肠必清栓对UC模型大鼠的治疗作用及机制的实验研究
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摘要
UC的病因及发病机制尚未完全明确,迄今为止,众多的研究不断揭示的机制认为UC是基因易感人群肠腔内抗原所引发的粘膜非正常免疫应答反应导致的炎症。为此,近年对本病的治疗焦点主要是采取各种方法封闭炎性通路、阻断炎症过程,从而达到治疗的目的。研究证明,若能阻断或抑制过激的免疫反应,或抑制参与的某些细胞因子、炎性介质,均可缓解病情；同时,免疫反应过程中抗炎症细胞因子和促炎症细胞因子间作用相互平衡从而限制炎症,二者的平衡被打破,可促使炎症的发生,故若能增强抗炎性细胞因子的活性亦能缓解UC病情。肠必清栓是本实验室研究筛选两种副作用小而抗菌抗炎疗效确切的药物4-氨基水杨酸(4-ASA)和盐酸小檗碱(BBH)为主料制成的栓剂,本实验用肠必清栓治疗UC模型大鼠,观察肠必清栓治疗UC的效果,并通过检测大鼠肠组织中细胞因子的表达,探讨其治疗UC的作用机制。
实验采用2,4-DNCB免疫加醋酸局部灌肠法建立大鼠UC模型后,将模型大鼠随机分为五组：A模型对照组(8只)、B肠必清栓低剂量组(10只)、C肠必清栓中剂量组(10只)、D肠必清栓高剂量组(10只)、E柳氮磺吡啶药物对照组(10只)另设F正常对照组(6只)。给药期间观察大鼠的一般情况,2周后处死,计算疾病活动指数(DAI)、结肠指数(CI)、结肠组织病理学评分(HPS),评价肠必清栓对UC模型大鼠肠组织炎症及损伤的治疗效果。结果：模型组大鼠的DAI、HPS明显增高(P<0.01),CI明显降低：与模型组比较,给药组各组大鼠的DAI、HPS表达显著降低(P<0.01),但与正常组比较仍有差异(P<0.01),CI有不同程度的增高,C、D组与模型组差异显著；B组与C、D组的HPS呈剂量依赖关系,差异显著(P<0.01),而C、D组与E组疗效相当,差异无显著性意义。结果显示,肠必清栓可显著减轻大鼠肠组织病理损伤促进组织修复,有效治疗实验大鼠UC。
为进一步研究肠必清栓治疗UC的作用机制,我们查阅大量的文献资料后,筛选出在UC发病及转归中起重要作用的细胞因子,包括在免疫调节中发挥重要作用的IL-1、TNF-α、IL-10,机体抗氧化系统的关键酶SOD,参与炎症及炎症因子转录的COX-2、NF-κBp65以及在组织损伤的修复中起重要调节作用的TGF-β1,通过检测肠必清栓治疗后这些细胞因子表达的变化,从细胞因子角度探讨其治疗UC的免疫学机理和抗炎、抗氧化作用机制,为肠必清栓治疗UC提供一定的实验基础和理论依据。细胞因子检测结果：模型组大鼠肠组织中IL-1β、TNF-α表达显著增多而IL-10显著减少,给药治疗可下调IL-1β、TNF-α的表达(P<0.01),提高组织中IL-10的表达量(P<0.01),肠必清栓低、中、高剂量组间呈剂量依赖关系,高剂量组与SASP组间差异无统计学差异；模型大鼠肠组织SOD仅少量表达,给药治疗可升高模型大鼠SOD的表达(P<0.01),肠必清栓中、高剂量组和SASP组与正常组间差异无显著性意义；模型组大鼠肠组织中COX-2、NF-κBp65和TGF-β1的表达明显增高(P<0.01)；与模型组比较,用肠必清栓治疗后,给药各组大鼠的COX-2、NF-κBp65和TGF-β1表达显著降低,肠必清栓低剂量组与中、高剂量组的COX-2、NF-κBp65和TGF-β1表达差异显著(P<0.01), SASP组的COX-2、NF-κBp65评分与肠必清栓低剂量组间差异无显著性意义,而TGF-β1评分与肠必清栓中、高剂量组相当,无统计学差异。细胞因子检测结果显示,肠必清栓可调节免疫、抗氧化、抗炎并促进组织修复,这可能为其治疗UC的作用机制。
The etiology of UC still remains incompletely understood, so far, more research continues to reveal the mechanism that UC is inflammation leaded by abnormal immune response which induced by intestine mucosal antigen with genetically susceptible people. with regards to this, In recent years, the treatment for UC is to adopt various methods mainly to focuse on the closure of mucosal inflammatory pathway, blocking the inflammatory process, so as to achieve the treatment goals. Studies have shown that, If we block the excessive immune response, or inhibit the certain cytokines, inflammatory mediators, may alleviate the condition. Meanwhile, the anti-inflammatory cytokine restrict the role of inflammation through the balance of pro-inflammatory cytokines in the progress of Immune response, the balance between was broken, can contribute to the occurrence of inflammation, therefore, if the activity of anti-inflammatory cytokines is increased,it can also alleviate the UC disease.ChangBiqing suppository was researched by our laborytory and is constituted by two kinds of materials with little side-effects but definite efficacy in anti-bacterial anti-inflammatory,4-amino-acid (4-ASA) and berberine based-hydrochloric (BBH).In this study, we treat thel UC model rats with ChangBiqing suppository, to investigate the effect of ChangBiqing suppository on ulcerative colitis in modle rats as well as on the expression of IL-1β、TNF-α、IL-10、SOD、COX-2、NF-κBp65 and TGF-β1 in colonic mucosa to reveal the possible mechanism for treatment.
To investigate the effect of ChangBiqing suppository on ulcerative colitis in modle rats. SD UC model rats induced by dinitrochlorobenzene (DNCB)and acetic acid were randomly divided into five groups from A to E:UC model group(A), low dose intervention group(B), moderate dose intervention group(C), large dose intervention group(D), SASP group(E), another six rats as normal control group(F) besides. The fresh colons of the rats were got and examined after 14 days of treatment, meanwhile the DAI, HPS and CI were evaluated. Results:DAI and HPS of the rats in the model group were significantly higher than the control group(P<0.01). Compared with the UC group, the DAI，HPS in group B to E decreased markedly(P<0.01), but they still differ significantly from the control group(P<0.01); The HPS decreased in a dose-dependent manner from B to D and group B differed significantly from group C and D(P<0.01). In contrast, no significant differences in HPS were observed among the three groups C, D and E. Conclusions：ChangBiqing suppository demonstrated good results in prevention and treatment on induced rat's UC.
To reveal the possible mechanism for treatment, we refer to a lot of literature information and Screened out some cytokines wich play an important role in the pathogenesis and healing of UC, included IL-1、TNF-αIL-10, which mainly regulate the immunity, SOD a cucial enzyme for antioxidant, COX-2 as inflammatory mediator, NF-icBp65 as transcription factor of Inflammatory cytokines and TGF-β1 which play an important role in regulating the repair of tissue injury. Observing the effect of ChangBiqing suppository on the expression of those cytokines in colonic mucosa of rats with ulcerative colitis to explore its therapeutic mechanism in immunology、anti-inflammatory and antioxidation, and provide some experimental basis and theoretical basis for ChangBiqing suppository in the treatment of UC. Results:The antigen expression of IL-1β、TNF-αin the model group were significantly higher(P<0.01) and expression of IL-10 was lower than the control group(P<0.01). Compared with the UC group, the expression of IL-1β、TNF-αin group B to E decreased markedly(P<0.01) and the expression of IL-10 increased significantly, and the change of cytokines were in a dose-dependent manner in group B to D; The antigen expression of SOD in the model group were significantly lower than the other groups(P<0.01), In contrast, no significant differences were observed among the four groups C, D,E and F; In modle rats with UC, the antigen expression of COX-2、NF-κBp65 and TGF-β1 were significantly higher(P<0.01) when compared with the control group.Compared with the UC group,the expression of COX-2、NF-κBp65 and TGF-β1 in group B to E decreased markedly(P<0.01) and in a dose-dependent manner in group B to D. In contrast, no significant differences in expression of COX-2 and NF-κBp65 were observed in group B and E as well as TGF-β1 in group C、D and E. Conclusions:ChangBiqing suppository can adjust immunization, anti-oxidation, anti-inflammatory and to promote tissue repair, this may be the mechanism for its treatment of UC.
实验采用2,4-DNCB免疫加醋酸局部灌肠法建立大鼠UC模型后,将模型大鼠随机分为五组：A模型对照组(8只)、B肠必清栓低剂量组(10只)、C肠必清栓中剂量组(10只)、D肠必清栓高剂量组(10只)、E柳氮磺吡啶药物对照组(10只)另设F正常对照组(6只)。给药期间观察大鼠的一般情况,2周后处死,计算疾病活动指数(DAI)、结肠指数(CI)、结肠组织病理学评分(HPS),评价肠必清栓对UC模型大鼠肠组织炎症及损伤的治疗效果。结果：模型组大鼠的DAI、HPS明显增高(P<0.01),CI明显降低：与模型组比较,给药组各组大鼠的DAI、HPS表达显著降低(P<0.01),但与正常组比较仍有差异(P<0.01),CI有不同程度的增高,C、D组与模型组差异显著；B组与C、D组的HPS呈剂量依赖关系,差异显著(P<0.01),而C、D组与E组疗效相当,差异无显著性意义。结果显示,肠必清栓可显著减轻大鼠肠组织病理损伤促进组织修复,有效治疗实验大鼠UC。
为进一步研究肠必清栓治疗UC的作用机制,我们查阅大量的文献资料后,筛选出在UC发病及转归中起重要作用的细胞因子,包括在免疫调节中发挥重要作用的IL-1、TNF-α、IL-10,机体抗氧化系统的关键酶SOD,参与炎症及炎症因子转录的COX-2、NF-κBp65以及在组织损伤的修复中起重要调节作用的TGF-β1,通过检测肠必清栓治疗后这些细胞因子表达的变化,从细胞因子角度探讨其治疗UC的免疫学机理和抗炎、抗氧化作用机制,为肠必清栓治疗UC提供一定的实验基础和理论依据。细胞因子检测结果：模型组大鼠肠组织中IL-1β、TNF-α表达显著增多而IL-10显著减少,给药治疗可下调IL-1β、TNF-α的表达(P<0.01),提高组织中IL-10的表达量(P<0.01),肠必清栓低、中、高剂量组间呈剂量依赖关系,高剂量组与SASP组间差异无统计学差异；模型大鼠肠组织SOD仅少量表达,给药治疗可升高模型大鼠SOD的表达(P<0.01),肠必清栓中、高剂量组和SASP组与正常组间差异无显著性意义；模型组大鼠肠组织中COX-2、NF-κBp65和TGF-β1的表达明显增高(P<0.01)；与模型组比较,用肠必清栓治疗后,给药各组大鼠的COX-2、NF-κBp65和TGF-β1表达显著降低,肠必清栓低剂量组与中、高剂量组的COX-2、NF-κBp65和TGF-β1表达差异显著(P<0.01), SASP组的COX-2、NF-κBp65评分与肠必清栓低剂量组间差异无显著性意义,而TGF-β1评分与肠必清栓中、高剂量组相当,无统计学差异。细胞因子检测结果显示,肠必清栓可调节免疫、抗氧化、抗炎并促进组织修复,这可能为其治疗UC的作用机制。
The etiology of UC still remains incompletely understood, so far, more research continues to reveal the mechanism that UC is inflammation leaded by abnormal immune response which induced by intestine mucosal antigen with genetically susceptible people. with regards to this, In recent years, the treatment for UC is to adopt various methods mainly to focuse on the closure of mucosal inflammatory pathway, blocking the inflammatory process, so as to achieve the treatment goals. Studies have shown that, If we block the excessive immune response, or inhibit the certain cytokines, inflammatory mediators, may alleviate the condition. Meanwhile, the anti-inflammatory cytokine restrict the role of inflammation through the balance of pro-inflammatory cytokines in the progress of Immune response, the balance between was broken, can contribute to the occurrence of inflammation, therefore, if the activity of anti-inflammatory cytokines is increased,it can also alleviate the UC disease.ChangBiqing suppository was researched by our laborytory and is constituted by two kinds of materials with little side-effects but definite efficacy in anti-bacterial anti-inflammatory,4-amino-acid (4-ASA) and berberine based-hydrochloric (BBH).In this study, we treat thel UC model rats with ChangBiqing suppository, to investigate the effect of ChangBiqing suppository on ulcerative colitis in modle rats as well as on the expression of IL-1β、TNF-α、IL-10、SOD、COX-2、NF-κBp65 and TGF-β1 in colonic mucosa to reveal the possible mechanism for treatment.
To investigate the effect of ChangBiqing suppository on ulcerative colitis in modle rats. SD UC model rats induced by dinitrochlorobenzene (DNCB)and acetic acid were randomly divided into five groups from A to E:UC model group(A), low dose intervention group(B), moderate dose intervention group(C), large dose intervention group(D), SASP group(E), another six rats as normal control group(F) besides. The fresh colons of the rats were got and examined after 14 days of treatment, meanwhile the DAI, HPS and CI were evaluated. Results:DAI and HPS of the rats in the model group were significantly higher than the control group(P<0.01). Compared with the UC group, the DAI，HPS in group B to E decreased markedly(P<0.01), but they still differ significantly from the control group(P<0.01); The HPS decreased in a dose-dependent manner from B to D and group B differed significantly from group C and D(P<0.01). In contrast, no significant differences in HPS were observed among the three groups C, D and E. Conclusions：ChangBiqing suppository demonstrated good results in prevention and treatment on induced rat's UC.
To reveal the possible mechanism for treatment, we refer to a lot of literature information and Screened out some cytokines wich play an important role in the pathogenesis and healing of UC, included IL-1、TNF-αIL-10, which mainly regulate the immunity, SOD a cucial enzyme for antioxidant, COX-2 as inflammatory mediator, NF-icBp65 as transcription factor of Inflammatory cytokines and TGF-β1 which play an important role in regulating the repair of tissue injury. Observing the effect of ChangBiqing suppository on the expression of those cytokines in colonic mucosa of rats with ulcerative colitis to explore its therapeutic mechanism in immunology、anti-inflammatory and antioxidation, and provide some experimental basis and theoretical basis for ChangBiqing suppository in the treatment of UC. Results:The antigen expression of IL-1β、TNF-αin the model group were significantly higher(P<0.01) and expression of IL-10 was lower than the control group(P<0.01). Compared with the UC group, the expression of IL-1β、TNF-αin group B to E decreased markedly(P<0.01) and the expression of IL-10 increased significantly, and the change of cytokines were in a dose-dependent manner in group B to D; The antigen expression of SOD in the model group were significantly lower than the other groups(P<0.01), In contrast, no significant differences were observed among the four groups C, D,E and F; In modle rats with UC, the antigen expression of COX-2、NF-κBp65 and TGF-β1 were significantly higher(P<0.01) when compared with the control group.Compared with the UC group,the expression of COX-2、NF-κBp65 and TGF-β1 in group B to E decreased markedly(P<0.01) and in a dose-dependent manner in group B to D. In contrast, no significant differences in expression of COX-2 and NF-κBp65 were observed in group B and E as well as TGF-β1 in group C、D and E. Conclusions:ChangBiqing suppository can adjust immunization, anti-oxidation, anti-inflammatory and to promote tissue repair, this may be the mechanism for its treatment of UC.
引文
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