 1.49±0.04 1.68±0.04 0.48±0.03 1.07±0.06
④Sham组 6 0.47±0.06 0.71±0.05 1.00±0.06 0.40±0.02
总体比较          
F值   642.68 883.33 228.77 437.75
P值   <0.001 <0.001 <0.001 <0.001
多重比较的P值          
① vs ④   <0.001 <0.001 <0.001 <0.001
③ vs ①   >0.999 >0.999 >0.999 >0.999
② vs ③   <0.001 <0.001 <0.001 <0.001
图4 4组30 d龄SD大鼠造模后24 h时大脑皮质病理改变(图4A：CLP组与Veh＋CLP组大鼠大脑皮质组织病理改变相似，可见细胞核固缩，细胞水肿，细胞数目减少，排列紊乱、空泡改变；图4B：AD-Tcf12＋CLP组大鼠大脑皮质组织病理改变较CLP组与Veh＋CLP组明显好转，细胞水肿有所改善，形态结构及排列较规整；图4C：Veh＋CLP组；图4D：Sham组大鼠大脑皮质细胞排列有序、结构规整)(HE染色，中倍)注：CLP为盲肠结肠穿孔术
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