缺氧诱导因子-1α对坏死性小肠结肠炎小鼠脑损伤的保护作用

邹谋; 王雪; 余玉娟; 赵薇; 徐颖

doi:10.16016/j.2097-0927.202110078

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缺氧诱导因子-1α对坏死性小肠结肠炎小鼠脑损伤的保护作用

神经科学 | 更新时间：2026-01-09

- 缺氧诱导因子-1α对坏死性小肠结肠炎小鼠脑损伤的保护作用
- Protective effect of hypoxia-inducible factor-1α on brain injury in mice with necrotizing enterocolitis
- 陆军军医大学学报 2022年44卷第10期页码：1001-1008
- 作者机构：
  
  400014 重庆，重庆医科大学附属儿童医院麻醉科，国家儿童健康与疾病临床医学研究中心，儿童发育疾病研究教育部重点实验室，儿科学重庆市重点实验室
- 作者简介：
  
  [徐颖，E-mail：xuyingxy3066@126.com XU Ying, E-mail: xuyingxy3066@126.com
- 基金信息：
  
  重庆市科技计划项目(CSTC2018jscx-msybX0104)
- DOI：10.16016/j.2097-0927.202110078
  中图分类号： R725.745;R742.05;R977.6
- 收稿：2021-10-14，
  
  修回：2022-01-11，
  
  纸质出版：2022-05-30
- 稿件说明：
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邹谋, 王雪, 余玉娟, 等. 缺氧诱导因子-1α对坏死性小肠结肠炎小鼠脑损伤的保护作用[J]. 陆军军医大学学报, 2022,44(10):1001-1008.

Mou ZOU, Xue WANG, Yujuan YU, et al. Protective effect of hypoxia-inducible factor-1α on brain injury in mice with necrotizing enterocolitis[J]. Journal of Army Medical University, 2022, 44(10): 1001-1008.
邹谋, 王雪, 余玉娟, 等. 缺氧诱导因子-1α对坏死性小肠结肠炎小鼠脑损伤的保护作用[J]. 陆军军医大学学报, 2022,44(10):1001-1008. DOI： 10.16016/j.2097-0927.202110078.

Mou ZOU, Xue WANG, Yujuan YU, et al. Protective effect of hypoxia-inducible factor-1α on brain injury in mice with necrotizing enterocolitis[J]. Journal of Army Medical University, 2022, 44(10): 1001-1008. DOI： 10.16016/j.2097-0927.202110078.

摘要

目的

探究缺氧诱导因子-1α(hypoxia inducible factor-1α，HIF-1α)对坏死性小肠结肠炎(necrotizing enterocolitis，NEC)小鼠脑损伤的影响。

方法

将81只5日龄C57BL/6小鼠按随机数字表法分为：①对照组(CON组，

=15，与母鼠同笼，母乳喂养)，②坏死性小肠结肠炎组[NEC组，

=24，饲养在保育箱，采用配方奶喂养+缺氧+口服脂多糖(lipopolysaccharide，LPS)的方法诱导NEC小鼠模型

]

，③HIF-1α稳定剂组(DMOG组，

=19，在NEC组基础上给予HIF-1α稳定剂DMOG)，④HIF-1α抑制剂组(2ME2组，

=23，在NEC组基础上给予HIF-1α抑制剂2ME2)。建模过程中记录小鼠死亡情况，建模4 d后处死所有小鼠；HE染色观察小鼠肠道病理表现；Western blot检测脑组织中HIF-1α蛋白的表达水平；免疫组化检测小鼠海马活化的小胶质细胞、星形胶质细胞和少突胶质细胞的数量；RT-qPCR检测炎症因子IL-1β和TNF-α mRNA在小鼠脑中的表达水平。

结果

与CON组相比，NEC组小鼠肠道受损，海马活化的小胶质细胞数量增加(0.80±0.75

4.00±0.63，

0.05)，星形胶质细胞激活增加(

0.05)，炎症因子TNF-α、IL-1β表达水平升高(

0.05)，少突胶质细胞数量减少(64.40±7.26

45.60±2.80，

0.05)，HIF-1α表达水

平增加(

0.05)。给予腹腔注射HIF-1α稳定剂DMOG后，与NEC组相比，小鼠的生存率上升(66.67%

84.21%，

0.05)，肠道损伤减轻，小胶质细胞(4.00±0.63

1.60±0.49，

0.05)和星形胶质细胞的活化被抑制(

0.05)，炎症因子TNF-α、IL-1β表达水平下降(

0.05)，少突胶质细胞数量增多(45.60±2.80

56.00±5.22，

0.05)；腹腔注射HIF-1α抑制剂2ME2则得到相反的结果。

结论

HIF-1α在NEC小鼠脑中保护性上调，其稳定高表达可减轻NEC小鼠脑中神经炎症，具有脑保护作用。

Abstract

Objective

To investigate the effects of hypoxia inducible factor-1α (HIF-1α) on the brain injury of necrotizing enterocolitis (NEC) mice.

Methods

Eighty-one C57BL/6 mice aged 5 d were randomly divided into 4 groups: Control group (CON

=15

breastfed

in cages with their mothers)

NEC group (

=24

fed in an incubator

with formula milk+hypoxia+oral lipopolysaccharide to induce NEC mouse model)

DMOG group (

=19

given HIF-1α stabilizer DMOG on the base of NEC model)

and 2ME2 group (

=23

given HIF-1α inhibitor 2ME2 on the base of NEC model). The mortality of mice was recorded during modeling. All mice were sacrificed in 4 d after modeling

and the intestinal pathological features of mice were observed by HE staining. Western blotting and immunohistochemical assay were performed respectively to detect the expression of HIF-1α protein in brain tissue and the numbers of activated microglia

astrocytes and oligodendrocytes in the hippocampus. The mRNA levels of inflammatory cytokines IL-1β and TNF-α were determined by RT-qPCR in brain tissue.

Results

As compared with the CON group

the mice of the NEC group showed intestinal tract damage

increased activated microglia (0.80±0.75

4.00±0.63

0.05) and astrocytes (

0.05) in the hippocampus

decreased number of oligodendrocytes (64.40±7.26

45.60±2.80

0.05)

and higher levels of TNF-α

IL-1β and HIF-1α (

0.05). After intraperitoneal injection of HIF-1α stabilizer DMOG

the survival rate of mice in the DMOG group was increased (66.67%

84.21%

0.05)

and the intestinal injury was reduced. The activation of microglia (4.00±0.63

1.60±0.49

0.05) and astrocytes (

0.05) was inhibited

while the number of oligodendrocytes was elevated (45.60±2.80

56.00±5.22

0.05)

and the expression of TNF-α and IL-1β was down-regulated (

0.05). However

intraperitoneal injection of HIF-1α inhibitor 2ME2 resulted in opposite outcomes.

Conclusion

HIF-1α is protectively up-regulated in the brain of NEC mice

and its stable and high expression reduces the neuroinflammation in the brain of NEC mice

exerting a protective effect on the brain.

关键词

Keywords

references

HACKAM D, CAPLAN M. Necrotizing enterocolitis: pathophysiology from a historical context[J]. Semin Pediatr Surg, 2018, 27(1): 11-18. DOI: 10.1053/j.sempedsurg.2017.11.003.

JONES I H, HALL N J. Contemporary outcomes for infants with necrotizing enterocolitis——a systematic review[J]. J Pediatr, 2020, 220: 86-92.e3. DOI: 10.1016/j.jpeds.2019.11.011.

MUTANEN A, PIERRO A, ZANI A. Perioperative complications following surgery for necrotizing enterocolitis[J]. Zeitschrift Fur Kinderchirurgie, 2018, 28(2): 148-151. DOI: 10.1055/s-0038-1636943.

REES C M, PIERRO A, EATON S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis[J]. Arch Dis Child Fetal Neonatal Ed, 2007, 92(3): F193-F198. DOI: 10.1136/adc.2006.099929.

SHAH D K, DOYLE L W, ANDERSON P J, et al . Adverse neurodevelopment in preterm infants with postnatal sepsis or necrotizing enterocolitis is mediated by white matter abnormalities on magnetic resonance imaging at term[J ] . J Pediatr, 2008, 153(2): 170-175, 175. e1. DOI: 10.1016/j.jpeds.2008.02.033.

MERHAR S L, RAMOS Y, MEINZEN-DERR J, et al . Brain magnetic resonance imaging in infants with surgical necrotizing enterocolitis or spontaneous intestinal perforation versus medical necrotizing enterocolitis[J ] . J Pediatr, 2014, 164(2): 410-412.e1. DOI: 10.1016/j.jpeds.2013.09.055.

SHIN S H, KIM E K, YOO H, et al . Surgical necrotizing e nterocolitis versus spontaneous intestinal perforation in white matter injury on brain magnetic resonance imaging[J ] . Neonatology, 2016, 110(2): 148-154. DOI: 10.1159/000444387.

NIÑO D F, ZHOU Q J, YAMAGUCHI Y, et al . Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain[J ] . Sci Transl Med, 2018, 10(471): eaan0237. DOI: 10.1126/scitranslmed.aan0237.

DENGLER V L, GALBRAITH M, ESPINOSA J M. Transcriptional regulation by hypoxia inducible factors[J]. Crit Rev Biochem Mol Biol, 2014, 49(1): 1-15. DOI: 10.3109/10409238.2013.838205.

CHEN Y, CHANG K T, LIAN D W, et al . The role of ischemia in necrotizing enterocolitis[J ] . J Pediatr Surg, 2016, 51(8): 1255-1261. DOI: 10.1016/j.jpedsurg.2015.12.015.

BOWKER R M, YAN X C, MANAGLIA E, et al . Dimethyloxalylglycine preserves the intestinal microvasculature and protects against intestinal injury in a neonatal mouse NEC model: role of VEGF signaling[J ] . Pediatr Res, 2018, 83(2): 545-553. DOI: 10.1038/pr.2017.219.

MATSUDA T, ABE T, WU J L, et al . Hypoxia-inducible factor-1alpha DNA induced angiogenesis in a rat cerebral ischemia model[J ] . Neurol Res, 2005, 27(5): 503-508. DOI: 10.1179/016164105X25144.

CHEN Y, KOIKE Y, MIYAKE H, et al . Formula feeding and systemic hypoxia synergistically induce intestinal hypoxia in experimental necrotizing enterocolitis[J ] . Pediatr Surg Int, 2016, 32(12): 1115-1119. DOI: 10.1007/s00383-016-3997-8.

KHAN M, DHAMMU T S, BAARINE M, et al . GSNO promotes functional recovery in experimental TBI by stabilizing HIF-1α[J ] . Behav Brain Res, 2018, 340: 63-70. DOI: 10.1016/j.bbr.2016.10.037.

DRUCKER N A, JENSEN A R, TE WINKEL J P, et al . Loss of endothelial nitric oxide synthase exacerbates intestinal and lunginjury in experimental necrotizing enterocolitis[J ] . J Pediatr Surg, 2018, 53(6): 1208-1214. DOI: 10.1016/j.jpedsurg.2018.02.087.

OHMURA Y, KUNIYOSHI Y. A translational model to determine rodent's age from human foetal age[J]. Sci Rep, 2017, 7(1): 17248. DOI: 10.1038/s41598-017-17571-z.

马娜, Mohd Jaish Siddiqui, 夏斌. 新生儿坏死性小肠结肠炎发病机制的研究进展[J]. 中华妇幼临床医学杂志(电子版), 2020, 16(6): 739-744. DOI: 10.3877/cma.j.issn.1673-5250.2020.06.018.

MA N, SIDDIQUI M J, XIA B. Research progresses of pathogenesis of neonatal necrotizing enterocolitis[J]. Chin J Obstet Gynecol Pediatr Electron Ed, 2020, 16(6): 739-744. DOI: 10.3877/cma.j.issn.1673-5250.2020.06.018.

EYO U B, DAILEY M E. Microglia: key elements in neural development, plasticity, and pathology[J]. J Neuroimmune Pharmacol, 2013, 8(3): 494-509. DOI: 10.1007/s11481-013-9434-z.

LIDDELOW S A, GUTTENPLAN K A, CLARKE L E, et al . Neurotoxic reactive astrocytes are induced by activated microglia[J ] . Nature, 2017, 541(7638): 481-487. DOI: 10.1038/nature21029.

BIOUSS G, ANTOUNIANS L, LI B, et al . Experimental necrotizing enterocolitis induces neuroinflammation in the neonatal brain[J ] . J Neuroinflammation, 2019, 16(1): 97. DOI: 10.1186/s12974-019-1481-9.

BARKOVICH A J. Concepts of myelin and myelination in neuroradiology[J]. Am J Neuroradiol, 2000, 21(6): 1099-1109.

HOWARTH C, BANERJEE J, LEUNG T, et al . Cerebral oxygenation in preterm infants with necrot izing enterocolitis[J ] . Pediatrics, 2020, 146(3): e20200337. DOI: 10.1542/peds.2020-0337.

KEELY S, CAMPBELL E L, BAIRD A W, et al . Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis[J ] . Mucosal Immunol, 2014, 7(1): 114-123. DOI: 10.1038/mi.2013.29.

SEN T, SEN N. Treatment with an activator of hypoxia-inducible factor 1, DMOG provides neuroprotection after traumatic brain injury[J]. Neuropharmacology, 2016, 107: 79-88. DOI: 10.1016/j.neuropharm.2016.03.009.

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