| 引用本文: |
邱礼国, 许晓彤, 叶子丰, 邝高艳, 李纳平, 文志, 刘鑫, 卢敏.基于滑膜细胞焦亡探讨加味独活寄生合剂治疗膝骨关节炎的作用机制[J].湖南中医药大学学报,2026,46(2):268-276[点击复制] |
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| 基于滑膜细胞焦亡探讨加味独活寄生合剂治疗膝骨关节炎的作用机制 |
| 邱礼国,许晓彤,叶子丰,邝高艳,李纳平,文志,刘鑫,卢敏 |
| (湖南中医药大学第一附属医院, 湖南 长沙 410007;湖南中医药大学研究生院, 湖南 长沙 410208;湖南医药学院总院, 湖南 怀化 418099) |
| 摘要: |
| 目的 基于核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）/胱天蛋白酶-1（Caspase-1）/消皮素D（GSDMD）信号通路探究加味独活寄生合剂干预膝骨关节炎（KOA）的作用机制。方法 将50只雄性SPF级小鼠适应性喂养后，随机分为空白组（10只）、造模组（40只），造模组小鼠采用半月板失稳术建立KOA模型。将造模组小鼠随机分为模型组（等体积0.9%氯化钠注射液）、阳性药物组[美洛昔康片混悬液0.975 mg/（kg·d）]、加味独活寄生合剂中剂量组（JDJM-M组，16.25 mL/kg）和加味独活寄生合剂高剂量组（JDJM-H组，32.50 mL/kg），于术后一周灌胃给药，连续干预8周。观察各组小鼠一般情况；观察小鼠对冷刺激的耐受性；免疫组化检测滑膜组织中白细胞介素（IL）-6、IL-18的表达水平；HE染色观察滑膜形态结构并进行滑膜炎症评分；ELISA检测血清IL-6、IL-18含量；RT-PCR检测滑膜组织中Caspase-1、NLRP3、GSDMD mRNA表达水平；Western blot检测滑膜组织中Caspase-1、NLRP3、GSDMD蛋白表达水平。结果 与空白组相比，模型组小鼠对外界刺激反应相对迟缓，膝关节滑膜出现增生肥厚，结构破坏，可见炎症细胞广泛浸润；术后第7天，对冷刺激的耐受性降低（P<0.05）。与模型组相比，阳性药物组、JDJM-H组小鼠滑膜组织内衬层细胞层数减少，细胞排列较为规整，可见部分血管生成；术后第56天对冷刺激的耐受性升高（P<0.05），滑膜炎症评分及IL-6、IL-18含量均降低（P<0.05），Caspase-1、NLRP3、GSDMD蛋白及mRNA表达水平均降低（P<0.05）。与阳性药物组相比，JDJM-M组小鼠术后第56天对冷刺激的耐受性降低（P<0.05），滑膜炎症评分及IL-6、IL-18含量均升高（P<0.05），Caspase-1、GSDMD蛋白及mRNA表达水平均升高（P<0.05），NLRP3 mRNA表达水平升高（P<0.05）；JDJM-H组Caspase-1、NLRP3 蛋白表达水平均降低（P<0.05）。与JDJM-M组相比，JDJM-H组小鼠术后第56天对冷刺激的耐受性升高（P<0.05），滑膜炎症评分及IL-18含量降低（P<0.05），GSDMD、Caspase-1、NLRP3蛋白及mRNA表达水平均降低（P<0.05）。结论 加味独活寄生合剂可能通过NLRP3/Caspase-1/GSDMD信号通路调控滑膜细胞焦亡，抑制滑膜炎症，从而起到缓解KOA症状的作用。 |
| 关键词: 膝骨关节炎 加味独活寄生合剂 细胞焦亡 滑膜炎症 核苷酸结合寡聚化结构域样受体蛋白3 胱天蛋白酶-1 消皮素D |
| DOI：10.3969/j.issn.1674-070X.2026.02.007 |
| 投稿时间：2025-11-05 |
| 基金项目:国家自然科学基金项目(82405445,82274543);湖南省教育厅课题(23C0154);湖南省自然科学基金项目(2024JJ6353,2024JJ6360);长沙市自然科学基金项目(kq2403099);湖南省中医药管理局中医药类科研基金项目(B2024062,B2024250);湖南省卫生健康科研课题重点课题(20257930);湖南中医药大学校院联合项目(2023XYLH009,2023XYLH001,CX2024074,2022XYLH006);湖南省卫生健康委员会科研项目(D202319019171)。 |
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| Mechanism of action of Jiawei Duhuo Jisheng Mixture in treating knee osteoarthritis based on synovial cell pyroptosis |
| QIU Liguo, XU Xiaotong, YE Zifeng, KUANG Gaoyan, LI Naping, WEN Zhi, LIU Xin, LU Min |
| (The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China;Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;Hunan University of Medicine General Hospital, Huaihua, Hunan 418099, China) |
| Abstract: |
| Objective To investigate the mechanism of action of Jiawei Duhuo Jisheng Mixture (JWDHJSM) in intervening in knee osteoarthritis (KOA) based on the NOD-like receptor family pyrin domain containing protein 3 (NLRP3)/cysteine-dependent aspartate-specific protease-1 (Caspase-1)/gasdermin D (GSDMD) signaling pathway. Methods After adaptive feeding, 50 male SPF-grade mice were randomly divided into a blank group (n=10) and a modeling group (n=40). KOA models were established in mice in the modeling group using meniscal destabilization surgery. The modeling group was then randomized into a model group (equal volume of normal saline), a positive drug group[meloxicam tablet suspension 0.975 mg/(kg·d)], a medium-dose JWDHJSM group (JDJM-M group, 16.25 mL/kg), and a high-dose JWDHJSM group (JDJM-H group, 32.50 mL/kg). Intragastric administration was initiated one week after surgery, with continuous intervention for 8 weeks. The general conditions of mice in each group were observed; their tolerance to cold stimulation was assessed; expression levels of interleukin (IL)-6 and IL-18 in synovial tissues were measured by immunohistochemistry; synovial morphology was observed by HE staining and synovitis scores were assigned; serum IL-6 and IL-18 levels were measured by ELISA; mRNA expression levels of Caspase-1, NLRP3, and GSDMD in synovial tissues were determined by RT-PCR; and protein expression levels of Caspase-1, NLRP3, and GSDMD were determined by Western blot. Results Compared with the blank group, mice in the model group exhibited relatively sluggish responses to external stimuli, with synovial hyperplasia and thickening in the knee joint, structural damage, and widespread infiltration of inflammatory cells; their tolerance to cold stimulation decreased (P<0.05). Compared with the model group, the positive drug group and the JDJM-H group exhibited reduced layers of synovial lining cells, more regular cell arrangement, and partial vascular generation; increased tolerance to cold stimulation on day 56 (P<0.05), lower synovitis scores and reduced levels of IL-6 and IL-18 (P<0.05), and decreased protein and mRNA expression levels of Caspase-1, NLRP3, and GSDMD (P<0.05). Compared with the positive drug group, the JDJM-M group showed decreased tolerance to cold stimulation on day 56 (P<0.05), increased synovitis scores and elevated levels of IL-6 and IL-18 (P<0.05), increased protein and mRNA expression of Caspase-1 and GSDMD (P<0.05), and increased NLRP3 mRNA level (P<0.05). The JDJM-H group showed lower protein levels of Caspase-1 and NLRP3 (P<0.05). Compared with the JDJM-M group, the JDJM-H group displayed increased tolerance to cold stimulation on day 56 (P<0.05), decreased synovitis score and IL-18 level (P<0.05), and reduced protein and mRNA levels of GSDMD, Caspase-1, and NLRP3 (P<0.05). Conclusion JWDHJSM may alleviate KOA symptoms by regulating synovial cell pyroptosis through the NLRP3/Caspase-1/GSDMD signaling pathway, thereby inhibiting synovial inflammation. |
| Key words: knee osteoarthritis Jiawei Duhuo Jisheng Mixture pyroptosis synovitis NOD-like receptor family pyrin domain containing protein 3 cysteine-dependent aspartate-specific protease1 gasdermin D |
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