Gene expression profile of lung tissues in rats with high altitude pulmonary edema

Gang XU; Gang WU; Binda SUN; Bao LIU; Zhiqi GAO; Jian CHEN; Yuqi GAO; Wenxiang GAO; Dewei CHEN

doi:10.16016/j.2097-0927.202307015

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Gene expression profile of lung tissues in rats with high altitude pulmonary edema

Basic Medicine | 更新时间：2026-01-09

- Gene expression profile of lung tissues in rats with high altitude pulmonary edema
- Journal of Army Medical University Vol. 46, Issue 11, Pages: 1235-1243(2024)
- 作者机构：
  
  1.400038 重庆，陆军军医大学(第三军医大学)高原军事医学系：高原特需药品与器材研究室
  2.400038 重庆，陆军军医大学(第三军医大学)高原军事医学系：高原生理学与病理学教研室
  3.400038 重庆，陆军军医大学(第三军医大学)高原军事医学系：极端环境医学教育部重点实验室(培育)
- 作者简介：
- 基金信息：
  
  the National Natural Science Foundation for Young Scholars of China(82101968)
- DOI：10.16016/j.2097-0927.202307015
  CLC： R394-33;R541.63;R594.3
- Received：03 July 2023，
  
  Revised：2023-09-25，
  
  Published：15 June 2024
- 稿件说明：
移动端阅览
Gang XU, Gang WU, Binda SUN, et al. Gene expression profile of lung tissues in rats with high altitude pulmonary edema[J]. Journal of Army Medical University, 2024, 46(11): 1235-1243.
DOI：

Gang XU, Gang WU, Binda SUN, et al. Gene expression profile of lung tissues in rats with high altitude pulmonary edema[J]. Journal of Army Medical University, 2024, 46(11): 1235-1243. DOI： 10.16016/j.2097-0927.202307015.

摘要

目的

利用基因芯片技术分析高原肺水肿(high altitude pulmonary edema，HAPE)大鼠模型肺组织差异表达基因，为深入探讨HAPE发生的分子机制提供新线索。

方法

将8周龄健康雄性SD大鼠[体质量(200±20) g

]

按随机数字表法分为常氧对照(NC)组、脂多糖(Lipopolysaccharide，LPS)组、低压低氧(Hypoxia)组和低压低氧复合低剂量LPS(HL)组。LPS组和HL组按照每100 g体质量尾静脉注射0.1 mL浓度为0.05%的LPS溶液，NC组和Hypoxia组给予等量生理盐水；Hypoxia组和HL组进行模拟海拔5 000 m低压低氧处理6 h，NC组和LPS组于舱外同时饲养。检测肺组织的湿/干质量比(wet/dry mass ratio，WDR)、支气管肺泡灌洗液(bronchoalveolar lavage fluid，BALF)蛋白含量，HE染色观察肺组织病理改变。提取肺组织总RNA，采用Affymetrix基因芯片检测mRNA表达谱，采用Metascape在线基因注释和分析系统(

http://metascape.org

)对差异表达基因进行基因本体论(gene ontology，GO)和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes，KEGG)信号通路聚类分析。

结果

HL组大鼠肺组织表现出明显的充血、水肿、肺泡间隔增宽。与NC组比较，HL组大鼠肺WDR显著增加(

＜0.01)，BALF蛋白含量显著升高(

＜0.05)。基因表达检测发现，相对NC组，Hypoxia组有79个基因表达上调，59个基因表达下调，LPS组473个基因表达上调，695个基因表达下调，HL组669个基因表达上调，1 253个基因表达下调。GO和KEGG信号通路聚类分析显示：HL组差异表达上调基因主要富集于细胞因子介导的信号通路、对IL-1的反应、炎症反应调节等生物学过程，以及细胞因子-细胞因子受体相互作用、TNF、NF-κB、IL-17、补体和凝血级联反应等信号通路；表达下调的基因主要富集到细胞外基质组织、内皮细胞迁移调控、细胞-基质黏附等生物学过程，以及黏着斑、Wnt、cGMP-PKG、PI3K-Akt、Rap1等信号通路。HL组大鼠肺组织中

NF-κB

、

TNF-α

、

-1

以及

-6的mRNA表达均显著上调(

＜0.01)。

结论

低氧复合低剂量LPS可稳定复制大鼠HAPE模型，低氧可显著增强LPS诱导的炎症、免疫反应，显著增强炎症介质的表达，促进HAPE的发生发展。

Abstract

Objective

To analyze the differential expressed genes (DEGs) in the lung tissues of rat model of high altitude pulmonary edema (HAPE) by using microarray analysis in order to provide new clues for molecular mechanism of HAPE.

Methods

Healthy male SD rats (8 weeks old

weighing 200±20 g) were randomized into normoxia control (NC) group

lipopolysaccharide (LPS) group

hypoxia group and hypoxia +low-dose LPS (HL) group. The rats of the LPS gr

oup and HL group were injected with 0.1 mL 0.05% LPS per 100 g body weight

and those of the NC group and the hypoxia group were administered with an equivalent volume of normal saline. The rats of the hypoxia group and the HL group were housed in a hypobaric chamber simulating an altitude of 5 000 m

and those of the NC group and the LPS group were raised simultaneously outside of the chamber. The wet/dry mass ratio (WDR) of lung tissue and total protein content in bronchoalveolar lavage fluid (BALF) were measured

and the histopathological changes of lung tissue was observed using HE staining. The total RNA was extracted from the lung tissues

and the mRNA expression profile was obtained with Affymetrix microarray followed by Gene Ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis with Metascape (

http://metascape.org

Results

The rats of the HL group showed significant congestion

edema

and widened alveolar septa. Compared with the NC group

the HL group had significantly increased lung WDR (

0.01) and total protein content in BALF (

0.05). Gene expression analysis revealed that there were 79 genes up-regulated and 59 genes down-regulated in the hypoxia group

473 genes up-regulated and 695 genes down-regulated in the LPS group

and especially

669 genes up-regulated and 1 253 genes down-regulated in the HL group. GO and KEGG pathway analyses revealed that the upregulated genes in the HL group were mainly enriched in biological processes

such as cytokine mediated signaling pathways

response to IL-1

regulation of inflammatory response

as well as signaling pathways

including cytokine-cytokine receptor interactions

TNF

NF-κB

IL-17

complement and coagulation cascades

etc

. The down-regulated genes were mainly enriched in biological processes

such as extracellular matrix organization

regulation of endo

thelial cell migration

cell substrate adhesion

as well as signaling pathways

such as focal adhesion

Wnt

cGMP-PKG

PI3K-Akt

Rap1

etc

. The mRNA expression of

NF-κB

TNF-α

-1

and

-6 was significantly up-regulated in the lung tissue of the HL group (

0.01).

Conclusion

Hypoxia+low-dose LPS is an effective procedure to establish a reliable model for HAPE in rats. Hypoxia can significantly aggravate LPS-induced inflammation and immune response

enhance the expression of inflammatory mediators

and thus promote the pathogenesis of HAPE.

关键词

Keywords

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