中国药物警戒 ›› 2024, Vol. 21 ›› Issue (1): 83-88.
DOI: 10.19803/j.1672-8629.20230671

• 中药毒性物质和机制研究专栏 • 上一篇    下一篇

富马酸二甲酯对肠道辐射损伤防护作用及机制研究

张亮亮1,2, 胡昌坤2,3, 吴泽坤1,2, 周维2, 廖泽彬2#, 高月1,2,*   

  1. 1广东药科大学药学院,广东 广州 510006;
    2军事科学院军事医学研究院辐射医学研究所,北京 100850;
    3天津中医药大学,天津 301617
  • 收稿日期:2023-10-31 出版日期:2024-01-15 发布日期:2024-01-18
  • 通讯作者: *高月,女,研究员·博导,中药药理学。E-mail: gaoyue@bmi.ac.cn; #为共同通信作者。
  • 作者简介:张亮亮,男,在读硕士,药理学。
  • 基金资助:
    国家自然科学基金资助项目（82103776、82192911）

Protective effect and mechanism of dimethyl fumarate against intestinal radiation injury

ZHANG Liangliang1,2, HU Changkun2,3, WU Zekun1,2, ZHOU Wei2, LIAO Zebin2#, GAO Yue1,2,*   

  1. 1School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou Guangdong 510006, China;
    2Institute of Radiation Medicine, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China;
    3Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
  • Received:2023-10-31 Online:2024-01-15 Published:2024-01-18

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摘要： 目的 研究富马酸二甲酯（dimethyl fumarate,DMF）对全身辐照小鼠小肠辐射损伤的防护作用及机制。方法 利用60Co γ射线诱导小鼠辐射损伤,取照射后小鼠小肠组织切片行H&E、TUNEL染色,观察小肠组织病理学改变及细胞凋亡。通过酶联免疫吸附（ELISA）法测定辐照后小鼠小肠炎症因子白介素-1β（IL-1β）、白介素-6（IL-6）、白介素-18（IL-18）、肿瘤坏死因子-α（TNF-α）及炎症小体小鼠NOD样受体蛋白3（NLRP3）、小鼠黑色素瘤缺乏因子2（AIM2）含量变化。采用Western blot法、免疫荧光染色检测小肠中炎性小体NLRP3、AIM2的表达。使用激动剂验证DMF对小肠的辐射防护作用。结果 在γ射线诱导的小鼠全身辐照损伤模型中,DMF（15 mg·kg-1）明显改善小肠组织病理状况,降低了辐照后肠道细胞的凋亡。DMF能够显著调节辐照后炎症因子及炎症小体的表达。Western blot结果和组织免疫荧光染色表明,DMF能够显著降低NLRP3、AIM2表达。DMF与NLRP3、AIM2激动剂联合使用后组织TUNEL染色结果表明,DMF不能减轻小肠组织的细胞凋亡。结论 DMF对γ射线诱导的小鼠全身辐射损伤具有保护作用,其作用与抑制NLRP3/AIM2炎性小体有关,可作为潜在辐射损伤防护药物。

关键词: 富马酸二甲酯, 辐射损伤, 炎性小体, 肠道损伤, 酶联免疫吸附, 白介素-1β, 白介素-6, 白介素-18, 肿瘤坏死因子-α, 小鼠

Abstract: Objective To investigate the protective effect of dimethyl fumarate (DMF) on irradiation (IR)-induced intestinal damage and the underlying mechanism. Methods 60Co γ ray irradiator was used to induce radiation injury in mice. Small intestines were collected after irradiation and subjected to H&E and TUNEL staining to detect the pathological changes and apoptosis in situ. Inflammatory response was determined by quantifying levels of interleukin-1β (IL-1β), interleukin-6(IL-6), interleukin-18(IL-18), tumor necrosis factor-α(TNF-α), NOD-like receptor protein 3(NLRP3) or melanoma deficiency factor 2 (AIM2) in intestine with enzyme-linked immunosorbent assay. Western blot and immunofluorescence staining were used to detect the expression of NLRP3 and AIM2 in small intestine. To verify the essential role of NLRP3 and AIM3 on radio-protective of DMF on small intestine, the selective agonists were employed. Results DMF (15 mg·kg-1) significantly improved the pathological status of small intestine and decreased the apoptosis level of intestinal cells upon whole body IR exposure. DMF could also significantly inhibit the inflammatory response on small intestine induced IR injury. Western blot results and tissue immunofluorescence staining showed that DMF could significantly suppress the upregulation of NLRP3 and AIM2. With selective agonists, the radio-protective effect of DMF on small intestine was diminished, indicating the critical role of NLRP3 and AIM2 inflammasome signaling involved in the anti-radiation activity of DMF. Conclusion DMF is a promising agent to alleviate IR-induced intestinal injury, and the inhibition of NLRP3/AIM2 inflammasome signaling seem to be the underlying mechanism involved in the radio-protective effect of DMF.

Key words: Dimethyl fumarate, radiation injury, inflammasome, intestinal injury, ELISA, IL-1β, IL-6, IL-18, TNF-α, mice

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