[1]何镜,王艳杰,陈卓玥,等.基于调节性T细胞/辅助性T细胞17平衡探讨低强度脉冲聚焦超声治疗小鼠类风湿关节炎的作用机制[J].中医正骨,2025,37(04):30-40.
　HE Jing,WANG Yanjie,CHEN Zhuoyue,et al.Exploring the mechanism of focused low-intensity pulsed ultrasound in treating rheumatoid arthritis in mice based on the balance between regulatory T cell and T helper cell 17[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2025,37(04):30-40.
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基于调节性T细胞/辅助性T细胞17平衡探讨低强度脉冲聚焦超声治疗小鼠类风湿关节炎的作用机制()
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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:
30-40
栏目:
基础研究
出版日期:
2025-04-20

文章信息/Info

Title:
Exploring the mechanism of focused low-intensity pulsed ultrasound in treating rheumatoid arthritis in mice based on the balance between regulatory T cell and T helper cell 17
作者:
何镜1; 王艳杰2; 陈卓玥1; 崔博2; 蓝泉博3; 周文智4
1.成都体育学院,四川 成都 641418; 2.四川省骨科医院,四川 成都 610041; 3.纽约大学,纽约 10012; 4.成都市妇女儿童中心医院,四川 成都 610091
Author(s):
HE Jing1; WANG Yanjie2; CHEN Zhuoyue1; CUI Bo2; LAN Quanbo3; ZHOU Wenzhi4
1.Chengdu Sport University,Chengdu 641418,Sichuan,China 2.Sichuan Province Orthopedic Hospital,Chengdu 610041,Sichuan,China 3.New York University,New York 10012,USA 4.Chengdu Women's and Children's Central Hospital,Chengdu 610091,Sichuan,China
关键词:
关节炎; 类风湿;  胶原诱导性关节炎;  瘢痕灸疗法;  超声疗法;  T-淋巴细胞; 调控;  Th17细胞;  小鼠
Keywords:
arthritis; rheumatoid;  collagen-induced arthritis;  scarring moxibustion therapy;  ultrasonic therapy;  T-lymphocytes; regulatory;  Th17 cells;  mice
摘要:
目的:观察低强度脉冲聚焦超声治疗小鼠类风湿关节炎(rheumatoid arthritis,RA)的效果,并基于调节性T细胞(regulatory T cell,Treg)/辅助性T细胞17(helper T cell 17,Th17)平衡探讨其作用机制。方法:将36只雄性DBA/1J小鼠随机分为正常组、模型组、不治疗组、安慰剂组、瘢痕灸组和聚焦超声组,每组6只。除正常组外的各组小鼠均采用Ⅱ型胶原诱导法建立胶原诱导性关节炎模型。在造模结束时,采用关节炎指数评分评价小鼠双侧踝关节关节炎情况,判断造模是否成功。在造模成功后,模型组小鼠直接处死取材,聚焦超声组在小鼠肾俞、足三里穴位采用低强度脉冲聚焦超声治疗,瘢痕灸组在相同穴位采用艾柱直接灸,安慰剂组在相同部位采用棉花直接灸,正常组、不治疗组不采取任何治疗措施。聚焦超声组、瘢痕灸组、安慰剂组每天治疗1次,治疗6 d为1个疗程,共治疗2个疗程。在治疗1个疗程时、治疗结束时,记录小鼠双侧踝关节关节炎指数评分。治疗结束后,采用HE染色观察各组小鼠踝关节软骨和滑膜组织病变情况,采用流式细胞术检测各组小鼠脾脏组织中Th17、Treg的百分比,分别采用实时定量PCR和Western Blot法检测各组小鼠脾脏组织中叉头框蛋白3(forkhead box protein 3,FOXP3)、维甲酸受体相关孤儿受体(retinoid acid receptor-related orphan receptor,ROR)γt、核因子-κB(nuclear factor-κB,NF-κB)的mRNA表达水平和蛋白表达水平。结果:①小鼠踝关节关节炎指数评分结果。不治疗组和安慰剂组小鼠踝关节关节炎指数评分随时间变化均呈上升趋势(F=4.903,P=0.019; F=4.189,P=0.031),瘢痕灸组小鼠踝关节关节炎指数评分随时间变化基本保持不变(F=1.683,P=0.212),聚焦超声组小鼠踝关节关节炎指数评分随时间变化呈下降趋势(F=11.354,P=0.000)。治疗结束时,瘢痕灸组和聚焦超声组小鼠踝关节关节炎指数评分均低于不治疗组和安慰剂组(不治疗组:P=0.000,P=0.000; 安慰剂组:P=0.000,P=0.000),不治疗组和安慰剂组小鼠踝关节关节炎指数评分的差异无统计学意义(P=1.000),聚焦超声组小鼠踝关节关节炎指数评分低于瘢痕灸组(P=0.000)。②小鼠踝关节组织病理学观察结果。模型组小鼠软骨层变薄、软骨面粗糙不平、软骨细胞分布不均匀,滑膜组织细胞排列紊乱,有增生及炎症细胞浸润; 与模型组相比,不治疗组和安慰剂组小鼠踝关节组织病变略有加重,瘢痕灸组小鼠踝关节组织病变略有减轻,聚焦超声组小鼠踝关节组织病变明显减轻。③脾脏组织中Th17、Treg的百分比检测结果。不治疗组和安慰剂组小鼠脾脏组织中Th17的百分比均高于模型组(P=0.000,P=0.000),Treg的百分比均低于模型组(P=0.000,P=0.000); 瘢痕灸组、聚焦超声组小鼠脾脏组织中Th17的百分比均低于模型组(P=0.002,P=0.000),瘢痕灸组小鼠脾脏组织中Treg的百分比低于模型组(P=0.000),聚焦超声组小鼠脾脏组织中Treg的百分比高于模型组(P=0.000)。聚焦超声组小鼠脾脏组织中Th17的百分比低于瘢痕灸组(P=0.000),Treg的百分比高于瘢痕灸组(P=0.000)。④小鼠脾脏组织中FOXP3、RORγt、NF-κB的mRNA表达水平检测结果。不治疗组、安慰剂组小鼠脾脏组织中FOXP3的mRNA相对表达量均低于模型组(P=0.001,P=0.001),RORγt、NF-κB的mRNA相对表达量均高于模型组(RORγt:P=0.001,P=0.019; NF-κB:P=0.000,P=0.000); 瘢痕灸组小鼠脾脏组织中FOXP3、RORγt、NF-κB的mRNA相对表达量与模型组的组间差异均无统计学意义(P=0.999,P=0.052,P=0.995); 聚焦超声组小鼠脾脏组织中FOXP3的mRNA相对表达量均高于模型组(P=0.000),RORγt、NF-κB的mRNA相对表达量均低于模型组(P=0.000,P=0.000); 聚焦超声组小鼠脾脏组织中FOXP3的mRNA相对表达量均高于瘢痕灸组(P=0.000),RORγt、NF-κB的mRNA相对表达量均低于瘢痕灸组(P=0.000,P=0.000)。⑤小鼠脾脏组织中FOXP3、RORγt、NF-κB的蛋白表达水平检测结果。不治疗组、安慰剂组小鼠脾脏组织中FOXP3的蛋白相对表达量均低于模型组(P=0.001,P=0.000),RORγt、NF-κB的蛋白相对表达量均高于模型组(RORγt:P=0.010,P=0.013; NF-κB:P=0.014,P=0.001); 瘢痕灸组、聚焦超声组小鼠脾脏组织中FOXP3的蛋白相对表达量与模型组的差异均无统计学意义(P=0.573,P=0.304); 瘢痕灸组小鼠脾脏组织中RORγt、NF-κB的蛋白相对表达量与模型组的组间差异均无统计学意义(P=0.999,P=0.999),聚焦超声组小鼠脾脏组织中RORγt、NF-κB的蛋白相对表达量均低于模型组(P=0.017,P=0.010); 聚焦超声组小鼠脾脏组织中FOXP3的蛋白相对表达量高于瘢痕灸组(P=0.021),RORγt、NF-κB的蛋白相对表达量均低于瘢痕灸组(P=0.016,P=0.010)。结论:RA在不治疗的情况下病情会不断加重,瘢痕灸和低强度脉冲聚焦超声均能够遏制RA病情进展,且低强度脉冲聚焦超声的效果优于瘢痕灸; 其作用机制可能与调节FOXP3、RORγt、NF-κB的表达从而影响Treg/Th17平衡有关。
Abstract:
Objective:To observe the therapeutic effects of focused low-intensity pulsed ultrasound(FLIPUS)on rheumatoid arthritis(RA)in mice,and to explore its underlying mechanism based on the balance between regulatory T cell(Treg)and helper T cell 17(Th17).Methods:Thirty-six male DBA/1J mice were randomized into normal group,model group,untreated group,placebo group,scar moxibustion group,and FLIPUS group,with 6 cases in each group.All mice but the ones in normal group were modeled by typeⅡcollagen for inducing collagen-induced arthritis(CIA).At the end of the modeling,the arthritis of bilateral ankles were assessed using the arthritis index(AI)score to evaluate whether the modeling was successful.After successful modeling,the mice in model group were sacrificed for collecting their spleens and bilateral ankle joints.The ones in FLIPUS group were treated with FLIPUS at Shenshu(BL23)and Zusanli(ST36),the ones in scar moxibustion group with moxa cone moxibustion at the same acupoints as FLIPUS group,the ones in placebo group with cotton moxibustion at the same sites,and the ones in normal group and untreated group were not given any treatment.The mice in FLIPUS group,scar moxibustion group,and placebo group were treated once a day for consecutive 2 courses of treatment,6 days for each course.The AI scores of bilateral ankle joints were recorded after 6-day treatment and at the end of treatment,respectively.After the end of treatment,all mice but the ones in model group were sacrificed for harvesting their spleens and bilateral ankle joints,then the collected ankle cartilages and synovial tissues were stained with HE for observing the histopathological changes,and the percentages of Th17 and Treg in spleen tissues were detected by flow cytometry.Moreover,the mRNA and protein expression levels of forkhead box protein 3(FOXP3),retinoid acid receptor-rela-ted orphan receptor(ROR)γt,and nuclear factor-κB(NF-κB)in the spleen tissues of mice in each group were detected by real-time quantitative PCR(RT-qPCR)and Western Blot,respectively.Results:①The ankle AI score.The ankle AI score presented an upward trend over time in untreated group and placebo group(F=4.903,P=0.019; F=4.189,P=0.031),remained essentially unchanged over time in scar moxibustion group(F=1.683,P=0.212),and presented an downward trend over time in FLIPUS group(F=11.354,P=0.000).At the end of treatment,the ankle AI score was lower in scar moxibustion group and FLIPUS group compared to untreated group and placebo group(untreated group:P=0.000,P=0.000; placebo group:P=0.000,P=0.000),with no significant difference between untreated group and placebo group(P=1.000),and a much lower score in FLIPUS group compared to scar moxibustion group(P=0.000).②The pathological changes in ankle tissues.The changes,manifesting as thinned cartilage layer,roughened and uneven cartilage surface,and irregular distribution of chondrocyte,accompanied by disorderedly arranged synovial tissue architecture with hyperplasia and inflammatory cell infiltration,were observed in the ankle joint tissues of mice in model group; while,compared with that of model group,the ankle joint pathology slightly progressed in mice of untreated group and placebo group,whereas,which was moderately attenuated in scar moxibustion group,and marked attenuated in FLIPUS group.③The percentages of Th17 and Treg in spleen tissues.The percentage of Th17 in the spleen tissue was higher,while that of Treg was lower in untreated group and placebo group compared to model group(P=0.000,P=0.000; P=0.000,P=0.000).The percentage of Th17 in spleen tissue was lower in scar moxibustion group and FLIPUS group compared to model group(P=0.002,P=0.000),while that of Treg was lower in scar moxibustion group compared to model group,but was higher in FLIPUS group compared to model group(P=0.000,P=0.000).Furthermore,the percentage of Th17 in the spleen tissue was lower,while that of Treg was higher in FLIPUS group compared to scar moxibustion group(P=0.000,P=0.000).④The mRNA expression levels of FOXP3,RORγt,and NF-κB in the spleen tissues.The relative mRNA expression level of FOXP3 in the spleen tissues was lower,while that of RORγt and NF-κB were higher in untreated group and placebo group compared to model group(FOXP3:P=0.001,P=0.001; RORγt:P=0.001,P=0.019; NF-κB:P=0.000,P=0.000).The relative mRNA expression levels of FOXP3,RORγt,and NF-κB in the spleen tissues were not significantly different from each other between scar moxibustion group and model group(P=0.999,P=0.052,P=0.995).The relative mRNA expression level of FOXP3 in the spleen tissues was higher,while that of RORγt and NF-κB were lower in FLIPUS group compared to model group(P=0.000,P=0.000,P=0.000).Furthermore,the relative mRNA expression level of FOXP3 in the spleen tissues was higher,while that of RORγt and NF-κB were lower in FLIPUS group compared to scar moxibustion group(P=0.000,P=0.000,P=0.000).⑤The protein expression levels of FOXP3,RORγt,and NF-κB in the spleen tissues.The relative protein expression level of FOXP3 in the spleen tissues was lower,while that of RORγt and NF-κB were higher in untreated group and placebo group compared to model group(FOXP3:P=0.001,P=0.000; RORγt:P=0.010,P=0.013; NF-κB:P=0.014,P=0.001).The relative protein expression level of FOXP3 in the spleen tissues was not significantly different from each other between scar moxibustion group and model group,and between FLIPUS group and model group(P=0.573,P=0.304).The relative protein expression levels of RORγt and NF-κB in the spleen tissues were not significantly different from each other between scar moxibustion group and model group(P=0.999,P=0.999),while,were lower in FLIPUS group compared to model group(P=0.017,P=0.010).Furthermore,the relative protein expression level of FOXP3 in the spleen tissues was higher,while that of RORγt and NF-κB were lower in FLIPUS group compared to scar moxibustion group(P=0.021,P=0.016,P=0.010).Conclusion:The RA will continuously worsen without treatment.Both scar moxibustion and FLIPUS can slow the progression of RA,with FLIPUS demonstrating superior efficacy to scar moxibustion.It may work by influencing the balance of Treg/Th17 via modulating the expression of FOXP3,RORγt,and NF-κB.

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备注/Memo

备注/Memo:
基金项目:四川省中医药管理局科学技术研究专项课题(2023MS611)
通讯作者:王艳杰 E-mail:13236437@qq.com
更新日期/Last Update: 1900-01-01