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中华妇幼临床医学杂志(电子版) ›› 2023, Vol. 19 ›› Issue (06) : 665 -674. doi: 10.3877/cma.j.issn.1673-5250.2023.06.007

论著

Keap1/Nrf2信号通路在脂多糖诱导宫内感染致新生鼠支气管肺发育不良的作用机制
邓健1, 王少华1,†(), 陈尊1, 邹振庄1   
  1. 1. 广东省深圳市福田区妇幼保健院儿科，深圳　518045
  • 收稿日期:2023-02-14 修回日期:2023-08-01 出版日期:2023-12-01
  • 通信作者: 王少华

Mechanism of Keap1/Nrf2 pathway in role of intrauterine infection induced by lipopolysaccharide leading to bronchopulmonary dysplasia in neonatal rats

Jian Deng1, Shaohua Wang1,†(), Zun Chen1, Zhenzhuang Zou1   

  1. 1. Department of Pediatrics, Futian District Maternal and Child Health Hospital, Shenzhen 518045, Guangdong Province, China
  • Received:2023-02-14 Revised:2023-08-01 Published:2023-12-01
  • Corresponding author: Shaohua Wang
  • Supported by:
    Natural Science Foundation of Shenzhen Science and Technology Innovation Commission(JCYJ20190813141207091, JCYJ20210324111806016, JCYJ20220530142015035)
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引用本文：

邓健, 王少华, 陈尊, 邹振庄. Keap1/Nrf2信号通路在脂多糖诱导宫内感染致新生鼠支气管肺发育不良的作用机制[J]. 中华妇幼临床医学杂志(电子版), 2023, 19(06): 665-674.

Jian Deng, Shaohua Wang, Zun Chen, Zhenzhuang Zou. Mechanism of Keap1/Nrf2 pathway in role of intrauterine infection induced by lipopolysaccharide leading to bronchopulmonary dysplasia in neonatal rats[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2023, 19(06): 665-674.

目的

探讨Kelch样环氧氯丙烷相关蛋白1 (Keap1)/核因子E2相关因子2 (Nrf2)信号通路，在脂多糖诱导宫内感染致新生鼠发生支气管肺发育不良(BPD)中的作用机制。

方法

选择12只无特定病原体(SPF)级6～8周龄Sprague Dawley(SD)雌性大鼠，以及建模成功2组孕鼠所产新生鼠为研究对象。将SD孕鼠采取数字表法随机分为BPD组(于孕龄为18 d时，腹腔注入脂多糖溶液构建BPD病理模型)和对照组(孕鼠腹腔注入等体积无菌生理盐水，构建空白对照模型)，将其所产新生鼠采取随机数字表法，各选6只，分别纳入新生鼠BPD组与新生鼠对照组。①取2组新生鼠肺组织进行苏木精-伊红(HE)染色，采用HE染色观察其病理学变化；②采用生化检测氧化应激指标活性氧含量，相关抗氧化指标谷胱甘肽过氧化物酶(GSH-PX)及超氧化物歧化酶(SOD)活性；③采用酶联免疫吸附测定(ELISA)法检测炎症因子，如肿瘤坏死因子(TNF)-α，白细胞介素(IL)-1β、-6和转化生长因子(TGF)-β水平；④采用荧光定量聚合酶链式反应(qPCR)和Western blotting法检测Keap1/Nrf2信号通路Nrf2、血红素氧合酶1(HO-1)mRNA和蛋白表达水平。⑤采用SD大鼠Ⅱ型肺泡上皮细胞(ACEⅡ)进行细胞实验：将SD大鼠ACEⅡ按照处理方法不同分为6组，分别为ACEⅡ＋空载组(Cell＋NC组)、ACEⅡ＋Nrf2干扰组(Cell＋Si-Nrf2组)、脂多糖组(LPS组)、脂多糖＋空载组(LPS＋NC组)、脂多糖＋Nrf2干扰组(LPS＋Si-Nrf2组)及对ACEⅡ不做任何处理的对照组(control组)，流式细胞术检测各组活性氧表达水平。本实验获得深圳市福田区妇幼保健院医学伦理委员会批准(批准日期：2022-05-16)，实验过程对动物的处置符合动物伦理学要求。

结果

① HE染色结果显示，BPD组肺泡体积增大，肺泡间隔增厚，并存在部分炎症细胞浸润、出血现象。BPD组肺组织平均线性截距(MLI)和肺泡间隔厚度(AST)均较对照组增大、增多，2组比较，差异均有统计学意义(P<0.05)。②生化检测结果显示，BPD组的活性氧表达水平显著高于对照组，GSH-PX及SOD酶活性显著低于对照组，并且差异均有统计学意义(P<0.05)。③ELISA检测结果显示，BPD组TNF-α、IL-1β、IL-6、TGF-β水平显著高于对照组，差异均有统计学意义(P<0.05)。④qPCR及Western blotting检测结果显示，BPD组的HO-1 mRNA和蛋白表达水平均低于对照组，BPD组Nr2f2 mRNA相对表达水平低于对照组，并且差异具有统计学意义(P<0.05)。⑤流式细胞术检测各组细胞活性氧水平显示，LPS＋Si-Nrf2组的活性氧水平显著高于LPS组、Control组，并且差异具有统计学意义(P<0.05)。

结论

LPS激活氧化因子及炎症因子诱导宫内感染致新生鼠肺氧化应激性损伤从而引起BPD，Nrf2通过调控抗氧化因子对大鼠ACEⅡ发挥保护作用。

关键词: Nrf2, 脂多糖, 宫内感染, 支气管肺发育不良, 大鼠
Objective

To explore the mechanism of the Kelch like epichlorohydrin associated protein 1 (Keap1)/nuclear factor E2 associated factor 2 (Nrf2) signaling pathway in lipopolysaccharide induced intrauterine infection leading to bronchopulmonary dysplasia (BPD) in newborn mice.

Methods

Twelve Sprague-Dawley (SD) female rats of 6-8 weeks old with specific-pathogen-free (SPF) grade, and the newly born rats from successfully modeled pregnant rats were enrolled in this study. SD pregnant rats were randomly divided into BPD group (intraperitoneal injection of LPS solution on gestational day 18 to establish a BPD pathological model) and control group (intraperitoneal injection of equal volume of sterile normal saline to establish a blank control model) using the random number table method. The above 2 groups of pregnant rats will be randomly divided into a new born BPD group and a new born control group using the random number table method. Six newborns from each group will be selected and assigned to the corresponding group. Six newborn mice were randomly selected and included in BPD group and control group, respectively. The lung tissues of two groups of newborns were stained with hematoxylin-eosin (HE) and their pathological changes were observed. The levels of reactive oxygen species (ROS), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) activity, which are oxidative stress indicators, were detected. Enzyme-linked immunosorbent assay (ELISA) was used to measure inflammatory factors such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, -6, and transforming growth factor (TGF)-β levels. Fluorescence quantitative polymerase chain reaction (qPCR) was used to detect the relative expression levels of Nrf2 and heme oxygenase 1 (HO-1) mRNA in the Keap1/Nrf2 signaling pathway. Western blotting was used to measure the relative expression levels of Nrf2 and HO-1 protein in the Keap1/Nrf2 signaling pathway. An in vitro cell experiment was conducted using SD rats alveolar epithelial type Ⅱ cells (ACEⅡ). The ACEⅡ were divided into 6 groups according to different treatment methods, including ACEⅡ + empty vector group (Cell + NC group), ACEⅡ + Nrf2 interference group (Cell + Si-Nrf2 group), LPS group, LPS + empty vector group (LPS + NC group), LPS + Nrf2 interference group (LPS + Si-Nrf2 group), and control group without any treatment on ACEⅡ (Control group). Flow cytometry was used to detect the expression level of reactive oxygen species in each group. This experiment was approved by the Medical Ethics Committee of Shenzhen Futian District Maternal and Child Health Hospital, and the disposal of animals during the experiment meets the requirements of animal ethics.

Results

① The HE staining results showed that in BPD group of newborns, the alveolar volume increased, the alveolar septa thickened, and there were some inflammatory cell infiltration and bleeding phenomena. The mean linear intercept (MLI) and alveolar septal thickness (AST) of the lung tissue in BPD group increased compared to control group, and the difference was statistically significant (P<0.05). ② The biochemical test results showed that the expression level of reactive oxygen species in BPD group was significantly higher than that in control group, while the activities of GSH-PX and SOD enzymes were significantly lower than those of control group, and the differences were statistically significant (P<0.05). ③The ELISA detection results showed that the levels of TNF-α, IL-1β, IL-6, and TGF-β in BPD group of newborns were significantly higher than those in control group, and the differences were statistically significant (P<0.05). ④The qPCR detection results showed that the relative expression levels of Nrf2 and HO-1 mRNA in lung tissues of BPD group of newborns were lower than those in control group, and the difference were statistically significant (P<0.05). Further, Western blotting detection results showed that the relative expression level of HO-1 protein in lung tissue of BPD group of newborns was lower than that in control group, and the difference was statistically significant (P<0.05). ⑤The results of flow cytometry detection of reactive oxygen species in each group showed that the expression level of reactive oxygen species in the LPS+ Si-Nrf2 group was significantly higher than that in LPS group and control group, and the differences were statistically significant (P<0.05).

Conclusions

Lipopolysaccharide activates oxidative factors and inflammation factors, which induce intrauterine infection and cause oxidative stress-induced lung injury in newborns, leading to BPD. Nrf2 exerts protective effects on ACEⅡ in rats by regulating antioxidant factors.

Key words: Nrf2, Lipopolysaccharide, Intrauterine infection, Bronchopulmonary dysplasia, Rats
表1 新生鼠肺组织RNA qPCR引物序列
引物 引物序列 产物长度(bp)
β-actin正向引物 5′-GCCATGTACGTAGCCATCCA-3′ 375
β-actin反向引物 5′-GAACCGCTCATTGCCGATAG-3′ 375
Nrf2正向引物 5′-CTTCTGGGGATACAGTACAGCC-3′ 269
Nrf2反向引物 5′-CTCCTTGGACATCATTTCATTG-3′ 269
HO-1正向引物 5′-AGGTCCTGAAGAAGATTGCG-3′ 279
HO-1反向引物 5′-GGCGAAGAAACTCTGTCTGTGA-3′ 279
图1 2组新生鼠肺组织HE染色结果(图1A：BPD组；图1B：对照组) 注：BPD组为腹腔注入脂多糖溶液构建BPD病理模型的孕鼠所产新生鼠。对照组为孕鼠腹腔注入等体积无菌生理盐水构建空白对照模型所产新生鼠。HE为苏木素-伊红，BPD为支气管肺发育不良
表2 2组新生鼠MLI和AST比较(μm, ±s)
组别 鼠数 MLI AST
BPD组 6 54.0±3.1 9.8±0.7
对照组 6 40.3±1.5 5.6±0.3
t值   －9.68 －13.40
P值   <0.001 <0.001
表3 2组新生鼠活性氧含量、GSH-PX及SOD活性比较(±s)
组别 鼠数 活性氧 GSH-PX SOD
BPD组 6 23.7±4.0 36.7±1.0 2.2±0.4
对照组 6 20.4±4.3 50.3±1.5 2.5±0.4
t值   2.39 32.58 2.78
P值   0.022 <0.001 0.009
表4 2组新生鼠肺组织炎症因子水平比较(±s)
组别 鼠数 TNF-α(ng/mL) IL-1β(ng/mL) IL-6(ng/mL) TGF-β(pg/mL)
BPD组 6 62.0±6.1 9.2±1.1 66.4±6.7 53.2±5.5
对照组 6 55.4±4.8 7.6±0.6 53.8±5.3 47.9±4.8
t值   －3.56 －5.23 －6.25 －3.08
P值   0.001 <0.001 <0.001 0.004
表5 2组新生鼠肺组织Keap1/Nrf2信号通路Nrf2 mRNA和HO-1 mRNA相对表达水平比较(±s)
组别 鼠数 Nrf2 mRNA HO-1 mRNA
BPD组 6 0.62±0.08 0.63±0.08
对照组 6 1.01±0.13 1.00±0.12
t值   4.59 4.47
P值   0.016 0.015
图2 2组新生鼠肺组织Keap1/Nrf2信号通路HO-1、Nrf2蛋白表达的Western blotting法检测条带图 注：BPD组为腹腔注入脂多糖溶液构建BPD病理模型的孕鼠所产新生鼠。对照组为孕鼠腹腔注入等体积无菌生理盐水构建空白对照模型所产新生鼠。HO-1为血红素氧合酶1，Nrf2为核因子E2相关因子2, BPD为支气管肺发育不良
表6 2组新生鼠肺组织Keap1/Nrf2信号通路HO-1和Nrf2蛋白相对表达水平比较(±s)
组别 鼠数 HO-1 Nrf2
BPD组 6 0.27±0.03 0.56±0.05
对照组 6 0.55±0.08 0.58±0.08
t值   5.51 0.36
P值   0.005 0.743
图3 流式细胞术检测6组ACEⅡ的活性氧水平比较(图3A：Cell＋NC组；图3B：Cell＋Si-Nrf2组；图3C: LPS组；图3D：LPS＋NC组；图3E：LPS＋Si-Nrf2组；图3F：Control组) 注：ACEⅡ为Ⅱ型肺泡上皮细胞
表7 6组ACEⅡ的活性氧水平比较(±s)
组别 活性氧含量
①Cell＋NC组 1 648.3±3.2
②Cell＋Si-Nrf2组 2 443.7±13.7
③LPS组 1 808.3±27.0
④LPS＋NC组 1 828.3±16.6
⑤LPS＋Si-Nrf2组 3 089.7±6.7
⑥Control组 1 661.3±12.9
F值 4 204.93
P值 <0.001
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