双藤痹痛酊治疗类风湿关节炎的作用基础研究
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摘要
背景目的：
类风湿性关节炎(rheumatid arthritis,RA)是一种以关节滑膜炎为特征的慢性全身性自身免疫性疾病,滑膜炎持久反复发作,可导致关节内软骨和骨的破坏,关节功能障碍,本病发病以青壮年为多,预后欠佳,致残废率高,严重危害广大人民的身体健康,目前采取的治疗方案,虽然可以改善症状,减轻炎症,但最终均未能有效地防止骨侵蚀,阻断病程进展,且长期应用副作用大,到目前为止,西医药治疗本病仍无较为理想的方法。
本病属于中医学“痹证”、“历节”、“鹤膝风”等范畴。中医药治疗本病一般以辨证论治为主,通过多层次、多环节、多途径、多靶点共同作用,抗炎镇痛,调节免疫功能,阻止病变发展,具有较大优势。本课题以医院制剂双藤痹痛酊为研究对象,通过体内和体外实验,观察双藤痹痛酊对关节滑膜的保护作用,并探索其作用机理。
方法：
1.抗炎作用实验：建立二甲苯致小鼠耳肿胀、棉球肉芽肿、醋酸致小鼠腹腔毛细血管通透性增加及角叉菜胶致大鼠足肿胀,考察双藤痹痛酊对多种急慢性炎症的影响：
2.镇痛实验：应用热板法、醋酸致小鼠扭体反应慢性疼痛等模型,考察双藤痹痛酊镇痛作用。
3.对Ⅱ型胶原诱导性关节炎大鼠的影响：建立胶原诱导性关节炎(CIA)模型,观察双藤痹痛酊对大鼠Ⅱ型胶原诱导性关节炎评分、大鼠关节肿胀度及对组织病理学评分的影响,并结合酶联免疫、免疫组化、蛋白免疫印迹、逆转录聚合酶链式反应等方法,考察双藤痹痛酊对CIA大鼠转录核因子(NF-KB)炎症信号转导通路相关因子的影响。
4.对Ⅱ型胶原诱导性关节炎大鼠滑膜细胞的影响：分离培养原代滑膜细胞,观察双藤痹痛酊对原代滑膜细胞的增殖作用及对LPS诱导产生的IL-1β等因子的作用。
结果：
1.抗炎作用试验：
(1)二甲苯致小鼠耳肿胀实验：双藤痹痛酊各个剂量组致炎耳质量差值均小于模型组,与模型组相比,双藤痹痛酊中、高剂量有显著性差异(P<0.05或P<0.01)：
(2)棉球肉芽肿实验：双藤痹痛酊各个剂量组肉芽组织质量均小于模型组,其中高剂量组和中剂量组与模型组相比,有显著性差异(P<0.05或P<0.01)；
(3)醋酸致小鼠腹腔毛细血管通透性增加实验：双藤痹痛酊各个剂量组腹腔冲洗液OD值均小于模型组,其中高剂量组与模型组相比,有显著性差异(P<0.05);
(4)角叉菜胶致大鼠足肿胀实验：双藤痹痛酊各个剂量组足肿胀值均低于模型组,高剂量组致炎后1h、2h、4h、6h足肿胀与模型组比较,差异有显著性意义(P<0.05或P<0.01),中剂量组致炎后2h、4h足肿胀与模型组比较,差异有显著性意义(P<0.05或P<0.01),低剂量组致炎后1h、2h足肿胀与模型组比较,差异有显著性意义(P<0.05)。
2.镇痛试验：
(1)热板法实验：与空白组比较,双藤痹痛酊各剂量组疼痛反应出现时间均延长(P<0.05或P<0.01),其中高剂量组作用在给药后0.5h、1h、2h均有非常显著性意义;
(2)与模型组比较,双藤痹痛酊高、中、低剂量组疼痛反应出现时间稍延长,15min内扭体次数明显减少(P<0.01)。
3.对II型胶原诱导性关节炎大鼠的影响实验：
双藤痹痛酊各剂量组关节炎指数、足肿胀度均小于模型组,与模型组相比双藤痹痛酊各剂量均改善踝关节滑膜组织炎性浸润及增生等炎症反应,其中高剂量组与模型组相比有显著性差异(P<0.05或P<0.0l)。双藤痹痛酊各剂量组血清及组织中肿瘤坏死因子(TNF-α)、白介素(IL)-1β、IL-6、IL-8等含量均小于模型组,与模型组相比具有显著性差异(F0.05或P<0.01)；TNF-α、IL-6、IL-8、IL-10、TLR4、MyD88、NF-κB、IKκ、P-IκB蛋白及mRNA表达,双藤痹痛酊各剂量组均低于模型组,其中高剂量组降低最显著(P<0.01);IκB蛋白及mRNA表达,双藤痹痛酊各剂量组均升高,其中高剂量组降低最显著(P<0.01)：
4.对II型胶原诱导性关节炎大鼠滑膜细胞的影响：
双藤痹痛酊0.5、1mg/mL组和MTX组大鼠滑膜细胞A值均低于对照组,其中1mg/mL组和MTX组显著降低A值(P<0.05或P<0.01)；与对照组比较,给药组TNF-α、IL-1β水平均降低,IL-10水平升高,其中双藤痹痛酊1mg/mL组及MTX组TNF-α、IL-1β水平显著降低而IL-10水平升高(P<0.05或P<0.01)。
结论：
1.双藤痹痛酊能抑制二甲苯所致的耳肿胀、抗肉芽组织形成、抑制醋酸制小鼠腹腔毛细血管通透性的增高、抑制角叉菜胶致足肿胀.说明双藤痹痛酊对急性炎症反应和慢性炎症增生作用具有一定的抑制作用。
2.双藤痹痛酊给药后提高痛阈百分率、减少醋酸所致小鼠扭体反应次数.提示双藤痹痛酊具有一定的镇痛作用.
3.双藤痹痛酊给药后能抑制CIA大鼠足肿胀,改善躁关节滑膜组织炎性浸润及增生等炎症反应,调整TLR4/NF-KB炎症信号转导网络及相关因子,降低滑膜组织TLR4、MyD88、NF-κB、IKκ、P-IκB表达及血清及滑膜组织中TNF-α、IL-6、IL-8含量,可能是双藤痹痛酊的抗炎镇痛及抗类风湿关节炎的部分作用机制.
4.双藤痹痛酊可抑制CIA大鼠滑膜细胞的增生,降低滑膜细胞培养液中TNF-α、IL-1β水平,升高滑膜细胞培养液中IL-10水平。
Objeetive:
RA is a chronic, systemic autoimmune disease that is characterized by arthrosynovitis. Its main clinical manifestations are chronic, symmetrical, multi-joint synovitis and articular damage, and it is classified as an autoimmune inflammatory disease. The rate of incidence is higher among young adults, and it severely impair health due to the difficulty of treatment. RA is costly for individuals, health services and socio-economic impact in our society. However, due to the lack of efficacy and undesirable side effects related to many western medical treatments, so far effective and safe therapeutic treatment of RA is still desired.
RA belongs to "Bizheng"."Lijie","Hexifeng" in traditional Chinese medicine. It is treated by traditional Chinese medicine syndrome differentiation and treatment under theory of traditional Chinese medicine. Traditional Chinese medicine play a pharmacodynamics through the multi-level, multi-link, multi-combination ways and target. They have advantages in anti-inflammatory and analgesic, regulating immune function. So Shuangtengbitong tincture was used to research its effects and investigate it mechanism of action.
Methods:
1. The anti-inflammatory activities of Shuangtengbitong tincture were oserved by utilizing the following models:carrageenin-induced paw edema in rats, xylene-induced ear edema, acetic acid-induced peritoneal capillary permeability and tampons-induced granuloma formation in mice.
2. The analgesic effeets of Shuangtengbitong tincture were evaluated by hot-plate test and acetic acid-induced writhing response in mice as well as chlonic pain model in collagen-induced arthritic rats.
3. Collagen-induced arthritic rat model was established to evaluate the anti-arthritic effetes of Shuangtengbitong tincture. We determined the change of primary paw swelling. Seeondary paw swelling, the arthritis scores and histological assessment of ankle articular synovium of all CIA rats. The levels of TNF-α, IL-1β and IL-6were measured by ELISA. Then the levels of the TNF-α、 IL-6. et al. in synovial tissues were examined by immunohistological staining, western blot and reverse transcription-polymerase chain reaction (RT-PCR) analysis.
4. Synovial cells were isolated from CIA rats, then cultured. Effect of Shuangtengbitong tincture on synovial cells was observed, as well as the level of cytokines. such as IL-1β
Results:
1. Anti-inflammatory experiments:
(1) xylene-induced ear edema experiment:the ear weigh of Shuangtengbitong tincture groups all were less than the model, and there were significant difference compared with the model group (P<0.05orP<0.01):
(2) Cotton pellet granuloma formation experiment:granulation tissue weigh of Shuangtengbitong tincture groups all were less than the model, and there were significant difference compared with the model group (P<0.05or P<0.01);
(3) Acetic acid induced capillary permeability in mice experiment:the OD value of Shuangtengbitong tincture groups all were less than the model, and there were significant difference compared with the model group in Shuangtengbitong tincture medial-dose and high-dose groups (P<0.05);
(4) Carrageenin induced foot pad swelling experiment:foot pad swelling of Shuangtengbitong tincture groups all were less than the model, and there were significant difference compared with the model group only in Shuangtengbitong tincture high-dose groups at1h,2h,4h,6h:
2. Analgesic experiments:
(1) The hot plate experiment:the pain response time of Shuangtengbitong tincture groups were prolonged (P<0.05or P<0.01).
(2) Chemical irritants experiment:the pain response time of Shuangtengbitong tincture medial-dose and high-dose groups were prolonged compared with the model group, and torsion times of mice within15mins was obviously reduced (P<0.05or P<0.01).
3. Effect on CIA rats experiments:
Aarthritis index and paw swelling of Shuangtengbitong tincture groups were less than the model group. And also improved the inflammatory response in synovial tissues. High-dose group had significant difference compared to the model group (P<0.05or P<0.01). The levels of TNF-α, IL-1β, IL-6, IL-8, et al. of Shuangtengbitong tincture groups in serum and synovial tissues were less than the model group (P<0.05or P<0.01). Meanwhile protein and mRNA expression levels of TNF-a. IL-6. IL-8. IL-10. TLR4. MyD88. NF-κB. IKκ. P-IκB were less than the model group. and high-dose group had significant difference compared to the model group (P<0.01). However protein and mRNA expression level of IκB was up-regulated and high-dose group had significant difference compared to the model group (P<0.01).
4. Effect on synovial cells experiments:
Shuangtengbitong tincture0.5and1mg/mL groups and MTX group decreased A value, and compared with control group.1mg/mL group and MTX group could obviously decreased A value (P<0.05or P<0.01).1mg/mL group and MTX group also reduced TNF-α、 IL-1β generation in LPS induced inflammatory response, improved IL-10level as well (P<0.05or P<0.01).
Conclusions:
1. Shuangtengbitong tincture could significantly inhibite the inerease in Paw edema induced by carrageenin. ear edema induced by xylene. vaseular permeability induced by acetic acid and granuloma induced by agar.
2. Shuangtengbitong tincture obviously prolonged the writhing latent period and reduced writhing time in acetic acid-induced mice. Moreover. Shuangtengbitong tincture also increased the paw withdrawal threshold in CIA rats. However. the effect of Shuangtengbitong tincture on hot-plate pain threshold was not obvious.
3. Shuangtengbitong tincture could remarkably inhibite the primary and secondary paw swelling, reduce the arthritis scores. And Shuangtengbitong tincture also significantly regulated inflammatory signal transduction networks and related factors, which manifested as reducing levels of serum TNF-α, IL-1β and IL-6. Meanwhile, the pathological examination demonstrated that synovial hyperplasia and infiammatory cells in filtration in CIA rats were suppressed by Shuangtengbitong tincture.
4. Shuangtengbitong tincture inhibited synovial cells proliferation and reduced TNF-α、 IL-1β generation in LPS induced inflammatory response, improved IL-10level as well.
类风湿性关节炎(rheumatid arthritis,RA)是一种以关节滑膜炎为特征的慢性全身性自身免疫性疾病,滑膜炎持久反复发作,可导致关节内软骨和骨的破坏,关节功能障碍,本病发病以青壮年为多,预后欠佳,致残废率高,严重危害广大人民的身体健康,目前采取的治疗方案,虽然可以改善症状,减轻炎症,但最终均未能有效地防止骨侵蚀,阻断病程进展,且长期应用副作用大,到目前为止,西医药治疗本病仍无较为理想的方法。
本病属于中医学“痹证”、“历节”、“鹤膝风”等范畴。中医药治疗本病一般以辨证论治为主,通过多层次、多环节、多途径、多靶点共同作用,抗炎镇痛,调节免疫功能,阻止病变发展,具有较大优势。本课题以医院制剂双藤痹痛酊为研究对象,通过体内和体外实验,观察双藤痹痛酊对关节滑膜的保护作用,并探索其作用机理。
方法：
1.抗炎作用实验：建立二甲苯致小鼠耳肿胀、棉球肉芽肿、醋酸致小鼠腹腔毛细血管通透性增加及角叉菜胶致大鼠足肿胀,考察双藤痹痛酊对多种急慢性炎症的影响：
2.镇痛实验：应用热板法、醋酸致小鼠扭体反应慢性疼痛等模型,考察双藤痹痛酊镇痛作用。
3.对Ⅱ型胶原诱导性关节炎大鼠的影响：建立胶原诱导性关节炎(CIA)模型,观察双藤痹痛酊对大鼠Ⅱ型胶原诱导性关节炎评分、大鼠关节肿胀度及对组织病理学评分的影响,并结合酶联免疫、免疫组化、蛋白免疫印迹、逆转录聚合酶链式反应等方法,考察双藤痹痛酊对CIA大鼠转录核因子(NF-KB)炎症信号转导通路相关因子的影响。
4.对Ⅱ型胶原诱导性关节炎大鼠滑膜细胞的影响：分离培养原代滑膜细胞,观察双藤痹痛酊对原代滑膜细胞的增殖作用及对LPS诱导产生的IL-1β等因子的作用。
结果：
1.抗炎作用试验：
(1)二甲苯致小鼠耳肿胀实验：双藤痹痛酊各个剂量组致炎耳质量差值均小于模型组,与模型组相比,双藤痹痛酊中、高剂量有显著性差异(P<0.05或P<0.01)：
(2)棉球肉芽肿实验：双藤痹痛酊各个剂量组肉芽组织质量均小于模型组,其中高剂量组和中剂量组与模型组相比,有显著性差异(P<0.05或P<0.01)；
(3)醋酸致小鼠腹腔毛细血管通透性增加实验：双藤痹痛酊各个剂量组腹腔冲洗液OD值均小于模型组,其中高剂量组与模型组相比,有显著性差异(P<0.05);
(4)角叉菜胶致大鼠足肿胀实验：双藤痹痛酊各个剂量组足肿胀值均低于模型组,高剂量组致炎后1h、2h、4h、6h足肿胀与模型组比较,差异有显著性意义(P<0.05或P<0.01),中剂量组致炎后2h、4h足肿胀与模型组比较,差异有显著性意义(P<0.05或P<0.01),低剂量组致炎后1h、2h足肿胀与模型组比较,差异有显著性意义(P<0.05)。
2.镇痛试验：
(1)热板法实验：与空白组比较,双藤痹痛酊各剂量组疼痛反应出现时间均延长(P<0.05或P<0.01),其中高剂量组作用在给药后0.5h、1h、2h均有非常显著性意义;
(2)与模型组比较,双藤痹痛酊高、中、低剂量组疼痛反应出现时间稍延长,15min内扭体次数明显减少(P<0.01)。
3.对II型胶原诱导性关节炎大鼠的影响实验：
双藤痹痛酊各剂量组关节炎指数、足肿胀度均小于模型组,与模型组相比双藤痹痛酊各剂量均改善踝关节滑膜组织炎性浸润及增生等炎症反应,其中高剂量组与模型组相比有显著性差异(P<0.05或P<0.0l)。双藤痹痛酊各剂量组血清及组织中肿瘤坏死因子(TNF-α)、白介素(IL)-1β、IL-6、IL-8等含量均小于模型组,与模型组相比具有显著性差异(F0.05或P<0.01)；TNF-α、IL-6、IL-8、IL-10、TLR4、MyD88、NF-κB、IKκ、P-IκB蛋白及mRNA表达,双藤痹痛酊各剂量组均低于模型组,其中高剂量组降低最显著(P<0.01);IκB蛋白及mRNA表达,双藤痹痛酊各剂量组均升高,其中高剂量组降低最显著(P<0.01)：
4.对II型胶原诱导性关节炎大鼠滑膜细胞的影响：
双藤痹痛酊0.5、1mg/mL组和MTX组大鼠滑膜细胞A值均低于对照组,其中1mg/mL组和MTX组显著降低A值(P<0.05或P<0.01)；与对照组比较,给药组TNF-α、IL-1β水平均降低,IL-10水平升高,其中双藤痹痛酊1mg/mL组及MTX组TNF-α、IL-1β水平显著降低而IL-10水平升高(P<0.05或P<0.01)。
结论：
1.双藤痹痛酊能抑制二甲苯所致的耳肿胀、抗肉芽组织形成、抑制醋酸制小鼠腹腔毛细血管通透性的增高、抑制角叉菜胶致足肿胀.说明双藤痹痛酊对急性炎症反应和慢性炎症增生作用具有一定的抑制作用。
2.双藤痹痛酊给药后提高痛阈百分率、减少醋酸所致小鼠扭体反应次数.提示双藤痹痛酊具有一定的镇痛作用.
3.双藤痹痛酊给药后能抑制CIA大鼠足肿胀,改善躁关节滑膜组织炎性浸润及增生等炎症反应,调整TLR4/NF-KB炎症信号转导网络及相关因子,降低滑膜组织TLR4、MyD88、NF-κB、IKκ、P-IκB表达及血清及滑膜组织中TNF-α、IL-6、IL-8含量,可能是双藤痹痛酊的抗炎镇痛及抗类风湿关节炎的部分作用机制.
4.双藤痹痛酊可抑制CIA大鼠滑膜细胞的增生,降低滑膜细胞培养液中TNF-α、IL-1β水平,升高滑膜细胞培养液中IL-10水平。
Objeetive:
RA is a chronic, systemic autoimmune disease that is characterized by arthrosynovitis. Its main clinical manifestations are chronic, symmetrical, multi-joint synovitis and articular damage, and it is classified as an autoimmune inflammatory disease. The rate of incidence is higher among young adults, and it severely impair health due to the difficulty of treatment. RA is costly for individuals, health services and socio-economic impact in our society. However, due to the lack of efficacy and undesirable side effects related to many western medical treatments, so far effective and safe therapeutic treatment of RA is still desired.
RA belongs to "Bizheng"."Lijie","Hexifeng" in traditional Chinese medicine. It is treated by traditional Chinese medicine syndrome differentiation and treatment under theory of traditional Chinese medicine. Traditional Chinese medicine play a pharmacodynamics through the multi-level, multi-link, multi-combination ways and target. They have advantages in anti-inflammatory and analgesic, regulating immune function. So Shuangtengbitong tincture was used to research its effects and investigate it mechanism of action.
Methods:
1. The anti-inflammatory activities of Shuangtengbitong tincture were oserved by utilizing the following models:carrageenin-induced paw edema in rats, xylene-induced ear edema, acetic acid-induced peritoneal capillary permeability and tampons-induced granuloma formation in mice.
2. The analgesic effeets of Shuangtengbitong tincture were evaluated by hot-plate test and acetic acid-induced writhing response in mice as well as chlonic pain model in collagen-induced arthritic rats.
3. Collagen-induced arthritic rat model was established to evaluate the anti-arthritic effetes of Shuangtengbitong tincture. We determined the change of primary paw swelling. Seeondary paw swelling, the arthritis scores and histological assessment of ankle articular synovium of all CIA rats. The levels of TNF-α, IL-1β and IL-6were measured by ELISA. Then the levels of the TNF-α、 IL-6. et al. in synovial tissues were examined by immunohistological staining, western blot and reverse transcription-polymerase chain reaction (RT-PCR) analysis.
4. Synovial cells were isolated from CIA rats, then cultured. Effect of Shuangtengbitong tincture on synovial cells was observed, as well as the level of cytokines. such as IL-1β
Results:
1. Anti-inflammatory experiments:
(1) xylene-induced ear edema experiment:the ear weigh of Shuangtengbitong tincture groups all were less than the model, and there were significant difference compared with the model group (P<0.05orP<0.01):
(2) Cotton pellet granuloma formation experiment:granulation tissue weigh of Shuangtengbitong tincture groups all were less than the model, and there were significant difference compared with the model group (P<0.05or P<0.01);
(3) Acetic acid induced capillary permeability in mice experiment:the OD value of Shuangtengbitong tincture groups all were less than the model, and there were significant difference compared with the model group in Shuangtengbitong tincture medial-dose and high-dose groups (P<0.05);
(4) Carrageenin induced foot pad swelling experiment:foot pad swelling of Shuangtengbitong tincture groups all were less than the model, and there were significant difference compared with the model group only in Shuangtengbitong tincture high-dose groups at1h,2h,4h,6h:
2. Analgesic experiments:
(1) The hot plate experiment:the pain response time of Shuangtengbitong tincture groups were prolonged (P<0.05or P<0.01).
(2) Chemical irritants experiment:the pain response time of Shuangtengbitong tincture medial-dose and high-dose groups were prolonged compared with the model group, and torsion times of mice within15mins was obviously reduced (P<0.05or P<0.01).
3. Effect on CIA rats experiments:
Aarthritis index and paw swelling of Shuangtengbitong tincture groups were less than the model group. And also improved the inflammatory response in synovial tissues. High-dose group had significant difference compared to the model group (P<0.05or P<0.01). The levels of TNF-α, IL-1β, IL-6, IL-8, et al. of Shuangtengbitong tincture groups in serum and synovial tissues were less than the model group (P<0.05or P<0.01). Meanwhile protein and mRNA expression levels of TNF-a. IL-6. IL-8. IL-10. TLR4. MyD88. NF-κB. IKκ. P-IκB were less than the model group. and high-dose group had significant difference compared to the model group (P<0.01). However protein and mRNA expression level of IκB was up-regulated and high-dose group had significant difference compared to the model group (P<0.01).
4. Effect on synovial cells experiments:
Shuangtengbitong tincture0.5and1mg/mL groups and MTX group decreased A value, and compared with control group.1mg/mL group and MTX group could obviously decreased A value (P<0.05or P<0.01).1mg/mL group and MTX group also reduced TNF-α、 IL-1β generation in LPS induced inflammatory response, improved IL-10level as well (P<0.05or P<0.01).
Conclusions:
1. Shuangtengbitong tincture could significantly inhibite the inerease in Paw edema induced by carrageenin. ear edema induced by xylene. vaseular permeability induced by acetic acid and granuloma induced by agar.
2. Shuangtengbitong tincture obviously prolonged the writhing latent period and reduced writhing time in acetic acid-induced mice. Moreover. Shuangtengbitong tincture also increased the paw withdrawal threshold in CIA rats. However. the effect of Shuangtengbitong tincture on hot-plate pain threshold was not obvious.
3. Shuangtengbitong tincture could remarkably inhibite the primary and secondary paw swelling, reduce the arthritis scores. And Shuangtengbitong tincture also significantly regulated inflammatory signal transduction networks and related factors, which manifested as reducing levels of serum TNF-α, IL-1β and IL-6. Meanwhile, the pathological examination demonstrated that synovial hyperplasia and infiammatory cells in filtration in CIA rats were suppressed by Shuangtengbitong tincture.
4. Shuangtengbitong tincture inhibited synovial cells proliferation and reduced TNF-α、 IL-1β generation in LPS induced inflammatory response, improved IL-10level as well.
引文
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