Glucocorticoid regulates Keap1-Nrf2 pathway to relieve pulmonary oxidative stress in asthmatic mice

Kunjiao XUE; Lingying RUAN; Jie HU; Linyan YING; Wenjing ZOU; Zhou FU

doi:10.16016/j.1000-5404.201912057

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Glucocorticoid regulates Keap1-Nrf2 pathway to relieve pulmonary oxidative stress in asthmatic mice

更新时间：2026-01-09

- Glucocorticoid regulates Keap1-Nrf2 pathway to relieve pulmonary oxidative stress in asthmatic mice
- Journal of Third Military Medical University Vol. 42, Issue 8, Pages: 807-814(2020)
- 作者机构：
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81670018)
- DOI：10.16016/j.1000-5404.201912057
  CLC：
- Received：06 December 2019，
  
  Published：30 April 2020
- 稿件说明：
移动端阅览
Kunjiao XUE, Lingying RUAN, Jie HU, et al. Glucocorticoid regulates Keap1-Nrf2 pathway to relieve pulmonary oxidative stress in asthmatic mice[J]. Journal of Third Military Medical University, 2020, 42(8): 807-814.
DOI：

Kunjiao XUE, Lingying RUAN, Jie HU, et al. Glucocorticoid regulates Keap1-Nrf2 pathway to relieve pulmonary oxidative stress in asthmatic mice[J]. Journal of Third Military Medical University, 2020, 42(8): 807-814. DOI： 10.16016/j.1000-5404.201912057.

摘要

Abstract

Objective

To investigate the level of oxidative stress in asthmatic mice and the mechanism of dexamethasone forrelieving oxidative stress.

Methods

Thirty female C57BL/6 mice were randomly divided into control group

asthma group and dexamethasone group. Following challenges with house dust mites in the latter 2 groups and prior dexamethasone treatment in dexamethasone group

the mice were examined for expression levels of lipid peroxide metabolites malondialdehyde (MDA) and oxidized glutathione (GSSG). Quantitative real-time PCR was used to detect the expression of nuclear factor erythroid 2-related factor 2 (NF-E2) and heme oxygenase 1 (HO-1) in the lung tissues. Immunohistochemistry was used to detect the expression of Nrf2 protein

and Western blotting was performed to detect the changes of Nrf2-Keap1 signaling pathway in the lungs of the mice.

Results

MDA and GSSG levels were significantly higher in the asthmatic mice than in control group (

0.01)

and were significantly lowered by dexamethasone treatment in the asthmatic mice (

0.05). Compared with the control group

the asthmatic mice showed significantly higher pulmonary expression levels of Nrf2 and HO-1 mRNA (

0.05)

which were obviously lowered by dexamethasone treatment (

0.05). Immunohistochemistry and immunofluorescence assay revealed a significantly highe

r expression of Nrf2 protein in the lung tissue of asthmatic mice (

0.01)

which was significantly lowered by dexamethasone treatment (

0.01). The asthmatic mice had a significantly lower expression of Keap1 protein in the lungs (

0.05)

which was obviously increased by dexamethasone treatment (

0.05).

Conclusion

Asthmatic mice have an increased level of oxidative stress. Dexamethasone inhibits the level of pulmonary oxidative stress in asthmatic mice possibly by inhibiting the expression of the downstream antioxidant elements

via

regulating the Keap1-Nrf2 pathway.

关键词

Keywords

references

CASTILLO J R PETERS S P BUSSE WW Asthma exacerbations: pathogenesis, prevention, and treatment J Allergy Clin Immunol Pract 2017 5 4 918 927 10.1016/j.jaip.2017.05.001 CASTILLO J R, PETERS S P, BUSSE WW. Asthma exacerbations: pathogenesis, prevention, and treatment[J]. J Allergy Clin Immunol Pract, 2017, 5(4): 918-927. DOI: 10.1016/j.jaip.2017.05.001.

GABALLAH HH GABER R A SHARSHAR R S NOD2 expression, DNA damage and oxido-inflammatory status in atopic bronchial asthma: Exploring their Nexus to disease severity Gene 2018 660 128 135 10.1016/j.gene.2018.03.061 GABALLAH HH, GABER R A, SHARSHAR R S, et al . NOD2 expression, DNA damage and oxido-inflammatory status in atopic bronchial asthma: Exploring their Nexus to disease severity[J ] . Gene, 2018, 660: 128-135. DOI: 10.1016/j.gene.2018.03.061.

WANG J C LU Q Y CAI J Y Nestin regulates cellular redox homeostasis in lung cancer through the Keap1-Nrf2 feedback loop Nat Commun 2019 10 1 5043 10.1038/s41467-019-12925-9 WANG J C, LU Q Y, CAI J Y, et al . Nestin regulates cellular redox homeostasis in lung cancer through the Keap1-Nrf2 feedback loop[J ] . Nat Commun, 2019, 10(1): 5043. DOI: 10.1038/s41467-019-12925-9.

MCGOVERN T FARAHNAK S CHEN M Organic dust, causing both oxidative stress and Nrf2 activation, is phagocytized by bronchial epithelial cells Am J Physiol Lung Cell Mol Physiol 2019 317 3 L305 L316 10.1152/ajplung.00377.2018 MCGOVERN T, FARAHNAK S, CHEN M, et al . Organic dust, causing both oxidative stress and Nrf2 activation, is phagocytized by bronchial epithelial cells[J ] . Am J Physiol Lung Cell Mol Physiol, 2019, 317(3): L305-L316. DOI: 10.1152/ajplung.00377.2018.

NHU Q M ACEVES SS Tissue remodeling in chronic eosinophilic esophageal inflammation: parallels in asthma and therapeutic perspectives Front Med (Lausanne) 2017 4 128 10.3389/fmed.2017.00128 NHU Q M, ACEVES SS. Tissue remodeling in chronic eosinophilic esophageal inflammation: parallels in asthma and therapeutic perspectives[J]. Front Med (Lausanne), 2017, 4: 128. DOI: 10.3389/fmed.2017.00128.

李彬李茹谢小华地塞米松对实验性自身免疫性脑脊髓炎小鼠的抗氧化损伤作用细胞与分子免疫学杂志 2013 29 11 1155 1158 10.13423/j.cnki.cjcmi.006935 李彬, 李茹, 谢小华, 等.地塞米松对实验性自身免疫性脑脊髓炎小鼠的抗氧化损伤作用[J].细胞与分子免疫学杂志, 2013, 29(11): 1155-1158. DOI: 10.13423/j.cnki.cjcmi.006935.

LI B LI R XIE X H Anti-oxidative effects of dexamethasone on mice with experimental autoimmune encephalomyelitis Chin J Cell Mol Immunol 2013 29 11 1155 1158 10.13423/j.cnki.cjcmi.006935 LI B, LI R, XIE X H, et al . Anti-oxidative effects of dexamethasone on mice with experimental autoimmune encephalomyelitis[J ] . Chin J Cell Mol Immunol, 2013, 29(11): 1155-1158. DOI: 10.13423/j.cnki.cjcmi.006935.

ZHU L J YI X L ZHAO J Betulinic acid attenuates dexamethasone-induced oxidative damage through the JNK-P38 MAPK signaling pathway in mice Biomed Pharmacother 2018 103 499 508 10.1016/j.biopha.2018.04.073 ZHU L J, YI X L, ZHAO J, et al . Betulinic acid attenuates dexamethasone-induced oxidative damage through the JNK-P38 MAPK signaling pathway in mice[J ] . Biomed Pharmacother, 2018, 103: 499-508. DOI: 10.1016/j.biopha.2018.04.073.

SINGH A K HALDAR C Melatonin modulates glucocorticoid receptor mediated inhibition of antioxidant response and apoptosis in peripheral blood mononuclearcells Mol Cell Endocrinol 2016 436 59 67 10.1016/j.mce.2016.07.024 SINGH A K, HALDAR C. Melatonin modulates glucocorticoid receptor mediated inhibition of antioxidant response and apoptosis in peripheral blood mononuclearcells[J]. Mol Cell Endocrinol, 2016, 436: 59-67. DOI: 10.1016/j.mce.2016.07.024.

ALAM MM OKAZAKI K NGUYEN L T T Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2 J Biol Chem 2017 292 18 7519 7530 10.1074/jbc.M116.773960 ALAM MM, OKAZAKI K, NGUYEN L T T, et al . Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2[J ] . J Biol Chem, 2017, 292(18): 7519-7530. DOI: 10.1074/jbc.M116.773960.

NIU C LIU N LIU J Vitamin A maintains the airway epithelium in a murine model of asthma by suppressing glucocorticoid-induced leucine zipper Clin Exp Allergy 2016 46 6 848 860 10.1111/cea.12646 NIU C, LIU N, LIU J, et al . Vitamin A maintains the airway epithelium in a murine model of asthma by suppressing glucocorticoid-induced leucine zipper[J ] . Clin Exp Allergy, 2016, 46(6): 848-860. DOI: 10.1111/cea.12646.

XIE J LONG X R GAO L Q Respiratory syncytial virus nonstructural protein 1 blocks glucocorticoid receptor nuclear translocation by targeting IPO13 and may account for glucocorticoid insensitivity J Infect Dis 2017 217 1 35 46 10.1093/infdis/jix445 XIE J, LONG X R, GAO L Q, et al . Respiratory syncytial virus nonstructural protein 1 blocks glucocorticoid receptor nuclear translocation by targeting IPO13 and may account for glucocorticoid insensitivity[J ] . J Infect Dis, 2017, 217(1): 35-46. DOI: 10.1093/infdis/jix445.

朱绮芬郑斌颜仁杰玉屏风颗粒对地塞米松诱导的免疫抑制幼鼠的影响世界临床药物 2018 39 5 329 333 10.13683/j.wph.2018.05.009 朱绮芬, 郑斌, 颜仁杰, 等.玉屏风颗粒对地塞米松诱导的免疫抑制幼鼠的影响[J].世界临床药物, 2018, 39(5): 329-333. DOI: 10.13683/j.wph.2018.05.009.

ZHU Q F ZHENG B YAN R J Effect of Yupingfeng granule on the immunosuppression induced by dexamethasone in immature mice World Clin Drugs 2018 39 5 329 333 10.13683/j.wph.2018.05.009 ZHU Q F, ZHENG B, YAN R J, et al . Effect of Yupingfeng granule on the immunosuppression induced by dexamethasone in immature mice[J ] . World Clin Drugs, 2018, 39(5): 329-333. DOI: 10.13683/j.wph.2018.05.009.

ANDRIANJAFIMASY M ZERIMECH F AKIKI Z Oxidative stress biomarkers and asthma characteristics in adults of the Egea study Eur Respir J 2017 50 6 1701193 10.1183/13993003.01193-2017 ANDRIANJAFIMASY M, ZERIMECH F, AKIKI Z, et al . Oxidative stress biomarkers and asthma characteristics in adults of the Egea study[J ] . Eur Respir J, 2017, 50(6): 1701193. DOI: 10.1183/13993003.01193-2017.

CORRADI M FOLESANI G ANDREOLI R Aldehydes and glutathione in exhaled breath condensate of children with asthma exacerbation Am J Respir Crit Care Med 2003 167 3 395 399 10.1164/rccm.200206-507OC CORRADI M, FOLESANI G, ANDREOLI R, et al . Aldehydes and glutathione in exhaled breath condensate of children with asthma exacerbation[J ] . Am J Respir Crit Care Med, 2003, 167(3): 395-399. DOI: 10.1164/rccm.200206-507OC.

蓝楠 . 氧化应激在支气管哮喘中的作用机制研究 [D ] . 泸州 : 泸州医学院 , 2012 . 蓝楠.氧化应激在支气管哮喘中的作用机制研究[D].泸州: 泸州医学院, 2012.

LAN N . Mechanism of oxidative stress in bronchial asthma [D ] . Luzhou : Luzhou Medical College . LAN N. Mechanism of oxidative stress in bronchial asthma[D]. Luzhou: Luzhou Medical College.

PAPI A BRIGHTLING C PEDERSEN S E Asthma Lancet 2018 391 10122 783 800 10.1016/s0140-6736(17)33311-1 PAPI A, BRIGHTLING C, PEDERSEN S E, et al . Asthma[J ] . Lancet, 2018, 391(10122): 783-800. DOI: 10.1016/s0140-6736(17)33311-1.

MISHRA V BANGA J SILVEYRA P Oxidative stress and cellular pathways of asthma and inflammation: Therapeutic strategies and pharmacologicaltargets PharmacolTher 2018 181 169 182 10.1016/j.pharmthera.2017.08.011 MISHRA V, BANGA J, SILVEYRA P. Oxidative stress and cellular pathways of asthma and inflammation: Therapeutic strategies and pharmacologicaltargets[J]. PharmacolTher, 2018, 181: 169-182. DOI: 10.1016/j.pharmthera.2017.08.011.

刘建秋马莹王雪慧淫羊藿苷对慢性哮喘大鼠氧化应激及肺组织Nrf2、HO-1表达的影响中华中医药学刊 2019 37 12 2823 2826 10.13193/j.issn.1673-7717.2019.12.001 刘建秋, 马莹, 王雪慧.淫羊藿苷对慢性哮喘大鼠氧化应激及肺组织Nrf2、HO-1表达的影响[J].中华中医药学刊, 2019, 37(12): 2823-2826. DOI: 10.13193/j.issn.1673-7717.2019.12.001.

LIU J Q MA Y WANG X H Effect of icariin on oxidative stress and Nrf2 and HO-1 expression in lung tissue of chronic asthma rats Chin Arch Tradit Chin Med 2019 37 12 2823 2826 10.13193/j.issn.1673-7717.2019.12.001 LIU J Q, MA Y, WANG X H. Effect of icariin on oxidative stress and Nrf2 and HO-1 expression in lung tissue of chronic asthma rats[J]. Chin Arch Tradit Chin Med, 2019, 37(12): 2823-2826. DOI: 10.13193/j.issn.1673-7717.2019.12.001.

FITZPATRICK A M STEPHENSON S T HADLEY G R Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor (erythroid-derived 2)-like 2 J Allergy Clin Immunol 2011 127 6 1604 1611 10.1016/j.jaci.2011.03.031 FITZPATRICK A M, STEPHENSON S T, HADLEY G R, et al . Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor (erythroid-derived 2)-like 2[J ] . J Allergy Clin Immunol, 2011, 127(6): 1604-1611. DOI: 10.1016/j.jaci.2011.03.031.

DWORSKI R HAN W BLACKWELL T S Vitamin E prevents NRF2 suppression by allergens in asthmatic alveolar macrophages in vivo Free Radic Biol Med 2011 51 2 516 521 10.1016/j.freeradbiomed.2011.04.040 DWORSKI R, HAN W, BLACKWELL T S, et al . Vitamin E prevents NRF2 suppression by allergens in asthmatic alveolar macrophages in vivo [J ] . Free Radic Biol Med, 2011, 51(2): 516-521. DOI: 10.1016/j.freeradbiomed.2011.04.040.

SUSSAN T E GAJGHATE S CHATTERJEE S Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function Am J Physiol Lung Cell Mol Physiol 2015 309 1 L27 L36 10.1152/ajplung.00398.2014 SUSSAN T E, GAJGHATE S, CHATTERJEE S, et al . Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function[J ] . Am J Physiol Lung Cell Mol Physiol, 2015, 309(1): L27-L36. DOI: 10.1152/ajplung.00398.2014.

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