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田赛, 贺严, 黄丽.清解合剂通过Nrf2/GPX4信号调控嗜酸性粒细胞活化及免疫功能改善变应性鼻炎作用机制研究[J].湖南中医药大学学报英文版,2025,45(10):1806-1815.[Click to copy
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| 清解合剂通过Nrf2/GPX4信号调控嗜酸性粒细胞活化及免疫功能改善变应性鼻炎作用机制研究 |
| 田赛,贺严,黄丽 |
| (中国中医科学院眼科医院, 北京 100040;中国中医科学院西苑医院, 北京 100091) |
| 摘要: |
| 目的 探讨清解合剂对变应性鼻炎（AR）小鼠嗜酸性粒细胞活化及免疫功能的影响，以及其对核因子E2相关因子2（Nrf2）/谷胱甘肽过氧化物酶4（GPX4）信号通路的调控机制。方法 通过卵白蛋白（OVA）诱导构建AR小鼠模型；将小鼠随机分为对照组、模型组、清解合剂低剂量组、清解合剂高剂量组、ML385+清解合剂高剂量组，每组10只。统计小鼠鼻部症状评分；迪夫快速（Diff-Quick）染色检测鼻腔灌洗液中嗜酸性粒细胞活化；HE染色检测鼻黏膜组织病理损伤；ELISA检测血清中OVA特异性免疫球蛋白E（IgE）、组胺、白细胞介素（IL）-4、γ-干扰素（IFN-γ）、IL-17、转化生长因子-β1（TGF-β1）含量；TUNEL染色检测鼻黏膜组织中的细胞凋亡情况；二氢乙啶（DHE）染色和ELISA检测鼻黏膜组织中的活性氧自由基（ROS）、超氧化物歧化酶（SOD）以及丙二醛（MDA）水平；qRT-PCR检测T盒子转录因子（T-bet）、GATA结合蛋白3（GATA3）、叉头框蛋白3（Foxp3）和维甲酸相关孤儿受体γt（RORγt）的mRNA表达；Western blot检测Nrf2、GPX4、B淋巴细胞瘤-2（Bcl-2）、Bcl-2相关X蛋白（Bax）的蛋白表达。结果 与对照组相比，模型组、清解合剂低剂量组、清解合剂高剂量组、ML385+清解合剂高剂量组小鼠鼻黏膜组织严重损伤，鼻部症状评分、鼻腔灌洗液中嗜酸性粒细胞数量，血清中OVA特异性IgE、组胺、IL-4和IL-17含量，鼻黏膜组织中细胞凋亡率、ROS和MDA水平、GATA3和RORγt mRNA表达以及Bax蛋白表达均升高（P＜0.05）；而血清中IFN-γ和TGF-β1含量，鼻黏膜组织中SOD水平、T-bet和Foxp3 mRNA表达以及Nrf2、GPX4和Bcl-2蛋白表达均降低（P＜0.05）。与模型组相比，清解合剂低剂量组、清解合剂高剂量组、ML385+清解合剂高剂量组鼻黏膜组织损伤减轻，鼻部症状评分、鼻腔灌洗液中嗜酸性粒细胞数量，血清中OVA特异性IgE、组胺、IL-4和IL-17含量，鼻黏膜组织中细胞凋亡率、ROS和MDA水平、GATA3和RORγt mRNA表达以及Bax蛋白表达均降低（P＜0.05）；而血清中IFN-γ和TGF-β1含量，鼻黏膜组织中SOD水平、T-bet和Foxp3 mRNA表达以及Nrf2、GPX4和Bcl-2蛋白表达均升高（P＜0.05）。与清解合剂高剂量组相比，ML385+清解合剂高剂量组小鼠鼻部症状评分、鼻腔灌洗液中嗜酸性粒细胞数量，血清中OVA特异性IgE、组胺、IL-4和IL-17含量，鼻黏膜组织中细胞凋亡率、ROS和MDA水平、GATA3和RORγt mRNA表达以及Bax蛋白表达均升高（P＜0.05）；而血清中IFN-γ和TGF-β1含量，鼻黏膜组织中SOD水平、T-bet和Foxp3 mRNA表达以及Nrf2、GPX4和Bcl-2蛋白表达均降低（P＜0.05）。结论 清解合剂能明显抑制AR小鼠中嗜酸性粒细胞的活性，抑制氧化应激的进展，改善动物的免疫功能，这可能与调控Nrf2/GPX4信号通路有关。 |
| 关键词: 清解合剂 变应性鼻炎 嗜酸性粒细胞活化 免疫功能 核因子E2相关因子2/谷胱甘肽过氧化物酶4信号通路 调节性T细胞/辅助性T细胞17细胞失衡 |
| DOI：10.3969/j.issn.1674-070X.2025.10.002 |
| Received:May 22, 2025 |
| 基金项目:中国中医科学院眼科医院中央高水平医院项目（GSP5-29）；中国中医科学院眼科医院院级科研启动基金人才项目（202028）。 |
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| Mechanism of action of Qingjie Mixture in alleviating allergic rhinitis by regulating eosinophil activation and immune function through the Nrf2/GPX4 signaling pathway |
| TIAN Sai, HE Yan, HUANG Li |
| (Ophthalmology Hospital of China Academy of Chinese Medical Sciences, Beijing 100040, China;Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China) |
| Abstract: |
| Objective To investigate the effects of Qingjie Mixture on the eosinophil activation and immune function in allergic rhinitis (AR) mice, as well as its regulatory mechanism on nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway. Methods An AR mouse model was established by ovalbumin (OVA) induction. Mice were randomly divided into control, model, low-dose Qingjie Mixture, high-dose Qingjie Mixture, and ML385+high-dose Qingjie Mixture groups, with 10 mice in each group. Nasal symptom scores of mice were calculated. Diff-Quick staining was used to assess the eosinophil activation in nasal lavage fluid. HE staining was used to observe the histopathological damage in nasal mucosal tissue. ELISA was employed to measure the levels of OVA-specific immunoglobulin E (IgE), histamine, interleukin(IL)-4, interferon-γ (IFN-γ), IL-17, and transforming growth factor-β1 (TGF-β1) in serum. TUNEL staining was used to check the apoptosis in nasal mucosal tissue. dihydroethidium （DHE） staining kit and ELISA were used to examine the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) in nasal mucosal tissue. The mRNA expression of T-box expressed in T cells (T-bet), GATA binding protein 3 (GATA3), forkhead box protein 3 (Foxp3), and retinoid-related orphan nuclear receptor γt (ROR γt) was determined using qRT-PCR. Protein expression of Nrf2, GPX4, B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein (Bax) was examined by Western blot analysis. Results Compared with the control group, the model, low-dose Qingjie Mixture, high-dose Qingjie Mixture, and ML385+high-dose Qingjie Mixture groups showed severe nasal mucosal damage; the nasal symptom scores, eosinophil counts in nasal lavage fluid, serum content of OVA-specific IgE, histamine, IL-4, and IL-17, nasal mucosal apoptosis rates, ROS and MDA levels, GATA3 and RORγt mRNA expression, as well as Bax protein expression were all elevated (P＜0.05). Meanwhile, IFN-γ and TGF-β1 levels in serum, and SOD levels, T-bet and Foxp3 mRNA expression, and protein expression of Nrf2, GPX4, and Bcl-2 in nasal mucosal tissue were all reduced (P＜0.05). Compared with the model group, the low-dose Qingjie Mixture, high-dose Qingjie Mixture, and ML385+high-dose Qingjie Mixture groups showed alleviated nasal mucosal damage; the nasal symptom scores, eosinophil counts in nasal lavage fluid, serum content of OVA-specific IgE, histamine, IL-4, and IL-17, nasal mucosal apoptosis rates, ROS and MDA levels, GATA3 and RORγt mRNA expression, as well as Bax protein expression were all reduced (P＜0.05). Meanwhile, IFN-γ and TGF-β1 levels in serum, and SOD levels, T-bet and Foxp3 mRNA expression, and protein expression of Nrf2, GPX4, and Bcl-2 in nasal mucosal tissue increased (P＜0.05). Compared with high-dose Qingjie Mixture group, the ML385+high-dose Qingjie Mixture group showed increased nasal symptom score, eosinophil count in nasal lavage fluid, serun content of OVA-specific IgE, histamine, IL-4, and IL-17, nasal mucosal apoptosis rate, ROS and MDA levels, GATA3 and RORγt mRNA expression, as well as Bax protein expression (P＜0.05). Meanwhile, IFN-γ and TGF-β1 levels in serum, and SOD level, T-bet and Foxp3 mRNA expression, and protein expression of Nrf2, GPX4, and Bcl-2 in nasal mucosal tissue decreased (P＜0.05). Conclusion Qingjie Mixture can significantly inhibit eosinophil activity in AR mice, suppress oxidative stress progression, and improve the immune function, which may be related to the regulation of Nrf2/GPX4 signaling pathway. |
| Key words: Qingjie Mixture allergic rhinitis eosinophil activation immune function nuclear factor E2-related factor 2/glutathione peroxidase 4 signaling pathway regulatory T cells/T helper cells 17 cell imbalance |
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