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

doi:10.3877/cma.j.issn.1673-5250.2023.06.007

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

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

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

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

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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