目的 探讨人参皂苷Rg1对急性肾损伤致急性肺损伤的保护作用及其调控机制。 方法 将60只雄性昆明小鼠随机分成4组，每组15只：A组（假手术组），B组（模型组），C组（人参皂苷Rg1组），D组（Nec-1对照组）。制备急性肾损伤模型，24 h后检测血清肌酐（serum creatinine，Scr）、尿素氮（blood urea nitrogen，BUN）含量，测量肺组织湿/干重比，应用HE染色观察肺组织病理改变，ELISA法检测血清肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6），白细胞介素-8（IL-8）等细胞因子表达，免疫组化和免疫印迹法检测肿瘤坏死因子受体1（tumor necrosis factor receptor 1，TNFR1）、肿瘤坏死因子受体蛋白激酶（receptor interacting protein kinase，RIPK）表达。 结果 与A组相比，B组Scr、BUN含量明显升高，C组、D组含量较B组均明显降低（P<0.01）；与A组相比，B组肺组织湿/干重比明显升高，C、D组较B组均明显降低（P<0.01）；A组为正常肺泡结构，B组部分肺泡腔塌陷，部分细胞变性坏死，可见明显的炎细胞浸润。与B组相比，C组、D组肺部损伤程度减轻；与A组比较，B组血清中细胞因子TNF-α、IL-1β、IL-6，IL-8水平显著增高，C、D组较B组均明显降低（P<0.01）；B组TNFR1、RIPK1、RIPK3蛋白含量明显高于A组，C、D组较B组均明显降低（P<0.01）。 结论 人参皂苷Rg1可改善急性肾损伤所诱导的急性肺损伤，其机制可能与抑制TNF-α/TNFR1/RIPKs信号通路有关。
Abstract
Objective To investigate the protective and regulative mechanism of Ginsenoside Rg1 on acute kidney injury (AKI) induced acute lung injury. Methods Sixty male Kunming mice were randomly divided into 4 groups with 15 mice per group: Group A (sham operation group), Group B (model group), Group C (Ginsenoside Rg1 group), and Group D (necrostatin-1 control group). AKI models were prepared，after 24h, the serum level of serum creatinine (Scr) and blood urea nitrogen (BUN) were detected. The wet/dry weight ratio of lung tissues were also measured. Pathological changes of lung tissues were evaluated by HE staining. Expression of tumor necrosis factor-α (TNF-α), IL-1β, IL-6 and IL-8 were detected by ELISA. Expressions of tumor necrosis factor receptor 1 (TNFR1) and receptor interacting protein kinase (RIPK) were observed by immunohistochemistry and western blotting. Results (1) Compared with Group A, the serum level of Scr and BUN in Group B were significantly increased, while compared with Group B, the serum level of Scr and BUN in Group C and Group D were significantly decreased (P<0.01). (2) Compared with Group A, the wet/dry ratio of lung tissues in Group B was significantly increased. Compared with Group B, the wet/dry ratio of lung tissues in Group C and Group D was significantly decreased (P<0.01). HE staining showed that the lung tissues structure of Group A was basically intact, while part of alveolar cavity was collapsed, cells were necrotic with the serious infiltration of inflammatory cells in Group B. Compared with Group B, the lung injury degree of Group C and Group D was alleviated. (3) ELISA showed that TNF-α, IL-1β, IL-6 and IL-8 in serum of Group B were significantly increased compared with Group A, while in Group C and Group D were significantly decreased compared with Group B (P<0.01). (4) Immunohistochemical and western blotting results showed that the protein content of TNFR1, RIPK1 and RIPK3 in Group B were significantly increased compared with Group A, while in Group C and Group D were significantly decreased compared with Group B (P<0.01). Conclusions Ginsenoside Rg1 can alleviate the acute lung injury induced by acute kidney injury, the mechanism may be related to the inhibition of TNF-α/TNFR1/RIPKs pathway.
关键词
人参皂苷Rg1； /
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TNF-α/TNFR1/RIPKs； /
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急性肾损伤； /
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急性肺损伤
Key words
Ginsenoside Rg1; /
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TNF-α/TNFR1/RIPKs; /
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AKI; /
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ALI /
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参考文献
[1] Kent Doi, Hamid Rabb. Impact of acute kidney injury on distant organ function: recent findings and potential therapeutic targets[J]. Kidney Int, 2016, 89(3): 555-564. DOI: 10.1016/j.kint.2015.11.019.
[2] Yang B, Wang R, Ji LL, et al. Exploration of the function of ginsenoside RD attenuates lipopolysaccharide induced lung injury: a study of network pharmacology and experimental validation[J]. Shock, 2022, 57(2): 212-220. DOI: 10.1097/SHK. 0000000000001824.
[3] Lee SA, Cozzi M, Bush EL, et al. Distant organ dysfunction in acute kidney injury: a review[J]. Am J Kidney Dis, 2018, 72(6): 846-856. DOI: 10.1053/j.ajkd.2018.03.028.
[4] 黄茸茸, 陆松侠, 孙玲玲. 人参皂苷Rg1下调NOX2-NLRP1减轻PC12细胞缺氧再复氧损伤的作用[J]. 中国药理学通报, 2021, 37(8): 1068-1075. DOI: 10.3969/j.issn.1001-1978.2021.08.007.
[5] 张天柱, 杨世海, 代文意, 等. 人参皂苷Rg1减轻脂多糖诱导的小鼠急性肺损伤的作用机制研究[J].中成药, 2015, 37(9): 2016-2048. DOI: 10.3969/j.issn.1001-1528.2015.09.041.
[6] 张振波, 徐秋萍. 人参皂苷Rg1联合抗生素治疗小鼠脓毒症急性肺损伤[J]. 四川大学学报, 2020, 51(3): 371-375. DOI: 10.12182/20200560204.
[7] 刘玉玲, 郭敏, 邵佑之, 等. 大鼠缺血性急性肾损伤对肺脏超微结构的影响[J]. 中国临床解剖学杂志, 2012, 30(5): 556-559. DOI: 10.13418/j.issn.1001-165x.2012.05.026.
[8] Wang L, Wang T, Li H, et al. Receptor interacting protein 3 mediated necroptosis promotes lipopolysaccharide induced inflammation and acute respiratory distress syndrome in mice[J]. PLoSOne, 2016, 11(5): e155723. DOI: 10.1371/journal.pone.0155723.
[9] 吴玲, 蒋廷, 唐安琪, 等. 缺血性急性肾损伤动物模型制备的研究进展[J]. 中华危重病急救医学, 2020, 32(9): 1149-1152. DOI: 10.3760/cma.j.cn121430-20200417-00309.
[10]Huang ZT, Michael Epperly, Simon C, et al. Necrostatin-1 rescues mice from lethal irradiation[J]. Biochim Biophys Acta, 2016, 1862(4): 850-856. DOI: 10.1016/j.bbadis.2016.01.014.
[11]马丽娟, 安永强, 刘巍. RIP1和RIP3在心血管疾病中的研究进展[J]. 中国循证心血管医学杂志, 2018, 10(10): 1261-1263. DOI: 10.3969/j.issn.1674-4055.2018.10.30.
[12]Jia L, Liu K, Fei T, et al. Programmed cell death-1/programmed cell death-ligand 1 inhibitors exert antiapoptosis and antiinflammatory activity in lipopolysaccharide stimulated murine alveolar macrophages[J]. Exp Ther Med, 2021, 21(4): 400. DOI: 10.3892/etm.2021.9831.
[13]胡汇敏, 王琳琳, 武庆平, 等. RIPK3介导的程序性坏死通路在LPS诱导的小鼠急性肺损伤模型中的作用[J]. 临床肺科杂志, 2016, 21(8): 1454-1457. DOI: 10.3969/j.issn.1009-6663.2016.08.029.
[14]赵攀, 杨昊臻, 高雪, 等. 急性肝衰竭小鼠necroptosis的发生及Nec-1的干预作用研究[J]. 疑难病杂志, 2019, 18(3): 193-196. DOI: 10.3969/j.issn.1671-6450.2019.03.018.
[15]Han W, Xie J, Li L, et al. Necrostatin-1 reverts shikonin-induced necroptosis to apoptosis[J]. Apoptosis, 2009, 14(5): 674-686. DOI: 10.1007/s10495-009-0334-x.
基金
国家自然科学基金资助项目（No. 81774116）；辽宁省教育厅项目（No.JYTJCZR2020083）
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