丁酸钠对猪心脏骤停复苏后心脑损伤的保护作用及机制研究

doi:10.3877/cma.j.issn.1674-6880.2023.05.002

中华危重症医学杂志(电子版) ›› 2023, Vol. 16 ›› Issue (05) : 355 -362. doi: 10.3877/cma.j.issn.1674-6880.2023.05.002

论著

丁酸钠对猪心脏骤停复苏后心脑损伤的保护作用及机制研究

孔莹莹, 谢璐涛, 卢晓驰, 徐杰丰, 周光居, 张茂^†(

)

310009　杭州，浙江大学医学院附属第二医院急诊医学科/浙江省严重创伤与烧伤诊治重点实验室/浙江省急危重症临床医学研究中心；现工作单位为绍兴第二医院急诊科
323000　浙江丽水，丽水市中心医院急诊医学科
310009　杭州，浙江大学医学院附属第二医院急诊医学科/浙江省严重创伤与烧伤诊治重点实验室/浙江省急危重症临床医学研究中心

收稿日期:2023-06-01 出版日期:2023-10-31
通信作者: 张茂
基金资助:
国家自然科学基金项目(82072126); 浙江省重点研发计划项目(2021C03073、2021C03036); 丽水市科技计划项目(2022SJZC014)

Protective effect and mechanism of sodium butyrate on cardio-brain injury after cardiac arrest resuscitation in pigs

Yingying Kong, Lutao Xie, Xiaochi Lu, Jiefeng Xu, Guangju Zhou, Mao Zhang^†()

Department of Emergency Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine/Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Severe Trauma and Burn/Zhejiang Provincial Acute and Critical Care Clinical Medical Research Center, Hangzhou 310009, China
Department of Emergency Medicine, Lishui Municipal Central Hospital, Lishui 323000, China

Received:2023-06-01 Published:2023-10-31
Corresponding author: Mao Zhang

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引用本文：

孔莹莹, 谢璐涛, 卢晓驰, 徐杰丰, 周光居, 张茂. 丁酸钠对猪心脏骤停复苏后心脑损伤的保护作用及机制研究[J]. 中华危重症医学杂志(电子版), 2023, 16(05): 355-362.

Yingying Kong, Lutao Xie, Xiaochi Lu, Jiefeng Xu, Guangju Zhou, Mao Zhang. Protective effect and mechanism of sodium butyrate on cardio-brain injury after cardiac arrest resuscitation in pigs[J]. Chinese Journal of Critical Care Medicine(Electronic Edition), 2023, 16(05): 355-362.

目的

探讨丁酸钠对猪心肺复苏后心脑损伤的保护效果及作用机制。

方法

采用随机数字法将24头健康国产雄性大白猪分为假手术组（n = 6）、心肺复苏组（n = 10）和丁酸钠组（n = 8）。假手术组只行气管插管和动静脉置管，不进行诱导心室颤动及心肺复苏。心肺复苏组和丁酸钠组动物采用电刺激法诱导心室颤动9 min、心肺复苏6 min的方法制备猪心脏骤停-心肺复苏模型。于复苏成功后5 min时，丁酸钠组经股静脉泵入丁酸钠75 mg/kg维持1 h。假手术组和心肺复苏组采用同样方法给予等量等渗NaCl溶液。于心脏骤停前和复苏后1、2、4和24 h时采集静脉血样，应用酶联免疫吸附测定法检测血清心肌肌钙蛋白I（cTnI）、肌酸激酶同工酶（CK-MB）、神经元特异性烯醇化酶（NSE）和S100钙结合蛋白B（S100B）表达水平。于复苏后24 h时，应用蛋白印迹法检测动物心肌及大脑皮层组织微管相关蛋白1轻链3（LC3）、泛素结合蛋白62（p62）蛋白表达水平，并采用TUNEL法检测细胞凋亡率。

结果

心肺复苏组有9头猪复苏成功，其中7头存活至24 h；丁酸钠组有7头猪复苏成功，且均存活至24 h。3组动物24 h复苏成功情况比较，差异无统计学意义（χ² = 3.381，P = 0.184）。复苏后1、2、4、24 h，3组动物血清cTnI（F = 62.736、201.265、330.083、643.538，P均< 0.001）、CK-MB（F = 90.380、181.548、669.657、707.485，P均< 0.001）、NSE（F = 92.302、125.730、590.627、1 130.372，P均< 0.001）和S100B（F = 42.831、152.004、295.517、1 023.409，P均< 0.001）水平比较，差异均有统计学意义。与假手术组相比，心肺复苏组与丁酸钠组动物复苏后出现心脑损伤，表现为复苏后2、4、24 h血清cTnI、CK-MB、NSE和S100B水平均显著升高，且心肺复苏组更高（P均< 0.05）。复苏后24 h时，3组动物心肌细胞及大脑皮层细胞自噬标记物LC3（F = 81.671、49.204，P均< 0.001）、p62（F = 127.620、65.594，P均< 0.001）水平及凋亡率（F = 116.750、249.105，P均< 0.001）比较，差异均有统计学意义。与假手术组相比，心肺复苏组与丁酸钠组动物复苏后24 h心肌组织及大脑皮层组织LC3表达均增加、p62表达均减少、细胞凋亡指数均显著升高（P均< 0.05）。但与心肺复苏组相比，丁酸钠组复苏后24 h心肌组织及大脑皮层组织LC3表达均减少、p62表达均增加、细胞凋亡指数均显著降低（P均< 0.05）。

结论

丁酸钠对心脏骤停复苏后心脑损伤具有保护作用，机制可能与抑制细胞自噬及凋亡有关。

关键词: 丁酸钠, 心脏骤停, 心肺复苏, 心肌损伤, 脑损伤, 自噬, 细胞凋亡

Objective

To explore the protective effect and mechanism of sodium butyrate on cardio-brain injury after cardiopulmonary resuscitation in pigs.

Methods

A total of 24 large white healthy male pigs were divided into a sham operation group (n = 6), a cardiopulmonary resuscitation group (n = 10) and a sodium butyrate group (n = 8) by a random number method. In the sham operation group, only tracheal intubation and arteriovenous catheterization were performed, and induced ventricular fibrillation and cardiopulmonary resuscitation were not performed. Cardiac arrest and cardiopulmonary resuscitation models were prepared by electrical stimulation for 9 min and cardiopulmonary resuscitation for 6 min. At 5 min after successful resuscitation, the sodium butyrate group was injected 75 mg/kg of sodium butyrate through the femoral vein for 1 h. Sham operation and cardiopulmonary resuscitation groups were given the same amount of isotonic NaCl solution by the same method. Serum levels of cardiac troponin I (cTnI), creatine kinase MB (CK-MB), neuron specific enolase (NSE) and S100 calcium-binding protein B (S100B) were measured by the enzyme-linked immunosorbent assay (ELISA) before cardiac arrest and at 1, 2, 4, and 24 h after resuscitation. At 24 h after resuscitation, the expression levels of microtubule-associated protein 1 light chain 3 (LC3) and ubiquitin-binding protein 62 (p62) in the cardiac muscle and cerebral cortex tissue were detected by western-blotting, and the apoptosis rate was detected by the TUNEL method.

Results

In the cardiopulmonary resuscitation group, nine pigs were successfully resuscitated, seven of which survived to 24 h. In the sodium butyrate group, seven pigs were resuscitated successfully, and all survived to 24 h. There was no significant difference in the success of 24-h resuscitation among the three groups (χ² = 3.381, P = 0.184). At 1, 2, 4 and 24 h after resuscitation, serum cTnI (F = 62.736, 201.265, 330.083, 643.538; all P < 0.001), CK-MB (F = 90.380, 181.548, 669.657, 707.485; all P < 0.001), NSE (F = 92.302, 125.730, 590.627, 1 130.372; all P < 0.001) and S100B (F = 42.831, 152.004, 295.517, 1 023.409; all P < 0.001) were observed and compared in the three groups, and the differences were statistically significant. Compared with the sham operation group, the cTnI, CK-MB, NSE and S100B levels in serum were significantly increased at 2, 4 and 24 h after resuscitation in the cardiopulmonary resuscitation group and sodium butyrate group, which were highest in the cardiopulmonary resuscitation group (all P < 0.05). At 24 h after resuscitation, the levels of autophagy markers LC3 (F = 81.671, 49.204; both P < 0.001) and p62 (F = 127.620, 65.594; both P < 0.001) and the apoptosis rate (F = 116.750, 249.105; both P < 0.001) in cardiomyocytes and cerebral cortex cells were observed and compared in the three groups, and the differences were statistically significant. Compared with the sham operation group, the LC3 expression and apoptosis index were increased, and the p62 expression was decreased in myocardium and cerebral cortex of pigs in the cardiopulmonary resuscitation group and sodium butyrate group at 24 h after resuscitation (all P < 0.05). However, compared with the cardiopulmonary resuscitation group, the LC3 expression and apoptosis index were decreased, and the p62 expression was increased in the myocardium and cerebral cortex in the sodium butyrate group at 24 h after resuscitation (all P < 0.05).

Conclusion

Sodium butyrate has a protective effect on cardio-brain injury after resuscitation of cardiac arrest, and the mechanism may be related to inhibition of autophagy and apoptosis.

Key words: Sodium butyrate, Cardiac arrest, Cardiopulmonary resuscitation, Myocardial injury, Brain injury, Autophagy, Apoptosis

表1 各组动物复苏前后心率和平均动脉压比较（ ± s）

组别	头数	心率（次/min）						平均动脉压（mmHg）
组别	头数	心脏骤停前	复苏后0.5 h	复苏后1 h	复苏后2 h	复苏后3 h	复苏后4 h	心脏骤停前	复苏后0.5 h	复苏后1 h	复苏后2 h	复苏后3 h	复苏后4 h
假手术组	6	92 ± 9	91 ± 6	84 ± 8	88 ± 5	92 ± 11	93 ± 11	98 ± 12	103 ± 14	104 ± 13	105 ± 11	104 ± 8	107 ± 10
心肺复苏组	7	88 ± 10	156 ± 44^a	147 ± 36^a	141 ± 35^a	149 ± 42^a	142 ± 37^a	99 ± 8	104 ± 16	91 ± 20	94 ± 17	99 ± 15	99 ± 17
丁酸钠组	7	88 ± 7	130 ± 12^a	117 ± 13^ab	98 ± 12^b	101 ± 15^b	102 ± 11^b	100 ± 8	94 ± 15	92 ± 6	101 ± 15	107 ± 12	102 ± 9
F值		0.519	31.920	11.651	10.745	7.032	6.623	0.043	0.945	1.483	0.964	0.720	0.728
P值		0.603	< 0.001	< 0.001	0.002	0.009	0.011	0.958	0.406	0.252	0.399	0.499	0.496

表1 各组动物复苏前后心率和平均动脉压比较（ ± s）

组别	头数	心率（次/min）						平均动脉压（mmHg）
组别	头数	心脏骤停前	复苏后0.5 h	复苏后1 h	复苏后2 h	复苏后3 h	复苏后4 h	心脏骤停前	复苏后0.5 h	复苏后1 h	复苏后2 h	复苏后3 h	复苏后4 h
假手术组	6	92 ± 9	91 ± 6	84 ± 8	88 ± 5	92 ± 11	93 ± 11	98 ± 12	103 ± 14	104 ± 13	105 ± 11	104 ± 8	107 ± 10
心肺复苏组	7	88 ± 10	156 ± 44^a	147 ± 36^a	141 ± 35^a	149 ± 42^a	142 ± 37^a	99 ± 8	104 ± 16	91 ± 20	94 ± 17	99 ± 15	99 ± 17
丁酸钠组	7	88 ± 7	130 ± 12^a	117 ± 13^ab	98 ± 12^b	101 ± 15^b	102 ± 11^b	100 ± 8	94 ± 15	92 ± 6	101 ± 15	107 ± 12	102 ± 9
F值		0.519	31.920	11.651	10.745	7.032	6.623	0.043	0.945	1.483	0.964	0.720	0.728
P值		0.603	< 0.001	< 0.001	0.002	0.009	0.011	0.958	0.406	0.252	0.399	0.499	0.496

表2 各组动物复苏前后血清cTnI和CK-MB水平比较（ ± s）

组别	头数	cTnI（ng/L）					CK-MB（ng/L）
组别	头数	心脏骤停前	复苏后1 h	复苏后2 h	复苏后4 h	复苏后24 h	心脏骤停前	复苏后1 h	复苏后2 h	复苏后4 h	复苏后24 h
假手术组	6	139 ± 8	144 ± 13	135 ± 14	134 ± 16	149 ± 17	28.6 ± 5.0	26.0 ± 2.9	28.2 ± 3.5	32.6 ± 2.6	27.6 ± 4.6
心肺复苏组	7	147 ± 10	261 ± 41^a	366 ± 54^a	491 ± 51^a	577 ± 30^a	28.1 ± 2.1	50.3 ± 6.4^a	70.6 ± 6.6^a	90.9 ± 4.1^a	108.2 ± 4.6^a
丁酸钠组	7	146 ± 13	206 ± 6^ab	255 ± 8^ab	299 ± 7^ab	341 ± 13^ab	29.4 ± 3.9	44.6 ± 2.3^a	60.9 ± 3.6^ab	71.4 ± 1.1^ab	83.8 ± 2.1^ab
F值		1.263	62.736	201.265	330.083	643.538	0.368	90.380	181.548	669.657	707.485
P值		0.304	< 0.001	< 0.001	< 0.001	< 0.001	0.702	< 0.001	< 0.001	< 0.001	< 0.001

表2 各组动物复苏前后血清cTnI和CK-MB水平比较（ ± s）

组别	头数	cTnI（ng/L）					CK-MB（ng/L）
组别	头数	心脏骤停前	复苏后1 h	复苏后2 h	复苏后4 h	复苏后24 h	心脏骤停前	复苏后1 h	复苏后2 h	复苏后4 h	复苏后24 h
假手术组	6	139 ± 8	144 ± 13	135 ± 14	134 ± 16	149 ± 17	28.6 ± 5.0	26.0 ± 2.9	28.2 ± 3.5	32.6 ± 2.6	27.6 ± 4.6
心肺复苏组	7	147 ± 10	261 ± 41^a	366 ± 54^a	491 ± 51^a	577 ± 30^a	28.1 ± 2.1	50.3 ± 6.4^a	70.6 ± 6.6^a	90.9 ± 4.1^a	108.2 ± 4.6^a
丁酸钠组	7	146 ± 13	206 ± 6^ab	255 ± 8^ab	299 ± 7^ab	341 ± 13^ab	29.4 ± 3.9	44.6 ± 2.3^a	60.9 ± 3.6^ab	71.4 ± 1.1^ab	83.8 ± 2.1^ab
F值		1.263	62.736	201.265	330.083	643.538	0.368	90.380	181.548	669.657	707.485
P值		0.304	< 0.001	< 0.001	< 0.001	< 0.001	0.702	< 0.001	< 0.001	< 0.001	< 0.001

表3 各组动物复苏前后血清NSE和S100B水平比较（ ± s）

组别	头数	NSE（μg/L）					S100B（ng/L）
组别	头数	心脏骤停前	复苏后1 h	复苏后2 h	复苏后4 h	复苏后24 h	心脏骤停前	复苏后1 h	复苏后2 h	复苏后4 h	复苏后24 h
假手术组	6	8.7 ± 1.1	8.0 ± 0.9	8.8 ± 1.5	7.8 ± 1.4	8.8 ± 0.8	1 395 ± 108	1 441 ± 184	1 379 ± 102	1 341 ± 191	1 414 ± 136
心肺复苏组	7	8.4 ± 0.8	16.1 ± 1.3^a	21.1 ± 1.4^a	26.3 ± 0.6^a	31.5 ± 0.9^a	1 472 ± 135	2 346 ± 188^a	2 840 ± 198^a	3 314 ± 106^a	3 914 ± 82^a
丁酸钠组	7	7.9 ± 1.1	11.5 ± 0.6^ab	15.9 ± 1.6^ab	19.1 ± 1.2^ab	22.9 ± 0.9^ab	1 484 ± 88	1 843 ± 47^ab	2 202 ± 139^ab	2 581 ± 61^ab	3 005 ± 78^ab
F值		1.036	92.302	125.730	590.627	1 130.372	1.196	42.831	152.004	295.517	1 023.409
P值		0.372	< 0.001	< 0.001	< 0.001	< 0.001	0.322	< 0.001	< 0.001	< 0.001	< 0.001

表3 各组动物复苏前后血清NSE和S100B水平比较（ ± s）

组别	头数	NSE（μg/L）					S100B（ng/L）
组别	头数	心脏骤停前	复苏后1 h	复苏后2 h	复苏后4 h	复苏后24 h	心脏骤停前	复苏后1 h	复苏后2 h	复苏后4 h	复苏后24 h
假手术组	6	8.7 ± 1.1	8.0 ± 0.9	8.8 ± 1.5	7.8 ± 1.4	8.8 ± 0.8	1 395 ± 108	1 441 ± 184	1 379 ± 102	1 341 ± 191	1 414 ± 136
心肺复苏组	7	8.4 ± 0.8	16.1 ± 1.3^a	21.1 ± 1.4^a	26.3 ± 0.6^a	31.5 ± 0.9^a	1 472 ± 135	2 346 ± 188^a	2 840 ± 198^a	3 314 ± 106^a	3 914 ± 82^a
丁酸钠组	7	7.9 ± 1.1	11.5 ± 0.6^ab	15.9 ± 1.6^ab	19.1 ± 1.2^ab	22.9 ± 0.9^ab	1 484 ± 88	1 843 ± 47^ab	2 202 ± 139^ab	2 581 ± 61^ab	3 005 ± 78^ab
F值		1.036	92.302	125.730	590.627	1 130.372	1.196	42.831	152.004	295.517	1 023.409
P值		0.372	< 0.001	< 0.001	< 0.001	< 0.001	0.322	< 0.001	< 0.001	< 0.001	< 0.001

图1 各组动物心肌和大脑皮层组织细胞LC3与p62蛋白表达水平的变化注：LC3.微管相关蛋白1轻链3；p62.泛素结合蛋白62；GAPDH. 3-磷酸甘油脱醛酶

表4 各组动物复苏24 h心肌细胞和大脑皮层细胞LC3、p62蛋白水平及凋亡率比较（ ± s）

组别	头数	心肌细胞			大脑皮层细胞
组别	头数	LC3	p62	凋亡率（%）	LC3	p62	凋亡率（%）
假手术组	6	0.72 ± 0.19	1.47 ± 0.07	2.4 ± 0.3	0.46 ± 0.18	1.24 ± 0.12	2.7 ± 0.4
心肺复苏组	7	1.84 ± 0.15^a	0.77 ± 0.05^a	41.5 ± 7.0^a	1.27 ± 0.10^a	0.63 ± 0.08^a	63.7 ± 7.7^a
丁酸钠组	7	1.41 ± 0.10^ab	1.09 ± 0.10^ab	13.2 ± 3.1^ab	0.88 ± 0.07^ab	0.95 ± 0.06^ab	21.5 ± 3.4^ab
F值		81.671	127.620	116.750	49.204	65.594	249.105
P值		< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

表4 各组动物复苏24 h心肌细胞和大脑皮层细胞LC3、p62蛋白水平及凋亡率比较（ ± s）

组别	头数	心肌细胞			大脑皮层细胞
组别	头数	LC3	p62	凋亡率（%）	LC3	p62	凋亡率（%）
假手术组	6	0.72 ± 0.19	1.47 ± 0.07	2.4 ± 0.3	0.46 ± 0.18	1.24 ± 0.12	2.7 ± 0.4
心肺复苏组	7	1.84 ± 0.15^a	0.77 ± 0.05^a	41.5 ± 7.0^a	1.27 ± 0.10^a	0.63 ± 0.08^a	63.7 ± 7.7^a
丁酸钠组	7	1.41 ± 0.10^ab	1.09 ± 0.10^ab	13.2 ± 3.1^ab	0.88 ± 0.07^ab	0.95 ± 0.06^ab	21.5 ± 3.4^ab
F值		81.671	127.620	116.750	49.204	65.594	249.105
P值		< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

图2 各组动物心肌和大脑皮层组织细胞凋亡程度的变化（TUNEL染色　× 200）注：棕黄色细胞为凋亡细胞，a ~ c图分别为假手术组、心肺复苏组和丁酸钠组动物心肌组织病理结果，d ~ f图分别为假手术组、心肺复苏组和丁酸钠组动物大脑皮层组织病理结果；a图示心肌组织结构完整，仅见散在棕黄色细胞；b图示心肌组织结构严重紊乱，可见大量棕黄色细胞；c图示心肌组织结构轻度紊乱，可见棕黄色细胞，病变轻于心肺复苏组；d图示皮层组织神经元细胞排列有序，细胞完整性良好，仅见散在棕黄色细胞；e图示皮层组织神经元细胞明显减少，细胞完整性破坏，内见大量棕黄色细胞；f图示神经元细胞数量减少，内见棕黄色细胞，病变轻于心肺复苏组

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Protective effect and mechanism of sodium butyrate on cardio-brain injury after cardiac arrest resuscitation in pigs

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Protective effect and mechanism of sodium butyrate on cardio-brain injury after cardiac arrest resuscitation in pigs