Protective effect of hypoxia-inducible factor-1α on brain injury in mice with necrotizing enterocolitis

Mou ZOU; Xue WANG; Yujuan YU; Wei ZHAO; Ying XU

doi:10.16016/j.2097-0927.202110078

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Protective effect of hypoxia-inducible factor-1α on brain injury in mice with necrotizing enterocolitis

Neurosciences | 更新时间：2026-01-09

- Protective effect of hypoxia-inducible factor-1α on brain injury in mice with necrotizing enterocolitis
- Journal of Army Medical University Vol. 44, Issue 10, Pages: 1001-1008(2022)
- 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：
- 基金信息：
  
  Supported by the Project of Science and Technology Research Plan of Chongqing(CSTC2018jscx-msybX0104)
- DOI：10.16016/j.2097-0927.202110078
  CLC： R725.745;R742.05;R977.6
- Received：14 October 2021，
  
  Revised：2022-01-11，
  
  Published：30 May 2022
- 稿件说明：
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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：

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

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