Protective efficacy of epalrestat on mitochondrial oxidative stress damage for radiation pneumonitis in mice
10.12092/j.issn.1009-2501.2024.07.011
- VernacularTitle:依帕司他对放射性肺炎小鼠线粒体氧化应激损伤的保护作用
- Author:
Zepeng LI
1
;
Wenqiang GU
;
Xiao CHEN
;
Yinhua WANG
;
Xianwei LI
Author Information
1. 皖南医学院药学院药理学教研室,芜湖 241002,安徽
- Keywords:
epalrestat;
radiation pneumonitis;
al-dose reductase;
mitochondria;
oxidative stress;
mouse
- From:
Chinese Journal of Clinical Pharmacology and Therapeutics
2024;29(7):809-818
- CountryChina
- Language:Chinese
-
Abstract:
AIM:To investigate the effects of epal-restat(Epa)on the mitochondrial oxidative stress damage of radiation pneumonitis(RP)mice and to explore its possible mechanism.METHODS:C57BL/6 mice were randomly divided into control(CON),Irradiation(IR),IR combined with Epa(10 mg/kg)and IR combined with Epa(20 mg/kg)group,16 mice in each group.Mouse models of RP were es-tablished by whole thorax irradiation at a dose of 15Gy using a 6-MV linear accelerator.Continuous intragastric administration after IR for 6 or 8 weeks.Lung histopathology was analyzed by HE staining.The expression of aldose reductase(AR)was deter-mined by immunohistochemistry.Mitochondrial morphology of lung tissues was observed by trans-mission electron microscopy.The levels of inflam-matory cytokines(IL-6,TNF-α and TGF-β1)in plas-ma were detected by ELISA.The contents of Malo-ndialdehyde(MDA)and 4-hydroxynonenal(4-HNE)in lung tissues were determined by colorimetry.Sin-gle cell suspension of lung tissues was prepared and reactive oxygen species(ROS)levels in the cells was examined using a DCFH-DA fluorescent probe.Real-time quantitative PCR was used to determine the expression of AR,IL-6,TNF-α and TGF-β1.The protein levels of AR,IL-6,TNF-α,TGF-β1,BAX,Bcl2,Cleaved Caspase-3,8-oxoguanine DNA glycosylase 1(OGG1)and silent information regulator 3(SIRT3)were detected by Western blot analysis.RESULTS:Compared with the CON group,the alveolar hyper-plasia,alveolar septum thickening and inflammato-ry cell infiltration were observed in the IR group.Moreover,the content of inflammatory factors such as IL-6,TNF-α and TGF-β1 and the expression of BAX and Cleaved Caspase-3 were significantly in-creased,and the expression of Bcl2 was obviously decreased after irradiation.Compared with the IR group,Epa robustly alleviated RP.Meanwhile,Epa down-regulated inflammatory cells infiltration and the expression of inflammatory cytokines,such as IL-6,TNF-α and TGF-β1.In addition,Epa could down-regulate the expression of BAX and Cleaved Caspase-3,and up-regulate Bcl2 in lung tissues.Compared with the CON group,the expression of AR,the levels of ROS,MDA and 4-HNE were signifi-cantly increased,the expression of OGG1 and SIRT3 were significantly decreased,and mitochon-drial damage was aggravated in the IR group.Com-pared with IR group,the expression of AR was sig-nificantly down-regulated,the levels of ROS,MDA and 4-HNE were significantly decreased,the expres-sions of OGG1 and SIRT3 were significantly in-creased,and the mitochondrial damage was signifi-cantly alleviated in IR group after 6 to 8 weeks of Epa administration.CONCLUSION:Epa has a pro-tective effect on RP,which may be related to the in-hibition of AR expression,the reduction of mito-chondrial oxidative stress injury,and the inhibition of inflammatory response and cell apoptosis.
