Effect of Buyang Huanwutang on Keap1/Nrf2/HO-1 Antioxidant Signaling Pathway in Rats with Idiopathic Pulmonary Fibrosis

Zhe ZHANG; Shu ZHAO; Yunpeng HAN; Feng JIN; Jiarong SHANG; Jiepeng WANG; Chaoyi FANG

doi:10.13422/j.cnki.syfjx.20221639

您当前的位置：

首页 >

文章列表页 >

Effect of Buyang Huanwutang on Keap1/Nrf2/HO-1 Antioxidant Signaling Pathway in Rats with Idiopathic Pulmonary Fibrosis

更新时间：2022-08-05

- Effect of Buyang Huanwutang on Keap1/Nrf2/HO-1 Antioxidant Signaling Pathway in Rats with Idiopathic Pulmonary Fibrosis
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 28, Issue 17, Pages: 9-16(2022)
- 作者机构：
  
  1.河北中医学院，石家庄 050200
  2.河北省中西医结合肺病研究重点实验室，石家庄 050091
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20221639
  CLC： R2-0;R33;R259;R318.13
- Received：19 March 2022，
  
  Published Online：29 June 2022，
  
  Published：05 September 2022
- 稿件说明：
移动端阅览
张喆,赵舒,韩云鹏等.补阳还五汤对特发性肺纤维化大鼠Keap1/Nrf2/HO-1抗氧化信号通路的影响[J].中国实验方剂学杂志,2022,28(17):9-16.

ZHANG Zhe,ZHAO Shu,HAN Yunpeng,et al.Effect of Buyang Huanwutang on Keap1/Nrf2/HO-1 Antioxidant Signaling Pathway in Rats with Idiopathic Pulmonary Fibrosis[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(17):9-16.
张喆,赵舒,韩云鹏等.补阳还五汤对特发性肺纤维化大鼠Keap1/Nrf2/HO-1抗氧化信号通路的影响[J].中国实验方剂学杂志,2022,28(17):9-16. DOI： 10.13422/j.cnki.syfjx.20221639.

ZHANG Zhe,ZHAO Shu,HAN Yunpeng,et al.Effect of Buyang Huanwutang on Keap1/Nrf2/HO-1 Antioxidant Signaling Pathway in Rats with Idiopathic Pulmonary Fibrosis[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(17):9-16. DOI： 10.13422/j.cnki.syfjx.20221639.

摘要

目的

观察补阳还五汤对特发性肺纤维化（IPF）大鼠Kelch样ECH相关蛋白1（Keap1）/核因子E

相关因子2（Nrf2）/血红素氧合酶-1（HO-1）抗氧化信号通路的影响，探讨该方干预IPF的作用机制。

方法

将40只SPF级雄性SD大鼠按照随机数字表法分为假手术组、模型组、补阳还五汤组、尼达尼布组，每组10只。除假手术组外，其余各组气管内滴注博来霉素（0.005 g·kg

-1

）制备IPF大鼠模型。补阳还五汤组灌服补阳还五汤煎液（14.84 g·kg

-1

），尼达尼布组灌服尼达尼布混悬液（0.1 g·kg

-1

），假手术组、模型组灌服等容积生理盐水，共28 d。肺功能检测后，取血清及肺组织。苏木素-伊红（HE）染色和马松（Masson）染色观察肺组织病理改变并行半定量分析；检测肺组织羟脯氨酸（HYP）含量；测定血清和肺组织丙二醛（MDA）含量及超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）、过氧化氢酶（CAT）活性；实时荧光定量聚合酶链式反应（Real-time PCR）、免疫组化和蛋白免疫印迹法（Western blot）分别检测Keap1、Nrf2、HO-1 mRNA与蛋白表达情况。

结果

与假手术组比较，模型组大鼠呼吸系统阻力和弹力增高，顺应性显著降低（

0.01）；肺指数和病理评分、HYP含量显著升高（

0.01）；血清和肺组织MDA含量增加，SOD、GSH-Px、CAT活性显著降低（

0.01）；肺组织Keap1 mRNA与蛋白表达降低，Nrf2、HO-1 mRNA与蛋白表达显著升高（

0.01）。与模型组比较，补阳还五汤组大鼠呼吸系统阻力和弹力下降，顺应性显著升高（

0.01）；肺指数、病理评分、肺组织HYP含量显著降低（

0.01）；血清和肺组织MDA含量下降、SOD、GSH-Px、CAT活性显著升高（

0.01）；肺组织Keap1表达降低，Nrf2、HO-1表达升高（

0.05，

0.01）。

结论

补阳还五汤可启动Keap1/Nrf2/HO-1介导的抗氧化效应，增强机体抗氧化能力，延缓IPF大鼠病理进程。

Abstract

Objective

To study the effect of Buyang Huanwutang on Kelch-like Ech-related protein 1 （Keap1）/nuclear factor E

-related factor 2 （Nrf2）/heme oxygenase-1 （HO-1） antioxidant signaling pathway in rats with idiopathic pulmonary fibrosis （IPF） and explore the mechanism of this prescription in the treatment of IPF.

Method

Forty SPF-grade male SD rats were assigned into a sham operation group， a model group， a Buyang Huanwutang group， and a nintedanib group according to random number table method， with 10 rats in each group. IPF rat model was established by intratracheal infusion of bleomycin （0.005 g·kg

-1

） in other groups except the sham operation group. Buyang Huanwutang group was administrated with Buyang Huanwutang (14.84 g·kg

-1

)，intragastric administration of nitedanib suspension (0.1 g·kg

-1

)，sham operation group and model group were given equal volume of normal saline， for 28 days. After lung function test， serum and lung tissue samples were collected. Hematoxylin-eosin （HE） staining and Masson trichrome staining were employed to observe the pathological changes of the lung tissue. The content of hydroxyproline （HYP） in lung tissue was detected. The levels of malondialdehyde （MDA） in serum and lung tissue， and the activities of superoxide dismutase （SOD）， glutathione peroxidase （GSH-Px） and catalase （CAT） were determined. The mRNA and protein levels of Keap1， Nrf2， and HO-1 was determined by Real-time fluorescent quantitative polymerase chain reaction， immunohistochemical staining， and Western blot.

Result

Compared with the sham operation group， the modeling increased the resistance and elasticity and decreased the compliance of respiratory system （

0.01）， elevated the lung index， pathological score， and HYP content in lung tissue （

0.01）， and enriched MDA in serum and lung tissue， while it decreased the activities of SOD， GSH-Px， and CAT （

0.01）. Furthermore， the modeling down-regulated the mRNA and protein levels of Keap1 and up-regulated those of Nrf2 and HO-1 in lung tissue （

0.01）. Compared with the model group， Buyang Huanwutang decreased the resistance and elasticity and increased the compliance of respiratory system （

0.01）， lowered the lung index， pathological score， and HYP content in lung tissue （

0.01）， and reduced MDA in serum and lung tissue， while it increased the activities of SOD， GSH-Px， and CAT （

0.01）. Additionally， Buyang Huanwutang down-regulated the expression of Keap1 and up-regulated that of Nrf2 and HO-1 in lung tissue （

0.05，

0.01）.

Conclusion

Buyang Huanwutang can activate Keap1/Nrf2/HO-1 signaling pathway to enhance the antioxidant capacity and slow down the pathological process of IPF in rats.

关键词

Keywords

references

PHAN T ， PALIOGIANNIS P ， NASRALLAH G ， et al . Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis ［J］. Cell Mol Life Sci ， 2021 ， 78 （ 5 ）： 2031 - 2057 .

HYLDGAARD C ， HILBERG O ， BENDSTRUP E . How does comorbidity influence survival in idiopathic pulmonary fibrosis？［J］. Respir Med ， 2014 ， 108 （ 4 ）： 647 - 653 .

ARYAL S ， NATHAN S D . An update on emerging drugs for the treatment of idiopathic pulmonary fibrosis ［J］. Expert Opin Emerg Drugs ， 2018 ， 23 （ 2 ）： 159 - 172 .

IKEDA S ， SEKINE A ， BABA T ， et al . Negative impact of anorexia and weight loss during prior pirfenidone administration on subsequent nintedanib treatment in patients with idiopathic pulmonary fibrosis ［J］. BMC Pulm Med ， 2019 ， 19 （ 1 ）： 78 .

COULTAS D B，Coagulation disorders and the IPF puzzle ［J］. Thorax ， 2014 ， 69 （ 3 ）： 203 - 204 .

吴孝政，黄高，李文，等 . 益气活血法治疗特发性肺纤维化的临床疗效和安全性的系统评价及Meta分析［J］. 世界中西医结合杂志， 2021 ， 16 （ 2 ）： 218 - 223 .

WANG J ， WANG H ， FANG F ， et al . Danggui Buxue Tang ameliorates bleomycin-induced pulmonary fibrosis by suppressing the TLR4/NLRP3 signaling pathway in rats ［J］. Evid Based Complement Alternat Med ， 2021 ， doi： 10.1155/2021/8030143 http://dx.doi.org/10.1155/2021/8030143 .

鲁辰希，王杰鹏，刘娜，等 . 当归补血汤对特发性肺纤维化大鼠血管新生因子HIF-1 α 和endostatin的影响［J］. 中华中医药杂志， 2021 ， 36 （ 3 ）： 1683 - 1687 .

张帆，尹正海，李震 . 补阳还五汤联合汉防己甲素片改善矽肺肺纤维化的效果［J］. 哈尔滨医药， 2019 ， 39 （ 1 ）： 70 - 71 .

WANG X ， LI X ， WANG L ， et al . Buyang Huanwu decoction ameliorates bleomycin-induced pulmonary fibrosis in rats via downregulation of related protein and gene expression ［J］. Evid Based Complement Alternat Med ， 2018 ， doi： 10.1155/2018/9185485 http://dx.doi.org/10.1155/2018/9185485 .

CHO H Y ， REDDY S P ， YAMAMOTO M ， et al . The transcription factor NRF2 protects against pulmonary fibrosis ［J］. FASEB J ， 2004 ， 18 （ 11 ）： 1258 - 1260 .

LIU Q ， GAO Y ， CI X . Role of Nrf2 and its activators in respiratory diseases ［J］. Oxid Med Cell Longev ， 2019 ， doi： 10.1155/2019/7090534 http://dx.doi.org/10.1155/2019/7090534 .

LIU T ， DE LOS SANTOS F G ， PHAN S H . The bleomycin model of pulmonary fibrosis ［J］. Methods Mol Biol ， 2017 ， 1627 ： 27 - 42 .

徐叔云，卞如濂，陈修 . 药理实验方法学［M］. 3版 . 北京：人民卫生出版社， 2002 ： 1937 .

蒋莉莉 . 尼达尼布对肺泡上皮细胞间质转分化的作用及机制研究［D］. 芜湖：皖南医学院， 2019 .

王杰鹏，王浩，方朝义，等 . 基于肺脏生理特性的络通纤溶饮调节细胞焦亡抑制肺纤维化机制研究［J］. 中华中医药杂志， 2020 ， 35 （ 5 ）： 2349 - 2354 .

SZAPIEL S V ， ELSON N A ， FULMER J D ， et al . Bleomycin-induced interstitial pulmonary disease in the nude，athymic mouse ［J］. Am Rev Respir Dis ， 1979 ， 120 （ 4 ）： 893 - 899 .

ASHCROFT T ， SIMPSON J M ， TIMBRELL V . Simple method of estimating severity of pulmonary fibrosis on a numerical scale ［J］. J Clin Pathol ， 1988 ， 41 （ 4 ）： 467 - 470 .

任璐瑶，孟泳，贺启萌 . 益气活血固本方治疗特发性肺纤维化的临床观察［J］. 中医临床研究， 2020 ， 12 （ 11 ）： 29 - 32 .

吴之煌，张晓霞 . 补肺活血汤治疗特发性肺纤维化临床观察［J］. 北京中医药， 2010 ， 29 （ 2 ）： 118 - 120 .

王杰鹏，王少贤，方朝义，等 . 当归补血汤干预肺纤维化大鼠气虚血瘀状态机制初探［J］. 解放军医学杂志， 2020 ， 32 （ 3 ）： 24 - 28 .

谭支奎，田正鉴 . 田正鉴教授运用补阳还五汤加减方治疗特发性肺纤维化疗效观察［J］. 四川中医， 2014 ， 32 （ 10 ）： 113 - 114 .

颜晓霞，袁帆，郑访江 . 补阳还五汤联合 N -乙酰半胱氨酸胶囊治疗特发性肺纤维化患者的效果评价［J］. 内科， 2015 ， 10 （ 4 ）： 468 - 470 .

FOIS A G ， PALIOGIANNIS P ， SOTGIA S ， et al . Evaluation of oxidative stress biomarkers in idiopathic pulmonary fibrosis and therapeutic applications：A systematic review ［J］. Respir Res ， 2018 ， 19 （ 1 ）： 51 .

ABED D A ， LEE S ， HU L . Discovery of disubstituted xylylene derivatives as small molecule direct inhibitors of Keap1-Nrf2 protein-protein interaction ［J］. Bioorg Med Chem ， 2020 ， 28 （ 6 ）： 115343 .

LEE S ， HU L . Nrf2 activation through the inhibition of Keap1-Nrf2 protein-protein interaction ［J］. Med Chem Res ， 2020 ， 29 （ 5 ）： 846 - 867 .

LEE J M ， CALKINS M J ， CHAN K ， et al . Identification of the NF-E 2 -related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis ［J］. J Bio Chem ， 2003 ， 278 （ 14 ）： 12029 - 12038 .

刘娜，王杰鹏，鲁辰希，等 . 当归补血汤对博莱霉素致肺纤维化大鼠PKD1/NF- κ B/MnSOD信号通路的影响［J］. 中国实验方剂学杂志， 2020 ， 26 （ 13 ）： 66 - 72 .

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Shengxiantang Alleviates Idiopathic Pulmonary Fibrosis in Rats by Regulating Oxidative Stress to Inhibit PANoptosis

Clinical Randomized Controlled Trial of Traditional Chinese Medicine Compound Shenlong Decoction Granules in Treatment of Idiopathic Pulmonary Fibrosis

Analysis of Treatment of Diabetic Kidney Disease with Modified Buyang Huanwutang Based on 5hmC-Seal Sequencing Technology

Exploring Immune Mechanism of Alveolar Epithelial Homeostasis in Idiopathic Pulmonary Fibrosis Based on Principle of "Spleen being in Charge of Defensive Function"

Related Author

Shu ZHAO

Yunpeng HAN

Feng JIN

Jiarong SHANG

Jiepeng WANG

LIANG Yulei

YAN Yanan

LI Wei

Related Institution

Hebei University of Chinese Medicine

Hebei Key Laboratory of Integrated Chinese and Western Medicine for Lung Disease Research

Liaoning University of Traditional Chinese Medicine（TCM）

Affiliated Hospital of Liaoning University of TCM

School of Pharmacy，Xinjiang Medical University

AI问答

Postal code：100700
Tel：010-84076882 Email：syfjx_2010@188.com
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备11006657号-10 京公网安备11010802024621
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰