小型猪痰瘀互结证冠心病模型的病理学研究及中药方剂的干预作用
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摘要
冠心病是危害中、老年人的严重疾病之一,在许多国家和地区的发病率和死亡率都很高,已成为严重危害人类健康的疾病。因此,抗冠心病药物的研究在世界各国日益受到重视。我国传统方药对冠心病保护作用的研究也日益受到重视。
对冠心病的研究,建立理想的动物模型必不可少。本实验室选用中国实验小型猪采用介入法球囊拉伤冠状动脉左前降支配合高脂饲料喂养,获得痰瘀互结证冠心病模型,其病理过程与人类极相似。
本实验室在中国小型猪痰瘀互结证冠心病模型上,选用瓜蒌薤白半夏汤合血府逐瘀汤作为痰瘀同治方、瓜蒌薤白半夏汤作为化痰方、血府逐瘀汤作为祛痰方进行治疗,对此模型给予三种不同的传统方药,探讨了方证相应理论的规律与本质(详见李欣志博士论文)。本实验在此基础上,对此模型的冠状血管损伤节段和梗死交界区心肌,进行病理形态学分析;并观察传统方药对冠状动脉及心肌的病理形态学的干预作用。并观察心肌凋亡细胞及bax、bcl—2、caspase-3、caspase-9表达在模型中的变化,并观察传统方药对心肌凋亡细胞及bax、bcl—2、caspase-3、caspase-9表达的干预作用。
材料和方法:
30只中国实验小型猪(Chinese experimental miniature swine,CEMS)随机分为6组:(1)正常对照组(Con):普通饲料,不拉伤冠状血管,n=5;(2)痰瘀互结证候模型组(Model):冠状动脉拉伤+高脂饲料,n=5;(3)西药对照组(XY):冠状动脉拉伤+高脂饲料+辛伐他汀0.5mg/kg,n=5;(4)化痰组(HT):冠状动脉拉伤+高脂饲料+瓜蒌薤白半夏汤6g生药/kg,n=5;(5)祛瘀组(QY):冠状动脉拉伤+高脂饲料+血府逐瘀汤8g生药/kg,n=5;(6)痰瘀同治组(TY):冠状动脉拉伤+高脂饲料+瓜蒌薤白半夏汤3g生药/kg合血府逐瘀汤4g生药/kg,n=5。冠状动脉拉伤后第2天开始给药,同时继续喂养高脂饲料,持续8周。
实验结束后,取实验各组的冠状血管损伤节段和梗死交界区心肌制成石蜡切片。用H.E染色法、弹力纤维EVG染色法、计算机图像分析系统、用SPSS11.5统计软件对受损血管管腔内膜增生及狭窄情况进行形态学观察、数据测量和数据统计分析;用H.E染色法和Masson三色染色法对受累心肌进行形态学分析。用TUNEL标记法识别心肌凋亡细胞,用免疫组织化学染色法表达bax、bcl—2基因蛋白和caspase-3、caspase-9蛋白酶,观察心肌凋亡细胞及bax、bcl—2、caspase-3、caspase-9表达在模型中的变化,并观察中药方剂对心肌细胞凋亡及bax、bcl—2、caspase-3、caspase-9表达的影响。
结果:
1、模型组冠状动脉管腔出现不同程度的偏心性狭窄,与对照组相比,差异极显著(P＜0.01)。各给药组冠状动脉管腔仍有不同程度的狭窄,但与模型组有显著减轻,其中化痰组、祛瘀组、痰瘀同治组有极显著差异(P＜0.01),西药组有明显差异(P＜0.05)。
2.模型组心肌内可见大片状心肌纤维断裂缺失,并被纤维组织填充替代,部分伴灶状肌纤维变性坏死、脂肪浸润及少数炎性细胞浸润,与对照组相比,差异极显著(P＜0.01)。各给药组,较模型组有明显减轻,其中化痰组、西药组有极显著差异(P＜0.01),祛瘀组、痰瘀同治组有明显差异(P＜0.05)。
3.用计算机图像分析软件测量冠状动脉并进行统计学分析发现:模型组管腔与对照组管腔相比显著狭窄(P＜0.01);模型组的管腔最大内膜厚度与对照组相比明显增厚(P＜0.01);模型组的管腔最大内膜厚度与中膜厚度的比值明显大于对照组(P＜0.01)。各给药组冠状动脉管腔狭窄程度明显轻于模型组(P＜0.01);各给药组的管腔最大内膜厚度明显比模型组薄(P＜0.01);各给药组的管腔最大内膜厚度与中膜厚度的比值显著小于模型组(P＜0.01)。
4.模型组bcl-2基因蛋白表达和bcl-2/bax的比值均明显低于对照组(P＜0.01),bax基因蛋白表达比对照组明显增强(P＜0.01);痰瘀同治组bcl-2基因蛋白表达和bcl-2/bax的比值均显著高于模型组(P＜0.01),bax基因蛋白表达较模型组显著降低(P＜0.01)。
5.模型组caspase-3、caspase-9表达均明显比对照组增强(P＜0.01);痰瘀同治组caspase-3、caspase-9表达均显著低于模型组(P＜0.01)。
6.TUNEL法检测各组心肌细胞凋亡情况:对照组、模型组及痰瘀同治组的凋亡指数(apoptosis index,AI)分别为0.92%、27.68%及17.28%,模型组和痰瘀同治组的凋亡细胞数均比对照组的多,凋亡指数均大于对照组(P＜0.01);模型组和痰瘀同治组相比,前者的凋亡细胞数明显多于后者且凋亡指数也大于后者(P＜0.01)。
结论
1.从病理学角度证实了中国小型猪痰瘀互结证冠心病模型的成立。
2.传统方药对痰瘀互结证冠心病模型有明显的防治效果。
3.传统方药对缺血心肌凋亡细胞有明显的保护作用。
Coronary heart disease is a severe disease to the adult,which has very high incidence and death rate in many countries and regions.Therefore,the development of drugs for coronary heart disease has been considered as the priority all over the world.More and more attention has been paid to the traditional Chinese medicine with regard to protecting coronary heart disease.
To study coronary heart disease,it is necessary to establish an ideal animal model. Chinese experimental miniature swine were used to establish the disease-syndrome integrated models with the syndrome of phlegm and stagnated blood by high fat diet with coronary artery injury in the Experiment Research Center of Xiyuan Hospital,the pathological changes of the models are similar to Man's.
To study the rule and nature of Fang-Zheng correlation theory,the model animals had been fed with three sorts of traditional Chinese medicinal formulae,which were Gualou Xiebai Banxia Tang as Hua Tan Fang,Xuefu Zhuyu Tang as Qu Yu Fang and Gualou Xiebai Banxia Tang plus Xuefu Zhuyu Tang as Tan Yu Tong Zhi Fang.Based on the diseased animal models and experimental researches,the current research aims to observe the histomorphology and structure of coronary artery injured and infracted myocardium,and to study the effects of traditional Chinese medicinal formulae.The present paper also investigated the change of myocardial apoptosis cells and expression of Bax,bcl-2,Caspase-3 and Caspase-9 of each group during the disease and the effect of traditional Chinese medicinal formulae was intensively evaluated.
Materials and Methods
Thirty Chinese experimental miniature swine(CEMS) were randomly divided into six groups:(1)Control group(Con),ordinary diet without coronary artery injury;n=5;(2)Phlegm and stagnated blood model group(Model),high fat diet with coronary artery injury,n=5; (3)Western Medicine group(XY),high fat diet with coronary artery injury plus Simvastatin 0.5mg/kg,n=5;(4)Hua Tan group(HT),high fat diet with coronary artery injury plus Guolou Xiebai Banxia Tang,6g raw herb/kg,n=5;(5)Qu Yu Group(QY),high fat diet with coronary artery injury plus Xuefu Zhuyu Tang,8g raw herb/kg,n=5;(6)Tan Yu Tong Zhi group(TY), high fat diet with coronary artery injury plus Guolou Xiebai Banxia Tang,3g raw herb/kg plus Xuefu Zhuyu Tang,4g raw herb/kg,n=5.After the surgical operation and on the second day, the animals were continuously fed with high fat diet for 8 weeks.
The coronary artery injured and infracted juncture myocardium was made into paraffin section after the experiment was over.The histomorphology and structure on coronary artery injured was observed through the HE stain,EVG stain and computer imagine analysis,and the detected data were analyzed with the software of the SPSS 11.5.The histomorphology and structure on infract juncture myocardium was analyzed through the HE stain and Masson stain.To investigate the Myocardial apoptosis cells of each group,situ TDT-mediate dUTP nick end labeling(TUNEL),bax,bcl-2,caspase-3 and caspase-9 in immunohistochemical staining were introduced into the study.Meanwhile we study the effect of traditional Chinese medicinal formulae on myocardial apoptosis cells and the expression ofbax,bcl-2,caspase-3 and caspase-9 in the diseased animal models.
Results
1.Compared with the control group,the lumens of coronary artery had eccentrically narrow to some different extent in the model group with significant difference(P＜0.01).The lumens of coronary artery were narrow in each treatment group.But compared with the model group,the very significant difference existed in HT group,QY group and TY group(P＜0.01), the significant difference existed in XY group(P＜0.05).
2.Cardiac muscle fibers in model group were showed to be broken and lost in a lamellar manner,and the region was replaced with fibrous tissue,with focus cardiac muscle fiber degeneration and necrosis,fatty infiltration and inflammatory cell infiltration.Compared with the control group,the very significant difference existed in model group(P＜0.01).Compared with the model group,the cardiac muscle pathological changes had significant relief,the very significant difference existed in HT group and XY group(P＜0.01),the significant difference existed in QY group and TY group(P＜0.05).
3.When the coronary artery injured was analyzed through the computer imagine analysis, the results were as follow:the lumens of coronary artery became significantly narrow (P＜0.01),and the max intimate thickness of the coronary artery have been obviously increased in the model(P＜0.01),compared with the control group.The proportion of the max intimate and tunica media thickness in model group was significantly larger than that of control group(P＜0.01).The narrow degree of coronary artery in each treatment group was significantly lighter than that of model group(P＜0.01).The max intimate thickness of the coronary artery in each treatment group was significantly less than that of model group (P＜0.01).The proportion of the max intimate and tunica media thickness in each treatment group was significantly less than that of model group(P＜0.01).
4.The results of immunohistochemistry showed that light density ofbcl-2 and bcl-2/bax in model group was significantly less than that of control group(P＜0.01),light density of bax in model group was significantly more than that of control group(P＜0.01).The results showed that light density of bcl-2 and bcl-2/bax in TY group was significantly more than that of model group(P＜0.01),light density ofbax in TY group was significantly less than that of model group(P＜0.01).
5.The positive expressions of caspase-3 and caspase-9 in model group were significantly more than that of control group(P＜0.01),The positive expressions of caspase-3 and caspase-9 in TY group were significantly less than that of model group(P＜0.01).
6.Myocardial apoptosis index of each group was determined by TUNEL,the results showed that apoptosis indexes in control group,model group and TY group were respectively 0.92%,27.68%and 17.28%.The numbers of positive Myocardial cells and myocardial apoptosis index in model group and TY group were significantly more than these of control group(P＜0.01).The results showed that the numbers of positive myocardial cells and Myocardial apoptosis index in model group were significantly more than these of TY group (P＜0.01).
Conclusion
1.It was confirmed through pathological methods that the establishment of Chinese miniature swine model with coronary heart diseases and the syndrome of phlegm and stagnated blood was successful.
2.The coronary heart diseases and the syndrome of phlegm and stagnated blood in the Chinese miniature swine model could be prevented and cured effectively by the traditional Chinese medicinal formulae.
3.The ischemic myocardial apoptosis cells in the Chinese miniature swine model could be protected effectively by the traditional Chinese medicinal formulae.
对冠心病的研究,建立理想的动物模型必不可少。本实验室选用中国实验小型猪采用介入法球囊拉伤冠状动脉左前降支配合高脂饲料喂养,获得痰瘀互结证冠心病模型,其病理过程与人类极相似。
本实验室在中国小型猪痰瘀互结证冠心病模型上,选用瓜蒌薤白半夏汤合血府逐瘀汤作为痰瘀同治方、瓜蒌薤白半夏汤作为化痰方、血府逐瘀汤作为祛痰方进行治疗,对此模型给予三种不同的传统方药,探讨了方证相应理论的规律与本质(详见李欣志博士论文)。本实验在此基础上,对此模型的冠状血管损伤节段和梗死交界区心肌,进行病理形态学分析;并观察传统方药对冠状动脉及心肌的病理形态学的干预作用。并观察心肌凋亡细胞及bax、bcl—2、caspase-3、caspase-9表达在模型中的变化,并观察传统方药对心肌凋亡细胞及bax、bcl—2、caspase-3、caspase-9表达的干预作用。
材料和方法:
30只中国实验小型猪(Chinese experimental miniature swine,CEMS)随机分为6组:(1)正常对照组(Con):普通饲料,不拉伤冠状血管,n=5;(2)痰瘀互结证候模型组(Model):冠状动脉拉伤+高脂饲料,n=5;(3)西药对照组(XY):冠状动脉拉伤+高脂饲料+辛伐他汀0.5mg/kg,n=5;(4)化痰组(HT):冠状动脉拉伤+高脂饲料+瓜蒌薤白半夏汤6g生药/kg,n=5;(5)祛瘀组(QY):冠状动脉拉伤+高脂饲料+血府逐瘀汤8g生药/kg,n=5;(6)痰瘀同治组(TY):冠状动脉拉伤+高脂饲料+瓜蒌薤白半夏汤3g生药/kg合血府逐瘀汤4g生药/kg,n=5。冠状动脉拉伤后第2天开始给药,同时继续喂养高脂饲料,持续8周。
实验结束后,取实验各组的冠状血管损伤节段和梗死交界区心肌制成石蜡切片。用H.E染色法、弹力纤维EVG染色法、计算机图像分析系统、用SPSS11.5统计软件对受损血管管腔内膜增生及狭窄情况进行形态学观察、数据测量和数据统计分析;用H.E染色法和Masson三色染色法对受累心肌进行形态学分析。用TUNEL标记法识别心肌凋亡细胞,用免疫组织化学染色法表达bax、bcl—2基因蛋白和caspase-3、caspase-9蛋白酶,观察心肌凋亡细胞及bax、bcl—2、caspase-3、caspase-9表达在模型中的变化,并观察中药方剂对心肌细胞凋亡及bax、bcl—2、caspase-3、caspase-9表达的影响。
结果:
1、模型组冠状动脉管腔出现不同程度的偏心性狭窄,与对照组相比,差异极显著(P＜0.01)。各给药组冠状动脉管腔仍有不同程度的狭窄,但与模型组有显著减轻,其中化痰组、祛瘀组、痰瘀同治组有极显著差异(P＜0.01),西药组有明显差异(P＜0.05)。
2.模型组心肌内可见大片状心肌纤维断裂缺失,并被纤维组织填充替代,部分伴灶状肌纤维变性坏死、脂肪浸润及少数炎性细胞浸润,与对照组相比,差异极显著(P＜0.01)。各给药组,较模型组有明显减轻,其中化痰组、西药组有极显著差异(P＜0.01),祛瘀组、痰瘀同治组有明显差异(P＜0.05)。
3.用计算机图像分析软件测量冠状动脉并进行统计学分析发现:模型组管腔与对照组管腔相比显著狭窄(P＜0.01);模型组的管腔最大内膜厚度与对照组相比明显增厚(P＜0.01);模型组的管腔最大内膜厚度与中膜厚度的比值明显大于对照组(P＜0.01)。各给药组冠状动脉管腔狭窄程度明显轻于模型组(P＜0.01);各给药组的管腔最大内膜厚度明显比模型组薄(P＜0.01);各给药组的管腔最大内膜厚度与中膜厚度的比值显著小于模型组(P＜0.01)。
4.模型组bcl-2基因蛋白表达和bcl-2/bax的比值均明显低于对照组(P＜0.01),bax基因蛋白表达比对照组明显增强(P＜0.01);痰瘀同治组bcl-2基因蛋白表达和bcl-2/bax的比值均显著高于模型组(P＜0.01),bax基因蛋白表达较模型组显著降低(P＜0.01)。
5.模型组caspase-3、caspase-9表达均明显比对照组增强(P＜0.01);痰瘀同治组caspase-3、caspase-9表达均显著低于模型组(P＜0.01)。
6.TUNEL法检测各组心肌细胞凋亡情况:对照组、模型组及痰瘀同治组的凋亡指数(apoptosis index,AI)分别为0.92%、27.68%及17.28%,模型组和痰瘀同治组的凋亡细胞数均比对照组的多,凋亡指数均大于对照组(P＜0.01);模型组和痰瘀同治组相比,前者的凋亡细胞数明显多于后者且凋亡指数也大于后者(P＜0.01)。
结论
1.从病理学角度证实了中国小型猪痰瘀互结证冠心病模型的成立。
2.传统方药对痰瘀互结证冠心病模型有明显的防治效果。
3.传统方药对缺血心肌凋亡细胞有明显的保护作用。
Coronary heart disease is a severe disease to the adult,which has very high incidence and death rate in many countries and regions.Therefore,the development of drugs for coronary heart disease has been considered as the priority all over the world.More and more attention has been paid to the traditional Chinese medicine with regard to protecting coronary heart disease.
To study coronary heart disease,it is necessary to establish an ideal animal model. Chinese experimental miniature swine were used to establish the disease-syndrome integrated models with the syndrome of phlegm and stagnated blood by high fat diet with coronary artery injury in the Experiment Research Center of Xiyuan Hospital,the pathological changes of the models are similar to Man's.
To study the rule and nature of Fang-Zheng correlation theory,the model animals had been fed with three sorts of traditional Chinese medicinal formulae,which were Gualou Xiebai Banxia Tang as Hua Tan Fang,Xuefu Zhuyu Tang as Qu Yu Fang and Gualou Xiebai Banxia Tang plus Xuefu Zhuyu Tang as Tan Yu Tong Zhi Fang.Based on the diseased animal models and experimental researches,the current research aims to observe the histomorphology and structure of coronary artery injured and infracted myocardium,and to study the effects of traditional Chinese medicinal formulae.The present paper also investigated the change of myocardial apoptosis cells and expression of Bax,bcl-2,Caspase-3 and Caspase-9 of each group during the disease and the effect of traditional Chinese medicinal formulae was intensively evaluated.
Materials and Methods
Thirty Chinese experimental miniature swine(CEMS) were randomly divided into six groups:(1)Control group(Con),ordinary diet without coronary artery injury;n=5;(2)Phlegm and stagnated blood model group(Model),high fat diet with coronary artery injury,n=5; (3)Western Medicine group(XY),high fat diet with coronary artery injury plus Simvastatin 0.5mg/kg,n=5;(4)Hua Tan group(HT),high fat diet with coronary artery injury plus Guolou Xiebai Banxia Tang,6g raw herb/kg,n=5;(5)Qu Yu Group(QY),high fat diet with coronary artery injury plus Xuefu Zhuyu Tang,8g raw herb/kg,n=5;(6)Tan Yu Tong Zhi group(TY), high fat diet with coronary artery injury plus Guolou Xiebai Banxia Tang,3g raw herb/kg plus Xuefu Zhuyu Tang,4g raw herb/kg,n=5.After the surgical operation and on the second day, the animals were continuously fed with high fat diet for 8 weeks.
The coronary artery injured and infracted juncture myocardium was made into paraffin section after the experiment was over.The histomorphology and structure on coronary artery injured was observed through the HE stain,EVG stain and computer imagine analysis,and the detected data were analyzed with the software of the SPSS 11.5.The histomorphology and structure on infract juncture myocardium was analyzed through the HE stain and Masson stain.To investigate the Myocardial apoptosis cells of each group,situ TDT-mediate dUTP nick end labeling(TUNEL),bax,bcl-2,caspase-3 and caspase-9 in immunohistochemical staining were introduced into the study.Meanwhile we study the effect of traditional Chinese medicinal formulae on myocardial apoptosis cells and the expression ofbax,bcl-2,caspase-3 and caspase-9 in the diseased animal models.
Results
1.Compared with the control group,the lumens of coronary artery had eccentrically narrow to some different extent in the model group with significant difference(P＜0.01).The lumens of coronary artery were narrow in each treatment group.But compared with the model group,the very significant difference existed in HT group,QY group and TY group(P＜0.01), the significant difference existed in XY group(P＜0.05).
2.Cardiac muscle fibers in model group were showed to be broken and lost in a lamellar manner,and the region was replaced with fibrous tissue,with focus cardiac muscle fiber degeneration and necrosis,fatty infiltration and inflammatory cell infiltration.Compared with the control group,the very significant difference existed in model group(P＜0.01).Compared with the model group,the cardiac muscle pathological changes had significant relief,the very significant difference existed in HT group and XY group(P＜0.01),the significant difference existed in QY group and TY group(P＜0.05).
3.When the coronary artery injured was analyzed through the computer imagine analysis, the results were as follow:the lumens of coronary artery became significantly narrow (P＜0.01),and the max intimate thickness of the coronary artery have been obviously increased in the model(P＜0.01),compared with the control group.The proportion of the max intimate and tunica media thickness in model group was significantly larger than that of control group(P＜0.01).The narrow degree of coronary artery in each treatment group was significantly lighter than that of model group(P＜0.01).The max intimate thickness of the coronary artery in each treatment group was significantly less than that of model group (P＜0.01).The proportion of the max intimate and tunica media thickness in each treatment group was significantly less than that of model group(P＜0.01).
4.The results of immunohistochemistry showed that light density ofbcl-2 and bcl-2/bax in model group was significantly less than that of control group(P＜0.01),light density of bax in model group was significantly more than that of control group(P＜0.01).The results showed that light density of bcl-2 and bcl-2/bax in TY group was significantly more than that of model group(P＜0.01),light density ofbax in TY group was significantly less than that of model group(P＜0.01).
5.The positive expressions of caspase-3 and caspase-9 in model group were significantly more than that of control group(P＜0.01),The positive expressions of caspase-3 and caspase-9 in TY group were significantly less than that of model group(P＜0.01).
6.Myocardial apoptosis index of each group was determined by TUNEL,the results showed that apoptosis indexes in control group,model group and TY group were respectively 0.92%,27.68%and 17.28%.The numbers of positive Myocardial cells and myocardial apoptosis index in model group and TY group were significantly more than these of control group(P＜0.01).The results showed that the numbers of positive myocardial cells and Myocardial apoptosis index in model group were significantly more than these of TY group (P＜0.01).
Conclusion
1.It was confirmed through pathological methods that the establishment of Chinese miniature swine model with coronary heart diseases and the syndrome of phlegm and stagnated blood was successful.
2.The coronary heart diseases and the syndrome of phlegm and stagnated blood in the Chinese miniature swine model could be prevented and cured effectively by the traditional Chinese medicinal formulae.
3.The ischemic myocardial apoptosis cells in the Chinese miniature swine model could be protected effectively by the traditional Chinese medicinal formulae.
引文
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