痹痛灵颗粒对类风湿性关节炎关节滑膜保护机理的研究
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摘要
研究背景：类风湿性关节炎(RA)是一种以关节和关节周围组织的非感染性炎症为主的全身性自身免疫性疾病,其病理特点为关节滑膜的慢性炎症,细胞浸润,滑膜翳形成,软骨及骨组织的侵袭,导致关节结构的破坏。RA目前仍属一种难治性疾病,误诊率和不合理用药率较高,且尚无特异有效根治本病的疗法和药物,而中医药治疗本病具有调节整体功能、疗效稳定、副作用小的特点,日益被人们所关注。
研究基础：类风湿性关节炎以关节肿痛、强直、畸形和功能障碍为主要临床表现,隶属祖国医学“痹证”范畴。全国名老中医汪履秋教授提出其病机关键在于寒湿阻络,创制经验方痹痛灵颗粒用于治疗RA初期,寒湿入络,阻滞不通,经数十年临床应用疗效显著。前期已开展的实验研究表明：该方具有抗炎镇痛及免疫调节作用,部分揭示其作用机理。
研究目的：通过中医理论与文献寻找RA寒湿阻络证的理论基础,确立寒湿阻络证是类风湿性关节炎临床主要证候,为散寒除湿、祛瘀通络法治疗RA提供客观依据；实验研究在既往研究的基础上,以Ⅱ型胶原诱导动物RA模型,通过体内和体外实验,着重观察痹痛灵颗粒对关节滑膜的保护作用,并探索其作用机理。
研究方法：通过回顾历代医家对RA(痹证)病名、病因、病机的认识,从理论角度探讨寒湿阻络是本病的基本病理改变,提出寒湿内侵、瘀血阻络是类风湿性关节炎的关键病机,为痹痛灵颗粒治疗RA提供理论依据。实验以CIA大鼠为受试对象,观察痹痛灵颗粒对CIA模型大鼠关节评分、关节体积、关节肿胀度及关节病理组织学的影响,对实验大鼠原代滑膜细胞增殖和对血清、原代滑膜细胞上清液中TNF-α、IL-1β的影响,对关节液中的VEGF、MMP-3含量及关节滑膜细胞VEGF mRNA、MMP-3 mRNA表达的影响,进一步揭示本方治疗RA的机理。
研究结果：寒湿必夹瘀,湿痰瘀胶结,导致病情进展,病程缠绵,寒湿内侵、瘀血阻络是RA的关键病机之一,散寒除湿、化瘀通络是治疗RA的常法。痹痛灵颗粒对CIA大鼠关节肿胀有一定的抑制作用,能减轻关节滑膜的增生程度及关节软骨的损伤程度。痹痛灵颗粒高中低剂量组均可明显抑制CIA模型大鼠原代滑膜细胞上清液中TNF-α、IL-1β含量,可明显降低关节液中VEGF、MMP-3含量及关节滑膜细胞VEGF mRNA、MMP-3 mRNA表达。
研究结论：通过对实验结果的讨论,得出①寒、湿是RA重要致病因素,寒湿必夹瘀,寒湿内侵、瘀血阻络是RA的关键病机之一,寒湿阻络证是临床常见证型。散寒除湿、化瘀通络是治疗RA的常用大法。临床治疗RA不必拘泥于“久病入络”,早用活血化瘀法具有重要意义。②CIA大鼠原代滑膜细胞增殖能力亢进,是类风湿性关节炎发病的主要病理改变。在类风湿性关节炎中,VEGF、MMP-3可以促进血管新生和软骨降解,为类风湿性关节炎发病的重要机制之一,并且VEGF、MMP-3可以作为检测RA活动性和软骨破坏程度指标。③痹痛灵颗粒可明显减轻CIA性关节炎大鼠足肿胀度、降低关节评分、减轻踝关节组织病理改变。④痹痛灵颗粒可能通过降低CIA大鼠滑膜细胞培养上清液IL-1β, TNF-α含量,达到减轻大鼠滑膜细胞增殖反应的作用,抑制滑膜血管新生与炎症反应,降低软骨关节的破坏。⑤痹痛灵颗粒可以通过降低血清及关节滑膜液中的VEGF、MMP-3含量,抑制Ⅱ型胶原关节炎大鼠关节滑膜组织VEGFmRNA、MMP-3mRNA过度表达,从而阻断血管新生和软骨降解,达到延缓关节软骨破坏和保护关节功能的目的,可以作为痹痛灵颗粒治疗类风湿性关节炎的疗效机理之一
创新点：通过观察痹痛灵颗粒对CIA大鼠关节原代滑膜细胞增殖及TNF-α、IL-1β变化情况,采用实时定量PCR法观察痹痛灵颗粒对滑膜组织中VEGFmRNA、MMP-3 mRNA表达的影响,提示痹痛灵颗粒对类风湿性关节炎关节滑膜保护的部分机理。
Background:Rheumatoid arthritis(RA) is one of the systemic autoimmune disease characterized as non-infection inflammation in joint and tissue around joint. The pathological features of RA is the chronic inflammation, cellular infiltration, invasion of gristle and bone and destroy the structure of the joint. RA is still a difficult disease for treatment and no special treatment. The Chinese Herbs was accepted by patients because it can regulate the body function with stable effect and less side effect.
Rationale of Research:RA manifested as joint swelling and pain, stiffness and joint malformation clinically, which belongs to "Bi" Syndrome in TCM. National well-known professor Wang Lvqiu proposed that the key pathogenesis of RA lies in Coldness and Dampness Obstructing Collaterals, he developed experienced formula Bi Tong Ling Powder for early stage of RA with the syndrome type of Collaterals Obstructed by Coldness and Dampness, which was born out to be effective after several decades of clinical practice. Pre-clinical research shows that this formula has the effect of anti-inflammation and immune suppression.
Objective:Reviewed the TCM literature for RA and divided the RA into different patterns. Based on the literature reported, RA model was established. The mechanism was study in vitro and in vivo.
Method:The literatures were reviewed and the TCM names, etiology, pathological mechanisms were defined and draw a conclusion that cold-damp invading in the interior and obstruction of collaterals by blood stasis were the most important TCM basis. The CIA rats were applied as the model and were treated by the Bitongling granule. The score of the joints, the volume of joint, the edema of joint and pathological findings were analyzed and the expression of VEGF,MMP-3, TNF-α、IL-1βwere analyzed in order to further explained the mechanisms of the BiTongLing particle for RA.
Results:Cold and Dampness was always accompanied by Stagnation, cold,dampness and phlegm, which influenced each other and caused the process of the RA persisting very long time. Therefore, dispel cold and removed the dampness, disperse blood stasis and dredge collateral were always used in treatment of RA. BiTongLing particle can decrease the joint edema and prevent the proliferation of synovial membrane and decrease injure of the cartilage. From the rat model, the BiTongLing particle can inhibit the expression of TNF-a and IL-1βin synovial membrane cell primary culture and decrease the expression of VEGF and MMP-3 in synovial membrane.
Conclusion:From the study, conclusions were drew as follows:①Cold and dampness are the important risk factor for RA and the cold-damp invading in the interior and obstruction of collaterals by blood stasis were the most important TCM interpretation of the cause. The channel obstruction by cold and dampness are the most common pattern of RA. Dispel cold and removed the dampness, disperse blood stasis and dredge collateral are always used in treatment of RA.②The proliferation of synovial membrane is very active in primary culture cell, as is the most important pathological findings in RA. In RA, the VEGF and MMP-3 can increase the vascular prolifereation and degrade the cartilage and they can be used as the markers of the activity and severity of RA.③BiTongLing particle can decrease the joint edema and prevent the proliferation of synovial membrane and decrease the injure of the cartilage.④BiTongLing particle can decrease the expression of IL-1βand TNF-αin synovial membrane cell primary culture and decrease the proliferation of the synovial membrane, inhibit the vascular growth and prevent the injure of joint.⑤BiTongLing particle can decrease the over-expression of VEGF and MMP-3 in synovial membrane and prevent the proliferation of the synovial membrane, inhibit the vascular growth and prevent the injure of joint.
Points of innovation:BiTongLing particle can decrease the expression of IL-1βand TNF-αin synovial membrane cell primary culture and inhibit the over-expression by real-time RT-PCR and the mechanisms of protection of BiTongLing particle for synovial membrane in RA are explained by this sutdy.
研究基础：类风湿性关节炎以关节肿痛、强直、畸形和功能障碍为主要临床表现,隶属祖国医学“痹证”范畴。全国名老中医汪履秋教授提出其病机关键在于寒湿阻络,创制经验方痹痛灵颗粒用于治疗RA初期,寒湿入络,阻滞不通,经数十年临床应用疗效显著。前期已开展的实验研究表明：该方具有抗炎镇痛及免疫调节作用,部分揭示其作用机理。
研究目的：通过中医理论与文献寻找RA寒湿阻络证的理论基础,确立寒湿阻络证是类风湿性关节炎临床主要证候,为散寒除湿、祛瘀通络法治疗RA提供客观依据；实验研究在既往研究的基础上,以Ⅱ型胶原诱导动物RA模型,通过体内和体外实验,着重观察痹痛灵颗粒对关节滑膜的保护作用,并探索其作用机理。
研究方法：通过回顾历代医家对RA(痹证)病名、病因、病机的认识,从理论角度探讨寒湿阻络是本病的基本病理改变,提出寒湿内侵、瘀血阻络是类风湿性关节炎的关键病机,为痹痛灵颗粒治疗RA提供理论依据。实验以CIA大鼠为受试对象,观察痹痛灵颗粒对CIA模型大鼠关节评分、关节体积、关节肿胀度及关节病理组织学的影响,对实验大鼠原代滑膜细胞增殖和对血清、原代滑膜细胞上清液中TNF-α、IL-1β的影响,对关节液中的VEGF、MMP-3含量及关节滑膜细胞VEGF mRNA、MMP-3 mRNA表达的影响,进一步揭示本方治疗RA的机理。
研究结果：寒湿必夹瘀,湿痰瘀胶结,导致病情进展,病程缠绵,寒湿内侵、瘀血阻络是RA的关键病机之一,散寒除湿、化瘀通络是治疗RA的常法。痹痛灵颗粒对CIA大鼠关节肿胀有一定的抑制作用,能减轻关节滑膜的增生程度及关节软骨的损伤程度。痹痛灵颗粒高中低剂量组均可明显抑制CIA模型大鼠原代滑膜细胞上清液中TNF-α、IL-1β含量,可明显降低关节液中VEGF、MMP-3含量及关节滑膜细胞VEGF mRNA、MMP-3 mRNA表达。
研究结论：通过对实验结果的讨论,得出①寒、湿是RA重要致病因素,寒湿必夹瘀,寒湿内侵、瘀血阻络是RA的关键病机之一,寒湿阻络证是临床常见证型。散寒除湿、化瘀通络是治疗RA的常用大法。临床治疗RA不必拘泥于“久病入络”,早用活血化瘀法具有重要意义。②CIA大鼠原代滑膜细胞增殖能力亢进,是类风湿性关节炎发病的主要病理改变。在类风湿性关节炎中,VEGF、MMP-3可以促进血管新生和软骨降解,为类风湿性关节炎发病的重要机制之一,并且VEGF、MMP-3可以作为检测RA活动性和软骨破坏程度指标。③痹痛灵颗粒可明显减轻CIA性关节炎大鼠足肿胀度、降低关节评分、减轻踝关节组织病理改变。④痹痛灵颗粒可能通过降低CIA大鼠滑膜细胞培养上清液IL-1β, TNF-α含量,达到减轻大鼠滑膜细胞增殖反应的作用,抑制滑膜血管新生与炎症反应,降低软骨关节的破坏。⑤痹痛灵颗粒可以通过降低血清及关节滑膜液中的VEGF、MMP-3含量,抑制Ⅱ型胶原关节炎大鼠关节滑膜组织VEGFmRNA、MMP-3mRNA过度表达,从而阻断血管新生和软骨降解,达到延缓关节软骨破坏和保护关节功能的目的,可以作为痹痛灵颗粒治疗类风湿性关节炎的疗效机理之一
创新点：通过观察痹痛灵颗粒对CIA大鼠关节原代滑膜细胞增殖及TNF-α、IL-1β变化情况,采用实时定量PCR法观察痹痛灵颗粒对滑膜组织中VEGFmRNA、MMP-3 mRNA表达的影响,提示痹痛灵颗粒对类风湿性关节炎关节滑膜保护的部分机理。
Background:Rheumatoid arthritis(RA) is one of the systemic autoimmune disease characterized as non-infection inflammation in joint and tissue around joint. The pathological features of RA is the chronic inflammation, cellular infiltration, invasion of gristle and bone and destroy the structure of the joint. RA is still a difficult disease for treatment and no special treatment. The Chinese Herbs was accepted by patients because it can regulate the body function with stable effect and less side effect.
Rationale of Research:RA manifested as joint swelling and pain, stiffness and joint malformation clinically, which belongs to "Bi" Syndrome in TCM. National well-known professor Wang Lvqiu proposed that the key pathogenesis of RA lies in Coldness and Dampness Obstructing Collaterals, he developed experienced formula Bi Tong Ling Powder for early stage of RA with the syndrome type of Collaterals Obstructed by Coldness and Dampness, which was born out to be effective after several decades of clinical practice. Pre-clinical research shows that this formula has the effect of anti-inflammation and immune suppression.
Objective:Reviewed the TCM literature for RA and divided the RA into different patterns. Based on the literature reported, RA model was established. The mechanism was study in vitro and in vivo.
Method:The literatures were reviewed and the TCM names, etiology, pathological mechanisms were defined and draw a conclusion that cold-damp invading in the interior and obstruction of collaterals by blood stasis were the most important TCM basis. The CIA rats were applied as the model and were treated by the Bitongling granule. The score of the joints, the volume of joint, the edema of joint and pathological findings were analyzed and the expression of VEGF,MMP-3, TNF-α、IL-1βwere analyzed in order to further explained the mechanisms of the BiTongLing particle for RA.
Results:Cold and Dampness was always accompanied by Stagnation, cold,dampness and phlegm, which influenced each other and caused the process of the RA persisting very long time. Therefore, dispel cold and removed the dampness, disperse blood stasis and dredge collateral were always used in treatment of RA. BiTongLing particle can decrease the joint edema and prevent the proliferation of synovial membrane and decrease injure of the cartilage. From the rat model, the BiTongLing particle can inhibit the expression of TNF-a and IL-1βin synovial membrane cell primary culture and decrease the expression of VEGF and MMP-3 in synovial membrane.
Conclusion:From the study, conclusions were drew as follows:①Cold and dampness are the important risk factor for RA and the cold-damp invading in the interior and obstruction of collaterals by blood stasis were the most important TCM interpretation of the cause. The channel obstruction by cold and dampness are the most common pattern of RA. Dispel cold and removed the dampness, disperse blood stasis and dredge collateral are always used in treatment of RA.②The proliferation of synovial membrane is very active in primary culture cell, as is the most important pathological findings in RA. In RA, the VEGF and MMP-3 can increase the vascular prolifereation and degrade the cartilage and they can be used as the markers of the activity and severity of RA.③BiTongLing particle can decrease the joint edema and prevent the proliferation of synovial membrane and decrease the injure of the cartilage.④BiTongLing particle can decrease the expression of IL-1βand TNF-αin synovial membrane cell primary culture and decrease the proliferation of the synovial membrane, inhibit the vascular growth and prevent the injure of joint.⑤BiTongLing particle can decrease the over-expression of VEGF and MMP-3 in synovial membrane and prevent the proliferation of the synovial membrane, inhibit the vascular growth and prevent the injure of joint.
Points of innovation:BiTongLing particle can decrease the expression of IL-1βand TNF-αin synovial membrane cell primary culture and inhibit the over-expression by real-time RT-PCR and the mechanisms of protection of BiTongLing particle for synovial membrane in RA are explained by this sutdy.
引文
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