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孙红梅, 张然然, 李巧, 李倩, 高艳军.人参皂苷Rb1通过激活AMPK/Nrf2/FTH1通路抑制铁死亡改善脓肿分枝杆菌感染大鼠肺损伤[J].湖南中医药大学学报,2025,45(12):2254-2262[点击复制] |
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| 人参皂苷Rb1通过激活AMPK/Nrf2/FTH1通路抑制铁死亡改善脓肿分枝杆菌感染大鼠肺损伤 |
| 孙红梅,张然然,李巧,李倩,高艳军 |
| (河北省胸科医院, 河北 石家庄 050000;深州市医院, 河北 衡水 053800) |
| 摘要: |
| 目的 探讨人参皂苷Rb1对脓肿分枝杆菌感染大鼠肺损伤的改善作用，并基于腺苷酸活化蛋白激酶（AMPK）/核因子E2相关因子2（Nrf2）/铁蛋白重链1（FTH1）通路探讨其潜在机制。方法 将大鼠分为对照组（n=24）和造模组（n=90），造模组采用气管插管法注入1.0×105 CFU的脓肿分枝杆菌混悬液构建大鼠肺损伤模型。将造模成功的大鼠随机分为模型组、人参皂苷Rb1低剂量组、人参皂苷Rb1高剂量组和人参皂苷Rb1高剂量+铁死亡组，每组18只。人参皂苷Rb1低剂量组和人参皂苷Rb1高剂量组分别腹腔注射25、50 mg/kg的人参皂苷Rb1，人参皂苷Rb1高剂量+铁死亡组腹腔注射50 mg/kg的人参皂苷Rb1和10 mg/kg的铁死亡诱导剂Erastin，对照组和模型组腹腔注射等量的生理盐水，1次/d，连续干预28 d。计算各组大鼠体质量和肺组织中脓肿分枝杆菌数量；HE染色检测肺组织病理变化；qRT-PCR和ELISA检测肺组织中肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、IL-6、单核细胞趋化蛋白-1（MCP-1）的mRNA水平和含量；ELISA和比色法检测活性氧（ROS）、丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽（GSH）和Fe2+含量；Western blot检测肺组织中p-AMPK、AMPK、Nrf2、FTH1的蛋白表达水平。结果 与对照组相比，模型组大鼠支气管炎症细胞浸润增加，支气管壁增厚，肺泡腔扩张，肺泡壁变薄；脓肿分枝杆菌数量、TNF-α、IL-1β、IL-6、MCP-1的mRNA水平和含量以及ROS、MDA、Fe2+含量均升高（P＜0.05）；体质量、GSH和SOD含量、p-AMPK/AMPK蛋白表达水平比值、Nrf2和FTH1蛋白表达水平均降低（P＜0.05）。与模型组相比，人参皂苷Rb1低剂量组、人参皂苷Rb1高剂量组和人参皂苷Rb1高剂量+铁死亡组大鼠肺组织病理损伤明显减轻，其中人参皂苷Rb1高剂量组改善效果最明显；脓肿分枝杆菌数量、TNF-α、IL-1β、IL-6、MCP-1的mRNA水平和含量以及ROS、MDA、Fe2+含量均降低（P＜0.05）；体质量、GSH和SOD含量、p-AMPK/AMPK蛋白表达水平比值、Nrf2和FTH1蛋白表达水平均升高（P＜0.05）。与人参皂苷Rb1低剂量组相比，人参皂苷Rb1高剂量组和人参皂苷Rb1高剂量+铁死亡组脓肿分枝杆菌数量、TNF-α、IL-1β、IL-6、MCP-1的mRNA水平和含量以及ROS、MDA、Fe2+含量均降低（P＜0.05）；体质量、GSH和SOD含量、p-AMPK/AMPK蛋白表达水平比值、Nrf2、FTH1蛋白表达水平均升高（P＜0.05）。与人参皂苷Rb1高剂量组相比，人参皂苷Rb1高剂量+铁死亡组脓肿分枝杆菌数量、TNF-α、IL-1β、IL-6、MCP-1的mRNA水平和含量以及ROS、MDA、Fe2+含量均升高（P＜0.05）；体质量、GSH和SOD含量、p-AMPK/AMPK蛋白表达水平比值、Nrf2和FTH1蛋白表达水平均降低（P＜0.05）。结论 人参皂苷Rb1能够减轻大鼠炎症反应和氧化应激，抑制铁死亡，进而改善脓肿分枝杆菌感染引起的肺损伤，这可能与AMPK/Nrf2/FTH1信号通路的激活有关。 |
| 关键词: 肺损伤 人参皂苷Rb1 脓肿分枝杆菌 腺苷酸活化蛋白激酶/核因子E2相关因子2/铁蛋白重链1通路 铁死亡 非结核分枝杆菌肺病 |
| DOI：10.3969/j.issn.1674-070X.2025.12.003 |
| 投稿时间：2025-09-05 |
| 基金项目:河北省2023年度医学科学研究课题（20231230）。 |
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| Ginsenoside Rb1 ameliorates pulmonary injury in Mycobacterium abscessus-infected rats by inhibiting ferroptosis through activation of the AMPK/Nrf2/FTH1 pathway |
| SUN Hongmei, ZHANG Ranran, LI Qiao, LI Qian, GAO Yanjun |
| (Hebei Chest Hospital, Shijiazhuang, Hebei 050000, China;Shenzhou Municipal Hospital, Hengshui, Hebei 053800, China) |
| Abstract: |
| Objective To investigate the ameliorative effects of ginsenoside Rb1 on lung injury in rats infected with Mycobacterium abscessus, and to explore its potential mechanism via the adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2)/ferritin heavy chain 1 (FTH1) pathway. Methods Rats were assigned into control group (n=24) and modeling group (n=90). The modeling group underwent tracheal intubation for instillation of a 1×106 CFU Mycobacterium abscessus suspension to establish a rat model of lung injury. Rats with successful modeling were randomly assigned to the model, low-dose and high-dose ginsenoside Rb1 group, and high-dose ginsenoside Rb1 plus ferroptosis inducer group, with 18 rats per group. The low-dose and high-dose ginsenoside Rb1 groups were intraperitoneally injected with 25 mg/kg and 50 mg/kg ginsenoside Rb1, respectively. The high-dose ginsenoside Rb1 plus ferroptosis inducer group was intraperitoneally injected with 50 mg/kg ginsenoside Rb1 and 10 mg/kg ferroptosis inducer Erastin. The control and model groups received intraperitoneal injections of an equal volume of physiological saline. All administrations were performed once daily for 28 consecutive days. The body weight of rats in each group was measured, and the colony count of Mycobacterium abscessus in lung tissue was determined. Pathological changes in lung tissue were examined by HE staining. Quantitative real-time polymerase chain reaction (qRT-PCR) and ELISA were used to determine the mRNA expression levels and protein concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) in lung tissue, respectively. ELISA and colorimetric assays were employed to measure the levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH), as well as the Fe2+ content in lung tissue. Western blot was performed to measure the protein expression levels of p-AMPK, AMPK, Nrf2, and FTH1 in lung tissue. Results Compared with the control group, the model group exhibited increased inflammatory cell infiltration in the bronchi, dilated alveolar spaces, and thinned alveolar walls. Additionally, the colony count of Mycobacterium abscessus, mRNA expression levels, and protein concentrations of TNF-α, IL-1β, IL-6, and MCP-1, as well as the content of ROS, MDA, and Fe2+ were all elevated (P<0.05). In contrast, body weight, the levels of GSH and SOD, the p-AMPK/AMPK protein expression ratio, and the protein expression levels of Nrf2 and FTH1 were all reduced (P<0.05). Compared with the model group, lung tissue pathological damage was alleviated in the low-dose ginsenoside Rb1 group, high-dose ginsenoside Rb1 group, and high-dose ginsenoside Rb1 plus ferroptosis inducer group, with the high-dose ginsenoside Rb1 group showing the most pronounced improvement. Correspondingly, the colony count of Mycobacterium abscessus, mRNA expression levels and protein concentrations of TNF-α, IL-1β, IL-6, and MCP-1, as well as the content of ROS, MDA, and Fe2+ were all reduced (P<0.05). Conversely, body weight, GSH and SOD levels, the p-AMPK/AMPK protein expression ratio, and the protein expression levels of Nrf2 and FTH1 all increased (P<0.05). Compared with the low-dose ginsenoside Rb1 group, the high-dose ginsenoside Rb1 group and the high-dose ginsenoside Rb1 plus ferroptosis inducer group showed decreased colony count of Mycobacterium abscessus, mRNA expression levels, and protein concentrations of TNF-α, IL-1β, IL-6, and MCP-1, as well as content of ROS, MDA, and Fe2+ (P<0.05). Meanwhile, body weight, GSH and SOD levels, the p-AMPK/AMPK protein expression ratio, and the protein expression levels of Nrf2 and FTH1 were all higher (P<0.05). Compared with the high-dose ginsenoside Rb1 group, the high-dose ginsenoside Rb1 plus ferroptosis inducer group exhibited increased colony count of Mycobacterium abscessus, mRNA expression levels and protein concentrations of TNF-α, IL-1β, IL-6, and MCP-1, as well as content of ROS, MDA, and Fe2+ (P<0.05). In contrast, body weight, GSH and SOD levels, the p-AMPK/AMPK protein expression ratio, and the protein expression levels of Nrf2 and FTH1 were all lower (P<0.05). Conclusion Ginsenoside Rb1 can alleviate inflammatory responses and oxidative stress in rats, inhibit ferroptosis, and thus can ameliorate lung injury induced by Mycobacterium abscessus infection, which may be associated with the activation of the AMPK/Nrf2/FTH1 signaling pathway. |
| Key words: lung injury ginsenoside Rb1 Mycobacterium abscessus adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2/ferritin heavy chain 1 pathway ferroptosis non-tuberculous mycobacterial lung disease |
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