加味白头翁汤对溃疡性结肠炎大鼠治疗作用及其机制的实验研究
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摘要
目的:溃疡性结肠炎(UC)是一种病因尚未完全明确的慢性炎症性肠病,主要临床表现是持续或反复发作的腹泻、粘液脓血便、腹痛和里急后重,常缠绵难愈、反复发作,且与结肠癌关系密切。近年来,现代医学有关UC发病的免疫学机制受到广泛关注,并取得较大进展,但由于对本病的发病机制尚未完全明确,目前还没有疗效显著、副作用小的治疗药物。
加味白头翁汤是湖北中医学院邱明义教授在白头翁汤基础上加减组成的经验方,从多年的临床经验看,本方对UC具有良好的疗效。本课题组前期实验亦已证实,白头翁汤对UC大鼠模型具有较好的疗效。由此,我们拟在前期研究的基础上,通过建立UC大鼠模型来研究加味白头翁汤对UC的治疗作用及机理,特别是观察其对UC大鼠细胞因子、黏附因子的影响,以期深入揭示加味白头翁汤治疗UC的作用机制,为中医药治疗UC提供一定实验基础和理论依据,进而为揭示中医药治疗该病的基本规律取得突破打下基础,为临床用药提供理论指导。
方法:将84只SD健康大鼠(雌雄各半),随机分6组,每组14只(雌雄各半),各组体重统计学比较无显著性差异(P＞0.05)。第1、2、3、4、5组为造模组,分别为加味白头翁汤大剂量组、加味白头翁汤中剂量组、加味白头翁汤小剂量组、SASP组和模型组,第6组为正常组。除正常对照组外,其余5个组均采用免疫加局部刺激(2,4二硝基氯苯加醋酸)复合法,复制UC大鼠模型。模型成功后,分别以加味白头翁汤大、中、小剂量、SASP、蒸馏水灌胃治疗15天,然后观察UC大鼠一般状况的变化和结肠病理改变情况,用免疫组化法检测病变结肠粘膜局部免疫指标IL-8、IL-13、CD44、CD54。
结果:(1)模型组大鼠可见粘液稀便及脓血便、消瘦、懒动、畏寒、毛发无光泽、食欲减退、体重减轻、结肠组织损伤积分增加。其中,体重、结肠组织损伤积分与正常对照组比较,差异有显著性(P＜0.01)。治疗后,各治疗组大鼠症状均有不同程度改善,各治疗组大鼠体重、结肠组织损伤积分与模型组比较差异有显著性(P＜0.01)。各治疗组中,加味白头翁汤大剂量组效果最好(结肠组织损伤积分与SASP组比较,P＜0.01),加味白头翁汤中剂量组与SASP组相当(结肠组织损伤积分相互比较,P＞0.05)。病理切片显示:在结肠粘膜上皮缺损情况、腺体排列是否规则、粘膜充血状况、炎细胞浸润等方面,模型组与正常对照组比较,有明显的差异;加味白头翁汤各组、SASP组与模型组比较,有明显的差异。
(2)模型组大鼠结肠组织中IL-8含量高于正常对照组(P＜0.01),IL-13含量低于正常组(P＜0.01)。治疗后,各治疗组大鼠结肠组织中IL-8低于模型组(P＜0.01),IL-13高于模型组(P＜0.01)。各治疗组中,加味白头翁汤大剂量组效果最好(IL-8、IL-13含量与SASP组比较,P＜0.01),加味白头翁汤中剂量组与SASP组相当(IL-8、IL-13与SASP组比较,P＞0.05)。
(3)模型组大鼠结肠组织中CD44、CD54含量高于正常组(P＜0.01)。治疗后,各治疗组大鼠结肠组织中CD44、CD54低于模型组(P＜0.01)。各治疗组中,加味白头翁汤大剂量组效果最好(CD44、CD54含量与SASP组比较,P＜0.01),加味白头翁汤中剂量组与SASP组相当(CD44、CD54与SASP组比较,P＞0.05)。
结论:以上实验结果表明:(1)该实验造模是成功的。(2)、细胞因子IL-8、IL-13均参与UC形成,溃疡性结肠炎肠组织中IL-8升高而IL-13降低;加味白头翁汤通过降低IL-8、升高IL-13来调节UC结肠粘膜异常的免疫反应。(3)黏附因子CD44、CD54参与UC形成,溃疡性结肠炎肠组织中CD44、CD54均升高;加味白头翁汤通过降低黏附因子CD44、CD54来调节UC结肠粘膜异常的免疫反应。(4)加味白头翁汤对UC有良好的治疗作用。
Objective:Ulcerative colitis(UC)is an idiopathic chronic inflammatory bowel disease(IBD).Its main manifestations are diarrhea,bloody mucopurulent stool,abdominal pain and tenesmus,which is lingering difficult to cure and repeated attack.UC is regarded as in close relation with the occurrence of colon carcinoma.In recent years,the immunological mechanism of the pathogenesis of UC in modem medicine has attracted a wide spread attention and made much progress.But because the pathogenesis of UC is not completely clear,there is not one kind of treatment medicine of remarkable curative effect and small side effect at present.
Modified BaiTouWeng decoction is professor Qiu Mingyi's experienced prescription based on BaiTouWeng decoction.According to many years' clinical experiences,it has good curative effect on UC.It has been proved by the previous experiments of our team that BaiTouWeng decoction has good curative effect on UC model rats.Thus,we plan to study the therapeutic effect and mechanism of modified BaiTouWeng decoction treating UC by setting up UC rat model,especially we observe modified BaiTouWeng decoction to affect Expression of cytokine and adhesion molecule on basis of previous research,which reveals deeply the action mechanism of modified BaiTouWeng decoction treating UC.That can provide some experimental basement and theoretical evidence for traditional Chinese medicine (TCM)treating UC,and then lay a foundation for revealing the basic rule of TCM treating UC to make the breakthrough,which can provide the theory instruction for the clinical medication.
Methods:In the experiment,eighty four SD class healthy rats were randomly divided into six groups.Every group had fourteen rats(seven rats were male,seven rats were female),which there was no significant difference in the rats' weight between each group(P＞0.05).The first group,the second one,the third one, the fourth one and the fifth one was the high dose group of modified BaiTouWeng decoction,the medium dose group of modified BaiTouWeng decoction,the low dose group of modified BaiTouWeng decoction,the SASP group and the model group respectively,and the sixth group is the normal group.Except the normal group,the other five groups were made through the integration of general immunity and local stimulation(DNCB and acetic acid)to create the rat model of UC.After the model was successful,the six groups were used the high,medium and low dose of modified BaiTouWeng decoction,SASP and distilled water respectively to treat by gastric perfusion in 15 days.Then we observed the changes in general status and pathological changes in colon tissue of UC model rats.The expression of local immunological index such as IL-8、IL-13、CD44、CD54 in lesions of colon mucosa were detected with immunohistochemical method.
Results:(1)The rats in the model group can been observed the changes such as mucus dilute stool and bloody purulent stool,emaciation,laziness,intolerance of cold,no luster in hair,poor appetite,loss of weight and increase of colonic damage scores.Among them,compared with the normal group,there was more significant difference in the weight and colonic damage scores in the model group(P＜0.01).After treatment,there was some improvement in different degree in symptoms in every treatment group.Compared with the normal group,there was more significant difference in the weight and colonic damage scores in every treatment group(P＜0.01).Among the treatment groups,the best effect was the high dose group of modified BaiYouWeng decoction(compared with the SASP group in colonic damage scores,P＜0.01);the effect of the medium dose group of modified BaiTouWeng decoction was equivalent to that of the SASP group(compared with the SASP group in colonic damage scores,P＞0.05).The pathological section showed that:there was more difference in local loss of colonic mucous membrane,gland arrangement being regular or not,mucosa hyperemia and inflammatory cell infiltration and so on between the model group and the normal control group.Meanwhile,compared with the model group,there was also more difference in those in the three modified BaiTouWeng decoction groups and the SASP group.
(2)The level of IL-8 in rats' colon tissue in the model group was significantly higher than that in normal group(P＜0.01);the level of IL-13 in rats' colon tissue in the model group was significantly lower than that in normal group(P＜0.01).After treatment,the level of IL-8 in rats' colon tissue in every treatment group was significantly lower than that in the model group(P＜0.01);the level of IL-13 in rats' colon tissue in every treatment group was significantly higher than that in model group(P＜0.01).Among the treatment groups,the best effect was the high dose group of modified BaiTouWeng decoction(compared with the SASP group in the level of IL-8 and IL-13,P＜0.01);the effect of the medium dose group of modified BaiTouWeng decoction was equivalent to that of the SASP group(compared with the SASP group in the level of IL-8 and IL-13,P＞0.05).
(3)The level of CD44 and CD54 in rats' colon tissue in the model group was significantly higher than that in normal group(P＜0.01).After treatment,the level of CD44 and CD54 in rats' colon tissue in every treatment group was significantly lower than that in the model group(P＜0.01).Among the treatment groups,the best effect was the high dose group of modified BaiTouWeng decoction(compared with the SASP group in the level of CD44 and CD54,P＜0.01);the effect of the medium dose group of modified BaiTouWeng decoction was equivalent to that of the SASP group (compared with the SASP group in the level of CD44 and CD54,P＞0.05).
Conclusion:The result of the experiments above shows that(1)This model made with DNCB and acetic acid is successful.(2)It is obvious that IL-8 and IL-13 are important role on UC,which the level of IL-8 increases and that of IL-13 decreases in colonic mucosa of UC.Modified BaiTouWeng decoction can regulate the abnormal immune response by decreasing the level of IL-8 and increasing the level of IL-13 in colonic mucosa of UC.(3)It is obvious that CD44 and CD54 are important role on UC,which the level of CD44 and CD54 increases in colonic mucosa of UC. Modified BaiTouWeng decoction can regulate the abnormal immune response by decreasing the level of CD44 and CD54 in colonic mucosa of UC.(4)Modified BaiTouWeng decoction has the better curative effect on UC.
加味白头翁汤是湖北中医学院邱明义教授在白头翁汤基础上加减组成的经验方,从多年的临床经验看,本方对UC具有良好的疗效。本课题组前期实验亦已证实,白头翁汤对UC大鼠模型具有较好的疗效。由此,我们拟在前期研究的基础上,通过建立UC大鼠模型来研究加味白头翁汤对UC的治疗作用及机理,特别是观察其对UC大鼠细胞因子、黏附因子的影响,以期深入揭示加味白头翁汤治疗UC的作用机制,为中医药治疗UC提供一定实验基础和理论依据,进而为揭示中医药治疗该病的基本规律取得突破打下基础,为临床用药提供理论指导。
方法:将84只SD健康大鼠(雌雄各半),随机分6组,每组14只(雌雄各半),各组体重统计学比较无显著性差异(P＞0.05)。第1、2、3、4、5组为造模组,分别为加味白头翁汤大剂量组、加味白头翁汤中剂量组、加味白头翁汤小剂量组、SASP组和模型组,第6组为正常组。除正常对照组外,其余5个组均采用免疫加局部刺激(2,4二硝基氯苯加醋酸)复合法,复制UC大鼠模型。模型成功后,分别以加味白头翁汤大、中、小剂量、SASP、蒸馏水灌胃治疗15天,然后观察UC大鼠一般状况的变化和结肠病理改变情况,用免疫组化法检测病变结肠粘膜局部免疫指标IL-8、IL-13、CD44、CD54。
结果:(1)模型组大鼠可见粘液稀便及脓血便、消瘦、懒动、畏寒、毛发无光泽、食欲减退、体重减轻、结肠组织损伤积分增加。其中,体重、结肠组织损伤积分与正常对照组比较,差异有显著性(P＜0.01)。治疗后,各治疗组大鼠症状均有不同程度改善,各治疗组大鼠体重、结肠组织损伤积分与模型组比较差异有显著性(P＜0.01)。各治疗组中,加味白头翁汤大剂量组效果最好(结肠组织损伤积分与SASP组比较,P＜0.01),加味白头翁汤中剂量组与SASP组相当(结肠组织损伤积分相互比较,P＞0.05)。病理切片显示:在结肠粘膜上皮缺损情况、腺体排列是否规则、粘膜充血状况、炎细胞浸润等方面,模型组与正常对照组比较,有明显的差异;加味白头翁汤各组、SASP组与模型组比较,有明显的差异。
(2)模型组大鼠结肠组织中IL-8含量高于正常对照组(P＜0.01),IL-13含量低于正常组(P＜0.01)。治疗后,各治疗组大鼠结肠组织中IL-8低于模型组(P＜0.01),IL-13高于模型组(P＜0.01)。各治疗组中,加味白头翁汤大剂量组效果最好(IL-8、IL-13含量与SASP组比较,P＜0.01),加味白头翁汤中剂量组与SASP组相当(IL-8、IL-13与SASP组比较,P＞0.05)。
(3)模型组大鼠结肠组织中CD44、CD54含量高于正常组(P＜0.01)。治疗后,各治疗组大鼠结肠组织中CD44、CD54低于模型组(P＜0.01)。各治疗组中,加味白头翁汤大剂量组效果最好(CD44、CD54含量与SASP组比较,P＜0.01),加味白头翁汤中剂量组与SASP组相当(CD44、CD54与SASP组比较,P＞0.05)。
结论:以上实验结果表明:(1)该实验造模是成功的。(2)、细胞因子IL-8、IL-13均参与UC形成,溃疡性结肠炎肠组织中IL-8升高而IL-13降低;加味白头翁汤通过降低IL-8、升高IL-13来调节UC结肠粘膜异常的免疫反应。(3)黏附因子CD44、CD54参与UC形成,溃疡性结肠炎肠组织中CD44、CD54均升高;加味白头翁汤通过降低黏附因子CD44、CD54来调节UC结肠粘膜异常的免疫反应。(4)加味白头翁汤对UC有良好的治疗作用。
Objective:Ulcerative colitis(UC)is an idiopathic chronic inflammatory bowel disease(IBD).Its main manifestations are diarrhea,bloody mucopurulent stool,abdominal pain and tenesmus,which is lingering difficult to cure and repeated attack.UC is regarded as in close relation with the occurrence of colon carcinoma.In recent years,the immunological mechanism of the pathogenesis of UC in modem medicine has attracted a wide spread attention and made much progress.But because the pathogenesis of UC is not completely clear,there is not one kind of treatment medicine of remarkable curative effect and small side effect at present.
Modified BaiTouWeng decoction is professor Qiu Mingyi's experienced prescription based on BaiTouWeng decoction.According to many years' clinical experiences,it has good curative effect on UC.It has been proved by the previous experiments of our team that BaiTouWeng decoction has good curative effect on UC model rats.Thus,we plan to study the therapeutic effect and mechanism of modified BaiTouWeng decoction treating UC by setting up UC rat model,especially we observe modified BaiTouWeng decoction to affect Expression of cytokine and adhesion molecule on basis of previous research,which reveals deeply the action mechanism of modified BaiTouWeng decoction treating UC.That can provide some experimental basement and theoretical evidence for traditional Chinese medicine (TCM)treating UC,and then lay a foundation for revealing the basic rule of TCM treating UC to make the breakthrough,which can provide the theory instruction for the clinical medication.
Methods:In the experiment,eighty four SD class healthy rats were randomly divided into six groups.Every group had fourteen rats(seven rats were male,seven rats were female),which there was no significant difference in the rats' weight between each group(P＞0.05).The first group,the second one,the third one, the fourth one and the fifth one was the high dose group of modified BaiTouWeng decoction,the medium dose group of modified BaiTouWeng decoction,the low dose group of modified BaiTouWeng decoction,the SASP group and the model group respectively,and the sixth group is the normal group.Except the normal group,the other five groups were made through the integration of general immunity and local stimulation(DNCB and acetic acid)to create the rat model of UC.After the model was successful,the six groups were used the high,medium and low dose of modified BaiTouWeng decoction,SASP and distilled water respectively to treat by gastric perfusion in 15 days.Then we observed the changes in general status and pathological changes in colon tissue of UC model rats.The expression of local immunological index such as IL-8、IL-13、CD44、CD54 in lesions of colon mucosa were detected with immunohistochemical method.
Results:(1)The rats in the model group can been observed the changes such as mucus dilute stool and bloody purulent stool,emaciation,laziness,intolerance of cold,no luster in hair,poor appetite,loss of weight and increase of colonic damage scores.Among them,compared with the normal group,there was more significant difference in the weight and colonic damage scores in the model group(P＜0.01).After treatment,there was some improvement in different degree in symptoms in every treatment group.Compared with the normal group,there was more significant difference in the weight and colonic damage scores in every treatment group(P＜0.01).Among the treatment groups,the best effect was the high dose group of modified BaiYouWeng decoction(compared with the SASP group in colonic damage scores,P＜0.01);the effect of the medium dose group of modified BaiTouWeng decoction was equivalent to that of the SASP group(compared with the SASP group in colonic damage scores,P＞0.05).The pathological section showed that:there was more difference in local loss of colonic mucous membrane,gland arrangement being regular or not,mucosa hyperemia and inflammatory cell infiltration and so on between the model group and the normal control group.Meanwhile,compared with the model group,there was also more difference in those in the three modified BaiTouWeng decoction groups and the SASP group.
(2)The level of IL-8 in rats' colon tissue in the model group was significantly higher than that in normal group(P＜0.01);the level of IL-13 in rats' colon tissue in the model group was significantly lower than that in normal group(P＜0.01).After treatment,the level of IL-8 in rats' colon tissue in every treatment group was significantly lower than that in the model group(P＜0.01);the level of IL-13 in rats' colon tissue in every treatment group was significantly higher than that in model group(P＜0.01).Among the treatment groups,the best effect was the high dose group of modified BaiTouWeng decoction(compared with the SASP group in the level of IL-8 and IL-13,P＜0.01);the effect of the medium dose group of modified BaiTouWeng decoction was equivalent to that of the SASP group(compared with the SASP group in the level of IL-8 and IL-13,P＞0.05).
(3)The level of CD44 and CD54 in rats' colon tissue in the model group was significantly higher than that in normal group(P＜0.01).After treatment,the level of CD44 and CD54 in rats' colon tissue in every treatment group was significantly lower than that in the model group(P＜0.01).Among the treatment groups,the best effect was the high dose group of modified BaiTouWeng decoction(compared with the SASP group in the level of CD44 and CD54,P＜0.01);the effect of the medium dose group of modified BaiTouWeng decoction was equivalent to that of the SASP group (compared with the SASP group in the level of CD44 and CD54,P＞0.05).
Conclusion:The result of the experiments above shows that(1)This model made with DNCB and acetic acid is successful.(2)It is obvious that IL-8 and IL-13 are important role on UC,which the level of IL-8 increases and that of IL-13 decreases in colonic mucosa of UC.Modified BaiTouWeng decoction can regulate the abnormal immune response by decreasing the level of IL-8 and increasing the level of IL-13 in colonic mucosa of UC.(3)It is obvious that CD44 and CD54 are important role on UC,which the level of CD44 and CD54 increases in colonic mucosa of UC. Modified BaiTouWeng decoction can regulate the abnormal immune response by decreasing the level of CD44 and CD54 in colonic mucosa of UC.(4)Modified BaiTouWeng decoction has the better curative effect on UC.
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