[1]伏厚宇,揭立士,茆军,等.膝痹宁Ⅱ干预小鼠膝骨关节炎寒湿痹阻证的效果及作用机制研究[J].中医正骨,2025,37(04):20-29.
　FU Houyu,JIE Lishi,MAO Jun,et al.Efficacy and mechanism of Xibi NingⅡ(膝痹宁Ⅱ)against knee osteoarthritis with cold-dampness stagnation syndrome in mice:an experimental study[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2025,37(04):20-29.
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膝痹宁Ⅱ干预小鼠膝骨关节炎寒湿痹阻证的效果及作用机制研究()
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《中医正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第37卷
期数:
2025年04期
页码:
20-29
栏目:
基础研究
出版日期:
2025-04-20

文章信息/Info

Title:
Efficacy and mechanism of Xibi NingⅡ(膝痹宁Ⅱ)against knee osteoarthritis with cold-dampness stagnation syndrome in mice:an experimental study
作者:
伏厚宇; 揭立士; 茆军; 张农山; 黄正泉; 丁亮; 邢润麟; 梅伟; 殷松江; 吴鹏; 李晓辰; 马振源; 王培民; 张立
南京中医药大学附属医院,江苏 南京 210029
Author(s):
FU Houyu; JIE Lishi; MAO Jun; ZHANG Nongshan; HUANG Zhengquan; DING Liang; XING Runlin; MEI Wei; YIN Songjiang; WU Peng; LI Xiaochen; MA Zhenyuan; WANG Peimin; ZHANG Li
Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210029,Jiangsu,China
关键词:
骨关节炎; 膝;  寒湿;  痹证;  膝痹宁Ⅱ;  疼痛;  敏化;  神经节; 脊;  滑膜;  肿瘤坏死因子;  白细胞介素类;  瞬时受体电位通道;  降钙素基因相关肽;  神经生长因子;  小鼠
Keywords:
osteoarthritis; knee;  cold dampness;  arthromyodynia;  Xibi Ning Ⅱ;  pain;  sensitization;  ganglia; spinal;  synovial membrane;  tumor necrosis factors;  interleukins;  transient receptor potential channels;  calcitonin gene-related peptide;  nerve growth factor;  mice
摘要:
目的:探讨膝痹宁Ⅱ干预小鼠膝骨关节炎(knee osteoarthritis,KOA)寒湿痹阻证的效果及作用机制。方法:将40只C57BL/6J小鼠随机分为假手术组、模型组、膝痹宁Ⅱ组、蠲痹汤组,每组10只。模型组、膝痹宁Ⅱ组、蠲痹汤组小鼠均行半月板失稳术,并在术后将小鼠置于人工气候箱(湿度60%、温度4 ℃、风速6 m·s-1)中构建KOA寒湿痹阻证模型; 假手术组仅切开膝关节处皮肤。造模成功后,膝痹宁Ⅱ组和蠲痹汤组小鼠分别用0.26 mL的膝痹宁Ⅱ药液(生药浓度1.0 g·mL-1)和0.26 mL的蠲痹汤药液(生药浓度1.9 g·mL-1)灌胃,假手术组和模型组小鼠均给予等量蒸馏水灌胃。每日给药1次,连续给药28 d。分别于造模开始前、造模结束后第7天及药物干预7 d、14 d、21 d、28 d,测定各组小鼠冷刺激缩足阈值和机械刺激缩足阈值。药物干预28 d后,采用ELISA法检测小鼠血清中肿瘤坏死因子(tumor necrosis factor,TNF)-α、白细胞介素(interleukin,IL)-1β和IL-6的含量,分别采用HE染色、Masson染色、天狼星红染色观察小鼠膝关节滑膜组织病理变化,采用免疫荧光法检测小鼠L3～L5背根神经节(dorsal root ganglia,DRG)组织中瞬时受体电位锚蛋白1(transient receptor potential ankyrin 1,TRPA1)、瞬时受体电位香草酸1(transient receptor potential vanilloid 1,TRPV1)、瞬时受体电位褪黑素8(transient receptor potential melastatin 8,TRPM8)通道,采用Western Bolt法检测L3～L5DRG组织中TRPA1、TRPV1、TRPM8、降钙素基因相关肽(calcitonin gene related peptide,CGRP)、神经生长因子(nerve growth factor,NGF)的蛋白表达水平。结果:①小鼠冷刺激缩足阈值和机械刺激缩足阈值测定结果。造模结束后第7天,模型组、膝痹宁Ⅱ组、蠲痹汤组小鼠冷刺激缩足阈值、机械刺激缩足阈值均低于假手术组(P=0.000,P=0.000,P=0.000; P=0.000,P=0.000,P=0.000),膝痹宁Ⅱ组、蠲痹汤组小鼠冷刺激缩足阈值、机械刺激缩足阈值与模型组的差异均无统计学意义(P=0.782,P=0.957; P=0.988,P=0.986),膝痹宁Ⅱ组小鼠冷刺激缩足阈值、机械刺激缩足阈值与蠲痹汤组的差异均无统计学意义(P=0.990,P=0.915); 药物干预7 d、14 d、21 d、28 d,模型组小鼠冷刺激缩足阈值、机械刺激缩足阈值均低于假手术组、膝痹宁Ⅱ组、蠲痹汤组(干预7 d:P=0.000,P=0.000,P=0.000; P=0.000,P=0.000,P=0.000。干预14 d:P=0.000,P=0.005,P=0.000; P=0.000,P=0.000,P=0.000。干预21 d:P=0.000,P=0.000,P=0.000; P=0.000,P=0.000,P=0.000。干预 28 d:P=0.000,P=0.000,P=0.000; P=0.000,P=0.000,P=0.000),膝痹宁Ⅱ组小鼠冷刺激缩足阈值、机械刺激缩足阈值与蠲痹汤组的差异均无统计学意义(干预7 d:P=0.714,P=0.767; 干预14 d:P=0.781,P=0.997; 干预21 d:P=0.994,P=0.762; 干预28 d:P=0.892,P=0.961)。②小鼠血清中TNF-α、IL-6、IL-1β含量测定结果。模型组小鼠血清中TNF-α、IL-6、IL-1β含量均高于假手术组、膝痹宁Ⅱ组、蠲痹汤组(TNF-α:P=0.000,P=0.000,P=0.000; IL-6:P=0.000,P=0.000,P=0.000; IL-1β:P=0.000,P=0.000,P=0.000),膝痹宁Ⅱ组小鼠血清中TNF-α、IL-6、IL-1β含量与蠲痹汤组的差异均无统计学意义(P=0.996,P=0.950,P=0.799)。③小鼠膝关节滑膜组织病理学观察结果。HE染色显示,模型组滑膜细胞排列紊乱,炎性浸润明显; 膝痹宁Ⅱ组、蠲痹汤组滑膜细胞排列较整齐,滑膜结构趋于正常,炎性浸润明显减少。Masson染色显示,模型组滑膜胶原纤维排列紊乱,胶原纤维沉积增多; 膝痹宁Ⅱ组、蠲痹汤组滑膜胶原纤维排列整齐,滑膜结构趋于正常,胶原纤维沉积明显减少。天狼星红染色显示,模型组Ⅱ型胶原减少,胶原纤维排列紊乱; 膝痹宁Ⅱ组、蠲痹汤组Ⅱ型胶原增多,胶原纤维排列较整齐。④小鼠L3～L5DRG组织中TRPA1、TRPV1、TRPM8通道检测结果。免疫荧光染色显示,假手术组TRPA1、TRPV1、TRPM8荧光强度最弱,模型组荧光强度最强,膝痹宁Ⅱ和蠲痹汤组荧光强度较模型组减弱。⑤小鼠L3～L5DRG组织中TRPA1、TRPM8、TRPV1、NGF、CGRP的蛋白表达水平检测结果。模型组小鼠L3～L5DRG组织中TRPA1、TRPM8、TRPV1、NGF、CGRP的蛋白相对表达量均高于假手术组、膝痹宁Ⅱ组、蠲痹汤组(TRPA1:P=0.000,P=0.000,P=0.000; TRPM8:P=0.000,P=0.000,P=0.000; TRPV1:P=0.000,P=0.000,P=0.000; NGF:P=0.000,P=0.000,P=0.000; CGRP:P=0.000,P=0.000,P=0.000),膝痹宁Ⅱ组TRPA1、TRPM8、TRPV1、NGF、CGRP的蛋白相对表达量与蠲痹汤组的差异均无统计学意义(P=0.939,P=0.998,P=0.981,P=0.961,P=0.794)。结论:膝痹宁Ⅱ能够减轻KOA寒湿痹阻证模型小鼠痛觉敏化和滑膜炎症,疗效与蠲痹汤相当,其作用机制可能与其能抑制DRG组织中TRP通道激活有关。
Abstract:
Objective:To observe the outcomes of Xibi NingⅡ(膝痹宁Ⅱ,XBNⅡ)against knee osteoarthritis(KOA)with the syndrome of cold-dampness stagnation in mice,and to explore its underlying mechanism.Methods:Forty C57BL/6J mice were selected and randomized into sham-operated group,model group,XBNⅡgroup and Juanbi Tang(蠲痹汤,JBT)group,with 10 ones in each group.All mice but the ones in sham-operated group were subjected to destabilization of the medial meniscus(DMM)surgery for inducing KOA,and then housed in an artificial climate chamber(humidity:60%,temperature:4 ℃,wind speed:6 m/s)for further inducing the syndrome of cold-dampness stagnation,while the ones in sham-operated group were merely incised the skin at the corresponding site.After successful modeling,the mice in XBNⅡgroup and JBT group were intervened by intragastric administration with 0.26 mL XBNⅡsolution(the crude drug concentration was 1.0 g/mL)and 0.26 mL JBT solution(the crude drug concentration was 1.9 g/mL),respectively,while the ones in the sham-operated group and model group with the same dose of distilled water,once a day for consecutive 28 days.The cold and mechanical stimulation paw withdrawal thresholds(PWTs)were measured before the modeling,on day 7 after the end of the modeling and after 7-,14-,21- and 28-day drug intervention,respectively.After 28-day drug intervention,the serum levels of tumor necrosis factor(TNF)-α,interleukin(IL)-1β,and IL-6 were detected by ELISA.After that,the mice knee synovial tissues were harvested and stained with HE staining,Masson staining,and Sirius red staining,respectively,to observe the pathological changes.Furthermore,the channels of transient receptor potential ankyrin 1(TRPA1),transient receptor potential vanilloid 1(TRPV1),and transient receptor potential melastatin 8(TRPM8)in the L3-L5 dorsal root ganglia(DRG)tissues was detected using immunofluorescence,and the protein expression levels of TRPA1,TRPV1,TRPM8,calcitonin gene related peptide(CGRP)and nerve growth factor(NGF)in the L3-L5 DRG tissues were detected using Western Blot.Results:①The cold and mechanical stimulation PWTs.On day 7 after the end of the modeling,the cold and mechanical stimulation PWTs were lower in model group,XBNⅡgroup and JBT group compared to sham-operated group(P=0.000,P=0.000,P=0.000; P=0.000,P=0.000,P=0.000),with no significant differences between XBNⅡgroup and model group,between JBT group and model group,between XBNⅡgroup and JBT group(P=0.782,P=0.957; P=0.988,P=0.986; P=0.990,P=0.915).After 7-,14-,21- and 28-day drug intervention,the cold and mechanical stimulation PWTs were lower in model group compared to sham-operated group,XBNⅡgroup and JBT group(7-day intervention:P=0.000,P=0.000,P=0.000; P=0.000,P=0.000,P=0.000.14-day intervention:P=0.000,P=0.005,P=0.000; P=0.000,P=0.000,P=0.000.21-day intervention:P=0.000,P=0.000,P=0.000; P=0.000,P=0.000,P=0.000.28-day intervention:P=0.000,P=0.000,P=0.000; P=0.000,P=0.000,P=0.000),with no significant differences between XBNⅡgroup and JBT group(7-day intervention:P=0.714,P=0.767; 14-day intervention:P=0.781,P=0.997; 21-day intervention:P=0.994,P=0.762; 28-day intervention:P=0.892,P=0.961).②The serum levels of TNF-α,IL-6,and IL-1β.The serum levels of TNF-α,IL-6,and IL-1β were higher in model group compared to sham-operated group,XBNⅡgroup and JBT group(TNF-α:P=0.000,P=0.000,P=0.000; IL-6:P=0.000,P=0.000,P=0.000; IL-1β:P=0.000,P=0.000,P=0.000),with no significant differences between XBNⅡgroup and JBT group(P=0.996,P=0.950,P=0.799).③The pathological changes in the knee synovial tissues.HE staining showed that,the changes,manifesting as disorderedly arranged synovial cells with obviously inflammatory infiltration,were observed in the knee synovial tissues of mice in model group; while,compared with that of model group,the knee synovial tissues in mice of XBNⅡgroup and JBT group was significantly improved,manifesting as neatly arranged synovial cells,with basically normalized synovial tissue architecture,and markedly reduced inflammatory infiltration.Masson staining revealed that,in model group,the synovial collagen fibers were disorderedly arranged with increased collagen fiber deposition; while,which was improved in XBNⅡgroup and JBT group,manifesting as aligned synovial collagen fibers with basically normalized synovial tissue architecture and significantly decreased collagen fiber deposition.Sirius red staining showed that,reduced typeⅡcollagen and disorganized collagen fiber arrangement were observed in the knee synovial tissues of mice in model group,while,compared with that of model group,the knee synovial tissues in mice of XBNⅡgroup and JBT group exhibited increased typeⅡcollagen with more improved arrangement in collagen fiber organization.④The channels of TRPA1,TRPV1 and TRPM8 in the L3-L5 DRG tissues.The immunofluorescence staining showed that the weakest fluorescence intensity of TRPA1,TRPV1 and TRPM8 was observed in sham-operated group,the strongest in model group,and attenuated in XBNⅡgroup and JBT group compared to model group.⑤The protein expression levels of TRPA1,TRPM8,TRPV1,NGF,and CGRP in the L3-L5 DRG tissues.The relative protein expression levels of TRPA1,TRPM8,TRPV1,NGF,and CGRP in the L3-L5 DRG tissues were higher in model group compared to sham-operated group,XBNⅡgroup and JBT group(TRPA1:P=0.000,P=0.000,P=0.000; TRPM8:P=0.000,P=0.000,P=0.000; TRPV1:P=0.000,P=0.000,P=0.000; NGF:P=0.000,P=0.000,P=0.000; CGRP:P=0.000,P=0.000,P=0.000),with no significant differences between XBNⅡgroup and JBT group(P=0.939,P=0.998,P=0.981,P=0.961,P=0.794).Conclusion:XBNⅡcan alleviate pain hypersensitivity and synovial inflammation in KOA model mice with the syndrome of cold-dampness stagnation,and it is similar to JBT in clinical efficacy.It may work by inhibiting the activation of TRP channels in DRG tissues.

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备注/Memo

备注/Memo:
基金项目:国家自然科学基金项目(82305276); 江苏省医学重点学科和医学重点实验室项目(JSDW202252); 江苏省中医院临床医学创新中心发展规划项目(Y2023zx05)
通讯作者:张立 E-mail:zhang4462053@126.com
更新日期/Last Update: 1900-01-01