补肾活血化痰法对动脉粥样硬化斑块炎性因子的干预研究
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摘要
背景
人类认识动脉粥样硬化(artherosclerosis,AS)是一种疾病并对其发病机制进行研究已有100余年的历史。随着社会发展和人们生活水平的提高,目前感染性疾病所导致的死亡不断减少,而动脉粥样硬化性血管疾病(atherosclerotic vascular disease,ASVD)已经成为全球首位死亡原因,包括冠心病(coronary heart diseases,CHD)、脑血管病(cerebro vascular disease)、外周动脉疾病(periphera larterial disease)。AS是一种多因性疾病,涉及到基因、环境、代谢等多种因素。事实上,在过去的十余年中,炎症在AS性疾病进展中的作用业已明确,大量的研究证据表明炎症在AS发生、发展和演变过程中起着重要作用。近年来,大量基础与临床研究结果也提示,CHD患者机体内存在的促炎与抗炎失衡可能是AS发生与发展的核心所在,AS的炎症和免疫学说应重新受到人们重视。
动脉粥样硬化是现代医学病名,祖国医学中与之相关的记载可见于“痰浊”、“眩晕”、“胸痹”、“中风”、“真心痛”等病的记载中。随着大量研究的不断深入,逐步认识到AS病机本质是本虚标实,虚实夹杂；本虚可累及心、脾、肝、肾四脏,为病之本,以痰瘀互阻为病之标。其病在血脉,而根在脏腑,正虚邪实相互影响,致使病变不断发展。近年来,大量临床研究表明痰浊血瘀的理论逐渐受到众多学者的重视。目前现代医学对于AS的治疗主要以他汀类药物为主,但随着他汀类药物临床副作用的报道日益增多,中医药则以其独特的整体观及辨证论治特点,在抗AS治疗方面取得了一系列成果。
基于以上背景,本课题以导师罗陆一教授对于AS的中医病机认识,即“肾虚兼痰瘀互结”为基础,以“补肾活血化痰法”为治疗原则,以“补肾活血化痰方”为研究基础方药,以AS斑块目前较为热点的研究方向“炎性机制”为主要出发点,选取具有代表性的五种炎性因子为临床研究及动物实验的干预目标,重点从血脂、炎性因子水平,免疫组化及透射电镜等多方面观察了补肾活血化痰法与他汀类药物相比对于治疗AS类疾病具有相同或相似疗效,并且探讨了中医药对于AS斑块炎性因子的影响,进一步明确了中医药具有抗炎及稳定AS斑块的作用；从而证明中医药对于AS的治疗是安全有效的,且中西医结合治疗临床效果更佳。这对于提高中西结合在AS中的诊断、治疗及预后评估的优势地位,有着积极的意义。本课题主要分为临床研究及动物实验两部分：
1临床研究
目的：本研究通过观察补肾活血化痰法对冠状动脉粥样硬化性心脏病(coronary atherosclerotic heart disease,CHD)患者治疗前后临床病情评分、临床疗效的影响,对血脂、脂蛋白,炎性因子水平的影响,以及对颈动脉多普勒超声检查结果的影响,包括颈动脉内中膜厚度(intima-media thickness,IMT)、颈动脉内斑块类型、数量,探讨补肾活血化痰法对AS斑块炎性因子的干预作用以及中西医结合在治疗AS上的独特优势。
方法：选取CHD患者120例,其中男68例,女52例。所有患者随机分为3组,分别为中药组(Traditional Chinese Medicine Group,TCMG n=40例)；西药组(WestMedicine Group,WMG n=40例)；中西药结合组(Zhong Xi Group,ZXG n=40例),以上三组患者分别给予中药补肾活血化痰方、西药阿托伐他汀钙以及中西药结合口服治疗,共给药24周。24周末观察治疗前后对三组患者的临床病情评分、临床疗效的影响；全自动生化分析仪检测患者血脂、脂蛋白水平,酶联接免疫吸附剂测定法(Enzyme-Linked Immunosorbnent Assay,ELISA)测定血清炎性因子水平,颈动脉多普勒超声检测颈动脉IMT及颈动脉内斑块的类型、数量,以上结果均进行治疗前后组内对比观察以及治疗后组间对比观察。采用SPSS 15.0统计软件包,数值用均数±标准差(X±S)表示,计量资料分析采用t检验及方差分析：组间比较采用独立样本t检验,组内治疗前后比较采用配对样本t检验,组间两两比较采用方差分析；计数资料分析采用卡方检验：率的比较采用卡方检验；等级资料比较采用Ridit分析。
结果：
(1)治疗前后组内比较,三组心绞痛疗效评分均明显降低(P<0.05或P<0.01),TCMG组及ZXG组中医症状评分均明显降低(P<0.01),而WMG组无明显改善(P>0.05)；三组在心绞痛疗效、心电图疗效、中医症候疗效显效率及总有效率方面均有不同程度地改善；三组TC、TG、LDL-C值均显著降低,HDL-C值显著升高(P<0.05或P<0.01)；三组5种炎性因子指标Fg、hs-CRP、IL-18、MCP-1、MMP-9均显著降低(P<0.05或P<0.01)；三组颈动脉IMT厚度明显降低(P<0.05),颈动脉内斑块数量明显减少(P<0.01)。
(2)治疗后组间比较,ZXG组在改善患者心绞痛疗效评分方面疗效优于单纯TCMG组或WMG组(P<0.05),在改善中医症状评分方面,疗效与TCMG组相当(P>0.05)：在改善心绞痛疗效、心电图疗效以及中医症候疗效显效率方面,疗效明显优于单纯TCMG组或WMG组(P<0.01)；在降低TC、TG、LDL-C值水平以及升高HDL-C值水平方面,疗效明显优于单纯TCMG组或WMG组(P<0.01)；在降低5种炎性因子指标水平方面,疗效明显优于单纯TCMG组或WMG组(P<0.01)；在降低动脉IMT厚度方面,疗效明显优于单纯TCMG组或WMG组(P<0.01),而减少颈动脉内斑块数量方面,疗效与单纯TCMG组或WMG组相当(P>0.05)。
结论：研究表明补肾活血化痰法联合阿托伐他汀钙治疗,可明显改善CHD患者心绞痛疗效及中医症状评分情况,在治疗后心绞痛疗效、心电图疗效及中医症候疗效显效率(总有效率)方面亦有显著效果,能很好地降低患者TC、TG及LDL-C水平,升高HDL-C水平,降低Fg、hs-CRP、IL-18、MCP-1、MMP-9五种炎性因子的水平,使颈动脉IMT明显变薄、斑块数量减少,从而减少斑块纤维帽降解,稳定AS斑块,达到更好地阻碍或延缓AS斑块进展为易损斑块的作用,对于个别患者甚至可起到逆转斑块的作用,有效地减少了CHD患者急性心脑血管事件的发生。推断对机体内血脂及炎性因子水平的调节可能是补肾活血化痰法抗AS的机制之一。本研究为中西医结合治疗AS类疾病开辟了崭新的方向,提供了科学、客观、有力的理论依据。
2实验研究
目的：本研究通过观察补肾活血化痰法对实验家兔AS模型斑块血脂、脂蛋白水平,包括甘油三酯(triglyceride,TG)、总胆固醇(total cholesterol,TC)、高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C),以及5个炎性因子的影响,包括纤维蛋白原(fibrinogen,Fg)、高敏C-反应蛋白(hypersensitive C-reaction protein,hs-CRP)、白介素-18(interleukin-18,IL-18)、单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)、基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9),研究补肾活血化痰法对AS斑块炎性因子的影响机制,探讨中西医结合在治疗AS性疾病及稳定AS斑块方面的优势。
方法：选取健康纯种雄性新西兰大白兔50只,适应性饲养观察2周后,随机分为5组：空白对照组(Blank Control Group,BCG n=10),模型对照组(Model Group,MG n=10),中药组(Traditional Chinese Medicine Group,TCMG n=10),西药组(West Medicine Group,WMG n=10),中西药结合组(Zhong Xi Group,ZXG n=10),后面4组为造模组。除BCG组子普通家兔饲料喂养外,其余4组均通过饲喂高脂饲料加耳缘静脉注射牛血清白蛋白造成免疫性内皮损伤的联合方法建立AS模型。MG组实验兔仅予高脂饲料喂养造模,不给药；高脂饲料喂养MG及三个治疗组家兔约12周,与BCG组比较显示造模成功后,’TCMG、WMG、ZXG三个治疗组分别给予中药补肾活血化痰方、西药阿托伐他汀钙、中西药结合灌胃给药治疗8周。治疗结束后,即第20周末,观察治疗前后对5组动物血脂、脂蛋白水平以及5个炎性因子ELISA结果的影响；对AS斑块主动脉进行病理形态学观察,包括肉眼观察、HE染色光镜观察、免疫组化染色(MCP-1、MMP-9指标)结果观察以及透射电镜观察,计算MCP-1、MMP-9的阳性细胞表达面积所占百分比。采用SPSS 15.0统计软件包,数值用均数±标准差(X±S)表示,计量资料分析采用t检验及方差分析：组间比较采用独立样本t检验,组内治疗前后比较采用配对样本t检验,组间两两比较采用方差分析；计数资料分析采用卡方检验：率的比较用卡方检验。
结果：
(1)血脂、脂蛋白检测结果：与BCG组比较,MG组、TCMG组、WMG组及ZXG组TG、TC、HDL-C、LDL-C值水平均有显著升高(P<0.01)；与MG组比较,TCMG组、WMG组及ZXG组TG、TC、LDL-C值均显著降低,HDL-C值显著升高(P<0.05或P<0.01)；三个治疗组比较,ZXG组较TCMG组及WMG组TG、TC、LDL-C值均显著降低,HDL-C值显著升高(P<0.05或P<0.01),而WMG组较TCMG组TG、TC、LDL-C值均显著降低,HDL-C值显著升高(P<0.05)。
(2)5种炎性因子检测结果：治疗前,与BCG组比较,MG组、TCMG组、WMG组及ZXG组Fg、hs-CRP、IL-1、MCP-1、MMP-9值均有显著升高(P<0.01)；治疗前后组内比较,三治疗组5种炎性因子指标均显著降低(P<0.05或P<0.01)；治疗后组间比较,与MG组比较,TCMG组、WMG组及ZXG组5种炎性因子指标均显著降低(P<0.01)；ZXG组在降低5种炎性因子指标水平方面,疗效明显优于单纯TCMG组或WMG组(P<0.01)；而TCMG组与WMG组比较,WMG组在降低hs-CRP方面,疗效优于TCMG组(P<0.05),其余4个指标两组无差异(P>0.05)。
(3) MCP-1、MMP-9免疫组化阳性细胞表达面积比较：与BCG组比较,MG组、TCMG组、WMG组及ZXG组MCP-1、MMP-9阳性细胞表达面积均有显著升高(P<0.01)；与MG组比较,TCMG组、WMG组及ZXG组MCP-1、MMP-9阳性细胞表达面积均显著降低(P<0.05或P<0.01)；ZXG组分别与TCMG组及WMG组比较,MCP-1、MMP-9阳性细胞表达面积均显著降低(P<0.01),而TCMG组与WMG组比较无差异(P>0.05)。
结论：
(1)通过高脂饲料喂养结合耳缘静脉注射牛血清白蛋白的方法,能成功建立家兔AS斑块模型；
(2)补肾活血化痰法联合阿托伐他汀钙治疗在改善AS家兔血脂、脂蛋白水平方面,疗效明显优于单纯中药组或西药组,可以认为对血脂水平的调节可能是其抗AS,稳定斑块的机制之一；
(3)补肾活血化痰法联合阿托伐他汀钙治疗可显著降低AS家兔Fg、hs-CRP、IL-18. MCP-1、MMP-9五种炎性因子水平,减少MCP-1及MMP-9免疫组化阳性细胞表达面积,且疗效明显优于单纯中药组或西药组,可以认为中西医结合治疗能明显抑制家兔AS斑块炎性因子的水平,减少斑块纤维帽降解,稳定AS斑块,从而延缓了AS斑块进展为易损斑块,推断炎性因子水平高低可能是决定AS斑块易损性的重要因素之一：
(4)肾虚痰瘀互结是影响AS发生发展的重要病机之一。补肾活血化痰法联合阿托伐他汀钙的中西结合治疗模式,可以从多角度、多靶点地起到调节血脂水平、降低炎性因子水平、抑制斑块纤维帽降解、保护血管内皮细胞功能等作用,从而更好地阻止AS斑块进展为易损斑块,减少相应不良事件的发生率。推断补肾活血化痰法可起到抑制机体内AS相关炎性因子的作用。
Backgroud
It was for more than 100 years history that the human known artherosclerosis(AS) was a kind of disease,and studied its pathogenesis.With the development of society and the improvement of people's living standard,at present,infectious disease caused the deaths is decreasing.While the atherosclerotic vascular disease(ASD) has become the world's first cause of death,including coronary heart diseases(CHD),cerebro vascular disease and periphera larterial disease.AS is a kind of disease,involved many factors of genes,environment and metabolism.In fact,in the past ten years,inflammation played a role in the AS disease progression has been clearly.A lot of research evidences indicate that inflammation plays an important role in AS' occurrence,development and evolution process.In recent years,lots of basic and clinical findings also suggest that it may be the core of AS' occurrence and development that the CHD patients in their body have the pro-inflammatory and anti-inflammatory imbalance.
Artherosclerosis is a name of disease in western medicine.The motherland medicine related records can be visible at Phlegm-turbid,Vertigo,Chest Stuffiness,Stroke and Angina Pectoris in the records.With the deepening of the research,we gradually realize that AS' pathogenesis is essential the deficiency i origin and excess in superficiality,and deficiency complicated with excessiveness.It is the fundamental cause that the deficiency of heart,spleen,liver and kidney,and with phlegm and blood stasis for each of the disease resistance.The disease is in the blood and root of the viscera,and it is continuous developing because of the body deficiency and pathogenic excess.In recent years,alarge number of clinical trials showed that stagnant blood stasis theory was gradually attracted many scholars'attentions.Now for the modern medical treatment of AS is mainly by statin drugs.But with statin drugs reported clinical effects of increasing,the traditional chinese medicine(TCM) in the treatment of AS make a series of achievements,because of its overall concept and uniquecharacteristics of the syndrome differentiation and treatment.
Based on the above background,this subject is based on TCM pathogenesis proposed by Professor Luo Lu-yi,which is kidney deficiency combined with phlegmand blood stasis.Also this study is with therapy of tonifying the kidney and activating blood and dissipating phlegm for therapeutic principles,with decoction of tonifying the kidney and activating blood and dissipating phlegm as the foundation formulas,with the hot research direction "inflammatory mechanisms" of AS as the main jumping-off place.The research selects the five kinds of typical inflammatory factors for clinical research and animal experiment's intervention goals,and the study focused on observation of the therapy of TCM and the statin drugs for the treatment of AS diseases has the same or similareffect or not,from various aspects of blood-lipid,inflammatory factor levels,immunohistochemistry and transmission electron microscopy.And it also discusses the TCM's influence on atherosclerotic plaque inflammatory factors,to further clarify the anti-inflammatory and stability of atherosclerotic plaque.Thus it is proved that the TCM therapy of atherosclerosis is safe and effective,and it has a better clinical effect by combination of TCM with western medicine.It has a positive meaning that to improve this integration in atherosclerosis in the diagnosis,treatment and prognosis assessment advantage.This subject mainly includes two parts,which are clinical research and animal experimental study.
1 Clinical Research
Objective:This Research observes the various influences on CHD patients bytherapy of tonifying the kidney and activating blood and dissipating phlegm,including clinical condition scores and clinical curative effect before and aftertreatment,lipid and lipoprotein and inflammatory factor levels,and the results of carotid doppler ultrasound examination through intima-media thickness(IMT),carotid plaques in types and quantities.The objective is to explore theintervention of this TCM therapeutic method on atherosclerotic plaque,inflammatory factors,and the distinct advantages of combination of TCM with western medicine in the treatment of AS.
Methods:This research choosed 120 cases of CHD patients,including 68 cases of male and 52 cases of female.All patients were randomly divided into 3 groups,Traditional Chinese Medicine Group(TCMG),West Medicine Group(WMG) and Zhong Xi Group(ZXG),and there were 40 cases in each group. All three groups of patients were given orallydrug therapy for 24 weeks,which were respectively given by decoction of tonifying the kidney and activating blood and dissipating phlegm,Atorvastatin calcium and combination of TCM with western medicine. At 24 weekend,for three groups were observed on clinical condition scores and clinical curative effect before and after treatment.Also the blood lipid and serum inflammatory factor levels were detected by Automatic biochemistry analyzer and Enzyme-Linked Immunosorbnent Assay(ELISA).The IMT,carotid plaques in types and quantities were examined by carotid doppler ultrasound.These above results were compared between before and after the treatment within the groupsand between each treatment groups.The numerical values were expressed by mean±tandard deviation(X±S) and statistical analyzed with the soft ware of SPSS 15.0.The quantitative data was analysised by t-test and Variance analysis.The independent sample t-test was used in comparison among groups, paired sample t-test was used in comparison before and after treatment,and Variance analysis was ued in pairwise comparison between groups.The enumeration data was analysised by Chi-square test. Chi-square test was used in rate comparison andRidit analysis was used in ranked data.
Results:
(1) Compared between before and after the treatment within the groups:Threegroups of angina pectoris effect scores decreased obviously(P< 0.05 or P< 0.01).The TCM symptoms scores of TCMG and ZXG both declined dramatically(P<0.01),while there was no significant improvement in WMG(P> 0.05).There were improvements in various degrees between three groups in the obvious effective rateand total effective rate of angina curative effect,electrocardiogram(ECG) curative effect and the total effective rates of TCM syndromes.The level of theserum TC,TG and LDL-C of three groups all decreased significantly and the level of HDL-C increased obviously(P<0.01 or P<0.05).The level of five inflammatory factors,such as Fg、hs-CRP、IL-18、MCP-1、MMP-9, declined significantly(P< 0.01 or P< 0.05).The carotid artery intima-media thickness decreased obviously(P<0.05),and the carotid plaques in quantities decreased significantly(P<0.01).
(2) Compared between each treatment groups:The improvement of angina pectorieffect scores in ZXG was superior to the groups of TCMG and WMG(P<0.05),and it was in balance with TCMG in the improvement of TCM symptoms scores(P>0.05). And the ZXG was superior to the groups of TCMG and WMG in the obvious effective rate of angina curative effect,ECG curative effect and the total effective rate of TCM syndromes(P< 0.01).And it was also superior to the groups of TCMG and WMG in decreaseing the level of the serum TC,TG and LDL-C,and rising HDL-C(P< 0.01).And so,it was superior to the groups of TCMG and WMG in decreaseing the level of five inflammatory factors(P<0.01).The ZXG was superior to the groups of TCMG and WMG in lessening the carotid artery intima-media thickness(P<0.01),but it was in balance with TCMG and WMG in reducing the carotid plaques in quantities(P>0.05).
Conclusions:The research shows that the treatment of the therapy of tonifying the kidney and activating blood and dissipating phlegm combined with the Atorvastatin calcium can reduce AS plaque fibrous cap degradation and stabilize AS plaque,so it can achieve better block or delay progression of vulnerable plaques for action,and for individual patients it also can reverse the AS plaque,thus effectively reduce CHD patients with acute cardio-cerebro vascular events.The above functions mainly take effect through the following several aspects,such as the apparent improvement of angina pectori effect and the TCM symptoms scores,the significant effect of the obvious effective rateand total effective rate of angina curative effect,electrocardiogram(ECG) curative effect and the total effective rates of TCM syndromes,decreaseing the level of the serum TC,TG and LDL-C,and rising HDL-C,decreaseing the level of five inflammatory factors,lessening the carotid artery intima-media thickness and the carotid plaques in quantities.We can conclude that it may be one mechanism of treatment of AS by the therapy of tonifying the kidney and activating blood and dissipating phlegm,by adjusting the body lipid and inflammatory factor levels.This study opens a new direction for the treatment of AS disease by combination of TCM with western medicine and provide a scientific,objective and strong theoretical basis.
2 Animal Experimental Study
Objective：The study investigates the mechanism of the inflammatory factors of the AS plaques of experimental rabbit models by therapy of tonifying the kidney and activating blood and dissipating phlegm,and to discuss the advantages of combination of TCM with western medicine in the treatment of AS and stabilizing AS plaques.The above functions mainly take effect through the following several aspects,including influence on the levels of lipid and lipoprotein,such as TC,TG,HDL-C and LDL-C and the five inflammatory factors,such as Fg,hs-CRP,IL-18,MCP-1 and MMP-9.
Methods：The study selected 50 healthy male purebred rabbits of New Zealand,2weeks after feeding observation adaptability,all rabbits were randomly divided into 5 groups,Blank Control Group(BCG),Model Group(MG),Traditional Chinese Medicine Group (TCMG),West Medicine Group(WMG),Zhong Xi Group(ZXG).There were 10 rabbits in every groups,and the later four groups were made into model.Besides the BCG rabbits were feed with the ordinary food,the other four groups were all established AS model through combined method,which was feeding high-lipid diet and injecting bovine serum albumin(BSA) via rabbit's ear vein to cause autoimmune endothelial injury.MG rabbits were just given high-lipid diet to bulid the modle,not given any drug treatment.MG and other three treatment groups were feed with high-lipid diet for about 12 weeks.Compared with BCG group after becoming successful model,the treatment groups of TCMG,WMG and ZXG were treated by intragastric administration for 12 weeks,which were respectively given by decoction of tonifying the kidney and activating blood and dissipating phlegm,Atorvastatin calcium and combination of TCM with western medicine.After the treatment,at 20 weekend, three treatment groups' rabbits were observed on the levels of the blood lipid and lipoprotein, and five serum inflammatory factors.The pathological morphology of AS aorta were observed,including macroscopic observation,examined by Hematoxylin-Eoin(HE) staining,immunohistochemical study(MCP-1 and MMP-9) and transmission electron microscopy.And we also calculated the positive cells express percentage of MCP-1 and MMP-9.The numerical values were expressed by mean±standard deviation(X±S) and statistical analyzed with the soft ware of SPSS 15.0.The quantitative data was analysised by t-test and Variance analysis.The independent sample t-test was used in comparison among groups, paired sample t-test was used in comparison before and after treatment,and Variance analysis was ued in pairwise comparison between groups.The enumeration data was analysised by Chi-square test. Chi-square test was used in rate comparison.
Results:
(1) The detected results of lipid and lipoprotein: Compared with BCG,the level of TC,TG,HDL-C and LDL-C of the other four groups increased significantly(P< 0.01).Compared with MG,the level of the serum TC,TG and LDL-C of three treatment groups all decreased significantly and the level of HDL-C increased obviously(P<0.01 or P< 0.05).Compared between each treatment groups,the group of ZXG was superior to the groups of TCMG and WMG in decreaseing the level of the serum TC,TG and LDL-C,and rising HDL-C(P<0.05或P<0.01).And compared with TCMG,the group of WMG was superior to the TCMG in decreaseing the level of the serum TC,TG and LDL-C,and rising HDL-C(P<0.05).
(2) The detected results of the five inflammatory factors:Compared with BCG before the treatment,the level of Fg、hs-CRP、IL-1、MCP-1 and MMP-9 of the other four groups increased significantly(P<0.01).The level of the five inflammatory factors,such as Fg、hs-CRP、IL-18、MCP-1 and MMP-9, declined significantly compared between before and after the treatment within the three groups(P<0.01 or P< 0.05).Compared between each treatment groups,with MG,the level of the five inflammatory factors of the three treatment groups declined significantly(P<0.01).The group of ZXG was superior to the groups of TCMG and WMG indecreaseing the level of five inflammatory factors(P< 0.01).And compared with TCMG,the group of WMG was superior to the TCMG in decreasing the level of the hs-CRP(P<0.05),but the other four indicators had no differences(P>0.05).
(3) The comparison of the positive cells express percentage of MCP-1 and MMP-9:Compared with BCG,the positive cells express percentage of MCP-1 and MMP-9 in the other four groups increased significantly(P< 0.01).Compared with MG,the percentage of the three treatment groups all decreased obviously(P<0.01 or P<0.05).The group of ZXG was superior to the groups of TCMG and WMG in decreaseing the positive cells express percentage of MCP-1 and MMP-9(P<0.01),but had no differences between TCMG and WMG(P> 0.05).
Conclusions:
(1) It is a successful method to establish rabbits AS model through feeding high-lipid diet and injecting bovine serum albumin via rabbit's ear vein.
(2) The research shows that the treatment of the therapy of tonifying the kidney and activating blood and dissipating phlegm combined with the Atorvastatin calcium may be superior to the groups of TCMG and WMG in improving the level of the lipid and lipoprotein.We can conclude that it may be one mechanism of treatment of AS and stabilizing AS plaque by adjusting the body lipid levels.
(3) The therapy of tonifying the kidney and activating blood and dissipating phlegm combined with the Atorvastatin calcium may be superior to the groups of TCMG and WMG in decreasing the levels of five inflammatory factors and the positive cells express percentage of MCP-1 and MMP-9.We can draw the conclusion that the combination of TCM with western medicine can achieve better block or delay progression of vulnerable plaques.The above functions mainly take effect through the following several aspects,such as restraining the levels of inflammatory factors of rabbits's AS plaque,reducing AS plaque fibrous cap degradation and stabilizing AS plaque.We can infer that the levels of inflammatory factors may be a important element to decide plaque ulnerability.
(4) Kidney deficiency combined with phlegm and blood stasis is one of the most important pathogenesis,which can influence the occurrence and development of AS.The combination therapy mode of tonifying the kidney and activating blood and dissipating phlegm combined with the Atorvastatin calcium can have effcet from different angles and more targets on regulating the levels of blood lipid,decreaseing the levels of inflammatory factors,restraining AS plaque fibrous cap degradation and protecting vascular endothelial cells function,and so on.Thus it can achieve better block or delay progression of vulnerable plaques for action,and effectively reduce the corresponding to the incidence of adverse events. So we infer that it can restrain the relevant inflammatory factors of AS patients through the therapy of tonifying the kidney and activating blood and dissipating phlegm.
人类认识动脉粥样硬化(artherosclerosis,AS)是一种疾病并对其发病机制进行研究已有100余年的历史。随着社会发展和人们生活水平的提高,目前感染性疾病所导致的死亡不断减少,而动脉粥样硬化性血管疾病(atherosclerotic vascular disease,ASVD)已经成为全球首位死亡原因,包括冠心病(coronary heart diseases,CHD)、脑血管病(cerebro vascular disease)、外周动脉疾病(periphera larterial disease)。AS是一种多因性疾病,涉及到基因、环境、代谢等多种因素。事实上,在过去的十余年中,炎症在AS性疾病进展中的作用业已明确,大量的研究证据表明炎症在AS发生、发展和演变过程中起着重要作用。近年来,大量基础与临床研究结果也提示,CHD患者机体内存在的促炎与抗炎失衡可能是AS发生与发展的核心所在,AS的炎症和免疫学说应重新受到人们重视。
动脉粥样硬化是现代医学病名,祖国医学中与之相关的记载可见于“痰浊”、“眩晕”、“胸痹”、“中风”、“真心痛”等病的记载中。随着大量研究的不断深入,逐步认识到AS病机本质是本虚标实,虚实夹杂；本虚可累及心、脾、肝、肾四脏,为病之本,以痰瘀互阻为病之标。其病在血脉,而根在脏腑,正虚邪实相互影响,致使病变不断发展。近年来,大量临床研究表明痰浊血瘀的理论逐渐受到众多学者的重视。目前现代医学对于AS的治疗主要以他汀类药物为主,但随着他汀类药物临床副作用的报道日益增多,中医药则以其独特的整体观及辨证论治特点,在抗AS治疗方面取得了一系列成果。
基于以上背景,本课题以导师罗陆一教授对于AS的中医病机认识,即“肾虚兼痰瘀互结”为基础,以“补肾活血化痰法”为治疗原则,以“补肾活血化痰方”为研究基础方药,以AS斑块目前较为热点的研究方向“炎性机制”为主要出发点,选取具有代表性的五种炎性因子为临床研究及动物实验的干预目标,重点从血脂、炎性因子水平,免疫组化及透射电镜等多方面观察了补肾活血化痰法与他汀类药物相比对于治疗AS类疾病具有相同或相似疗效,并且探讨了中医药对于AS斑块炎性因子的影响,进一步明确了中医药具有抗炎及稳定AS斑块的作用；从而证明中医药对于AS的治疗是安全有效的,且中西医结合治疗临床效果更佳。这对于提高中西结合在AS中的诊断、治疗及预后评估的优势地位,有着积极的意义。本课题主要分为临床研究及动物实验两部分：
1临床研究
目的：本研究通过观察补肾活血化痰法对冠状动脉粥样硬化性心脏病(coronary atherosclerotic heart disease,CHD)患者治疗前后临床病情评分、临床疗效的影响,对血脂、脂蛋白,炎性因子水平的影响,以及对颈动脉多普勒超声检查结果的影响,包括颈动脉内中膜厚度(intima-media thickness,IMT)、颈动脉内斑块类型、数量,探讨补肾活血化痰法对AS斑块炎性因子的干预作用以及中西医结合在治疗AS上的独特优势。
方法：选取CHD患者120例,其中男68例,女52例。所有患者随机分为3组,分别为中药组(Traditional Chinese Medicine Group,TCMG n=40例)；西药组(WestMedicine Group,WMG n=40例)；中西药结合组(Zhong Xi Group,ZXG n=40例),以上三组患者分别给予中药补肾活血化痰方、西药阿托伐他汀钙以及中西药结合口服治疗,共给药24周。24周末观察治疗前后对三组患者的临床病情评分、临床疗效的影响；全自动生化分析仪检测患者血脂、脂蛋白水平,酶联接免疫吸附剂测定法(Enzyme-Linked Immunosorbnent Assay,ELISA)测定血清炎性因子水平,颈动脉多普勒超声检测颈动脉IMT及颈动脉内斑块的类型、数量,以上结果均进行治疗前后组内对比观察以及治疗后组间对比观察。采用SPSS 15.0统计软件包,数值用均数±标准差(X±S)表示,计量资料分析采用t检验及方差分析：组间比较采用独立样本t检验,组内治疗前后比较采用配对样本t检验,组间两两比较采用方差分析；计数资料分析采用卡方检验：率的比较采用卡方检验；等级资料比较采用Ridit分析。
结果：
(1)治疗前后组内比较,三组心绞痛疗效评分均明显降低(P<0.05或P<0.01),TCMG组及ZXG组中医症状评分均明显降低(P<0.01),而WMG组无明显改善(P>0.05)；三组在心绞痛疗效、心电图疗效、中医症候疗效显效率及总有效率方面均有不同程度地改善；三组TC、TG、LDL-C值均显著降低,HDL-C值显著升高(P<0.05或P<0.01)；三组5种炎性因子指标Fg、hs-CRP、IL-18、MCP-1、MMP-9均显著降低(P<0.05或P<0.01)；三组颈动脉IMT厚度明显降低(P<0.05),颈动脉内斑块数量明显减少(P<0.01)。
(2)治疗后组间比较,ZXG组在改善患者心绞痛疗效评分方面疗效优于单纯TCMG组或WMG组(P<0.05),在改善中医症状评分方面,疗效与TCMG组相当(P>0.05)：在改善心绞痛疗效、心电图疗效以及中医症候疗效显效率方面,疗效明显优于单纯TCMG组或WMG组(P<0.01)；在降低TC、TG、LDL-C值水平以及升高HDL-C值水平方面,疗效明显优于单纯TCMG组或WMG组(P<0.01)；在降低5种炎性因子指标水平方面,疗效明显优于单纯TCMG组或WMG组(P<0.01)；在降低动脉IMT厚度方面,疗效明显优于单纯TCMG组或WMG组(P<0.01),而减少颈动脉内斑块数量方面,疗效与单纯TCMG组或WMG组相当(P>0.05)。
结论：研究表明补肾活血化痰法联合阿托伐他汀钙治疗,可明显改善CHD患者心绞痛疗效及中医症状评分情况,在治疗后心绞痛疗效、心电图疗效及中医症候疗效显效率(总有效率)方面亦有显著效果,能很好地降低患者TC、TG及LDL-C水平,升高HDL-C水平,降低Fg、hs-CRP、IL-18、MCP-1、MMP-9五种炎性因子的水平,使颈动脉IMT明显变薄、斑块数量减少,从而减少斑块纤维帽降解,稳定AS斑块,达到更好地阻碍或延缓AS斑块进展为易损斑块的作用,对于个别患者甚至可起到逆转斑块的作用,有效地减少了CHD患者急性心脑血管事件的发生。推断对机体内血脂及炎性因子水平的调节可能是补肾活血化痰法抗AS的机制之一。本研究为中西医结合治疗AS类疾病开辟了崭新的方向,提供了科学、客观、有力的理论依据。
2实验研究
目的：本研究通过观察补肾活血化痰法对实验家兔AS模型斑块血脂、脂蛋白水平,包括甘油三酯(triglyceride,TG)、总胆固醇(total cholesterol,TC)、高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C),以及5个炎性因子的影响,包括纤维蛋白原(fibrinogen,Fg)、高敏C-反应蛋白(hypersensitive C-reaction protein,hs-CRP)、白介素-18(interleukin-18,IL-18)、单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)、基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9),研究补肾活血化痰法对AS斑块炎性因子的影响机制,探讨中西医结合在治疗AS性疾病及稳定AS斑块方面的优势。
方法：选取健康纯种雄性新西兰大白兔50只,适应性饲养观察2周后,随机分为5组：空白对照组(Blank Control Group,BCG n=10),模型对照组(Model Group,MG n=10),中药组(Traditional Chinese Medicine Group,TCMG n=10),西药组(West Medicine Group,WMG n=10),中西药结合组(Zhong Xi Group,ZXG n=10),后面4组为造模组。除BCG组子普通家兔饲料喂养外,其余4组均通过饲喂高脂饲料加耳缘静脉注射牛血清白蛋白造成免疫性内皮损伤的联合方法建立AS模型。MG组实验兔仅予高脂饲料喂养造模,不给药；高脂饲料喂养MG及三个治疗组家兔约12周,与BCG组比较显示造模成功后,’TCMG、WMG、ZXG三个治疗组分别给予中药补肾活血化痰方、西药阿托伐他汀钙、中西药结合灌胃给药治疗8周。治疗结束后,即第20周末,观察治疗前后对5组动物血脂、脂蛋白水平以及5个炎性因子ELISA结果的影响；对AS斑块主动脉进行病理形态学观察,包括肉眼观察、HE染色光镜观察、免疫组化染色(MCP-1、MMP-9指标)结果观察以及透射电镜观察,计算MCP-1、MMP-9的阳性细胞表达面积所占百分比。采用SPSS 15.0统计软件包,数值用均数±标准差(X±S)表示,计量资料分析采用t检验及方差分析：组间比较采用独立样本t检验,组内治疗前后比较采用配对样本t检验,组间两两比较采用方差分析；计数资料分析采用卡方检验：率的比较用卡方检验。
结果：
(1)血脂、脂蛋白检测结果：与BCG组比较,MG组、TCMG组、WMG组及ZXG组TG、TC、HDL-C、LDL-C值水平均有显著升高(P<0.01)；与MG组比较,TCMG组、WMG组及ZXG组TG、TC、LDL-C值均显著降低,HDL-C值显著升高(P<0.05或P<0.01)；三个治疗组比较,ZXG组较TCMG组及WMG组TG、TC、LDL-C值均显著降低,HDL-C值显著升高(P<0.05或P<0.01),而WMG组较TCMG组TG、TC、LDL-C值均显著降低,HDL-C值显著升高(P<0.05)。
(2)5种炎性因子检测结果：治疗前,与BCG组比较,MG组、TCMG组、WMG组及ZXG组Fg、hs-CRP、IL-1、MCP-1、MMP-9值均有显著升高(P<0.01)；治疗前后组内比较,三治疗组5种炎性因子指标均显著降低(P<0.05或P<0.01)；治疗后组间比较,与MG组比较,TCMG组、WMG组及ZXG组5种炎性因子指标均显著降低(P<0.01)；ZXG组在降低5种炎性因子指标水平方面,疗效明显优于单纯TCMG组或WMG组(P<0.01)；而TCMG组与WMG组比较,WMG组在降低hs-CRP方面,疗效优于TCMG组(P<0.05),其余4个指标两组无差异(P>0.05)。
(3) MCP-1、MMP-9免疫组化阳性细胞表达面积比较：与BCG组比较,MG组、TCMG组、WMG组及ZXG组MCP-1、MMP-9阳性细胞表达面积均有显著升高(P<0.01)；与MG组比较,TCMG组、WMG组及ZXG组MCP-1、MMP-9阳性细胞表达面积均显著降低(P<0.05或P<0.01)；ZXG组分别与TCMG组及WMG组比较,MCP-1、MMP-9阳性细胞表达面积均显著降低(P<0.01),而TCMG组与WMG组比较无差异(P>0.05)。
结论：
(1)通过高脂饲料喂养结合耳缘静脉注射牛血清白蛋白的方法,能成功建立家兔AS斑块模型；
(2)补肾活血化痰法联合阿托伐他汀钙治疗在改善AS家兔血脂、脂蛋白水平方面,疗效明显优于单纯中药组或西药组,可以认为对血脂水平的调节可能是其抗AS,稳定斑块的机制之一；
(3)补肾活血化痰法联合阿托伐他汀钙治疗可显著降低AS家兔Fg、hs-CRP、IL-18. MCP-1、MMP-9五种炎性因子水平,减少MCP-1及MMP-9免疫组化阳性细胞表达面积,且疗效明显优于单纯中药组或西药组,可以认为中西医结合治疗能明显抑制家兔AS斑块炎性因子的水平,减少斑块纤维帽降解,稳定AS斑块,从而延缓了AS斑块进展为易损斑块,推断炎性因子水平高低可能是决定AS斑块易损性的重要因素之一：
(4)肾虚痰瘀互结是影响AS发生发展的重要病机之一。补肾活血化痰法联合阿托伐他汀钙的中西结合治疗模式,可以从多角度、多靶点地起到调节血脂水平、降低炎性因子水平、抑制斑块纤维帽降解、保护血管内皮细胞功能等作用,从而更好地阻止AS斑块进展为易损斑块,减少相应不良事件的发生率。推断补肾活血化痰法可起到抑制机体内AS相关炎性因子的作用。
Backgroud
It was for more than 100 years history that the human known artherosclerosis(AS) was a kind of disease,and studied its pathogenesis.With the development of society and the improvement of people's living standard,at present,infectious disease caused the deaths is decreasing.While the atherosclerotic vascular disease(ASD) has become the world's first cause of death,including coronary heart diseases(CHD),cerebro vascular disease and periphera larterial disease.AS is a kind of disease,involved many factors of genes,environment and metabolism.In fact,in the past ten years,inflammation played a role in the AS disease progression has been clearly.A lot of research evidences indicate that inflammation plays an important role in AS' occurrence,development and evolution process.In recent years,lots of basic and clinical findings also suggest that it may be the core of AS' occurrence and development that the CHD patients in their body have the pro-inflammatory and anti-inflammatory imbalance.
Artherosclerosis is a name of disease in western medicine.The motherland medicine related records can be visible at Phlegm-turbid,Vertigo,Chest Stuffiness,Stroke and Angina Pectoris in the records.With the deepening of the research,we gradually realize that AS' pathogenesis is essential the deficiency i origin and excess in superficiality,and deficiency complicated with excessiveness.It is the fundamental cause that the deficiency of heart,spleen,liver and kidney,and with phlegm and blood stasis for each of the disease resistance.The disease is in the blood and root of the viscera,and it is continuous developing because of the body deficiency and pathogenic excess.In recent years,alarge number of clinical trials showed that stagnant blood stasis theory was gradually attracted many scholars'attentions.Now for the modern medical treatment of AS is mainly by statin drugs.But with statin drugs reported clinical effects of increasing,the traditional chinese medicine(TCM) in the treatment of AS make a series of achievements,because of its overall concept and uniquecharacteristics of the syndrome differentiation and treatment.
Based on the above background,this subject is based on TCM pathogenesis proposed by Professor Luo Lu-yi,which is kidney deficiency combined with phlegmand blood stasis.Also this study is with therapy of tonifying the kidney and activating blood and dissipating phlegm for therapeutic principles,with decoction of tonifying the kidney and activating blood and dissipating phlegm as the foundation formulas,with the hot research direction "inflammatory mechanisms" of AS as the main jumping-off place.The research selects the five kinds of typical inflammatory factors for clinical research and animal experiment's intervention goals,and the study focused on observation of the therapy of TCM and the statin drugs for the treatment of AS diseases has the same or similareffect or not,from various aspects of blood-lipid,inflammatory factor levels,immunohistochemistry and transmission electron microscopy.And it also discusses the TCM's influence on atherosclerotic plaque inflammatory factors,to further clarify the anti-inflammatory and stability of atherosclerotic plaque.Thus it is proved that the TCM therapy of atherosclerosis is safe and effective,and it has a better clinical effect by combination of TCM with western medicine.It has a positive meaning that to improve this integration in atherosclerosis in the diagnosis,treatment and prognosis assessment advantage.This subject mainly includes two parts,which are clinical research and animal experimental study.
1 Clinical Research
Objective:This Research observes the various influences on CHD patients bytherapy of tonifying the kidney and activating blood and dissipating phlegm,including clinical condition scores and clinical curative effect before and aftertreatment,lipid and lipoprotein and inflammatory factor levels,and the results of carotid doppler ultrasound examination through intima-media thickness(IMT),carotid plaques in types and quantities.The objective is to explore theintervention of this TCM therapeutic method on atherosclerotic plaque,inflammatory factors,and the distinct advantages of combination of TCM with western medicine in the treatment of AS.
Methods:This research choosed 120 cases of CHD patients,including 68 cases of male and 52 cases of female.All patients were randomly divided into 3 groups,Traditional Chinese Medicine Group(TCMG),West Medicine Group(WMG) and Zhong Xi Group(ZXG),and there were 40 cases in each group. All three groups of patients were given orallydrug therapy for 24 weeks,which were respectively given by decoction of tonifying the kidney and activating blood and dissipating phlegm,Atorvastatin calcium and combination of TCM with western medicine. At 24 weekend,for three groups were observed on clinical condition scores and clinical curative effect before and after treatment.Also the blood lipid and serum inflammatory factor levels were detected by Automatic biochemistry analyzer and Enzyme-Linked Immunosorbnent Assay(ELISA).The IMT,carotid plaques in types and quantities were examined by carotid doppler ultrasound.These above results were compared between before and after the treatment within the groupsand between each treatment groups.The numerical values were expressed by mean±tandard deviation(X±S) and statistical analyzed with the soft ware of SPSS 15.0.The quantitative data was analysised by t-test and Variance analysis.The independent sample t-test was used in comparison among groups, paired sample t-test was used in comparison before and after treatment,and Variance analysis was ued in pairwise comparison between groups.The enumeration data was analysised by Chi-square test. Chi-square test was used in rate comparison andRidit analysis was used in ranked data.
Results:
(1) Compared between before and after the treatment within the groups:Threegroups of angina pectoris effect scores decreased obviously(P< 0.05 or P< 0.01).The TCM symptoms scores of TCMG and ZXG both declined dramatically(P<0.01),while there was no significant improvement in WMG(P> 0.05).There were improvements in various degrees between three groups in the obvious effective rateand total effective rate of angina curative effect,electrocardiogram(ECG) curative effect and the total effective rates of TCM syndromes.The level of theserum TC,TG and LDL-C of three groups all decreased significantly and the level of HDL-C increased obviously(P<0.01 or P<0.05).The level of five inflammatory factors,such as Fg、hs-CRP、IL-18、MCP-1、MMP-9, declined significantly(P< 0.01 or P< 0.05).The carotid artery intima-media thickness decreased obviously(P<0.05),and the carotid plaques in quantities decreased significantly(P<0.01).
(2) Compared between each treatment groups:The improvement of angina pectorieffect scores in ZXG was superior to the groups of TCMG and WMG(P<0.05),and it was in balance with TCMG in the improvement of TCM symptoms scores(P>0.05). And the ZXG was superior to the groups of TCMG and WMG in the obvious effective rate of angina curative effect,ECG curative effect and the total effective rate of TCM syndromes(P< 0.01).And it was also superior to the groups of TCMG and WMG in decreaseing the level of the serum TC,TG and LDL-C,and rising HDL-C(P< 0.01).And so,it was superior to the groups of TCMG and WMG in decreaseing the level of five inflammatory factors(P<0.01).The ZXG was superior to the groups of TCMG and WMG in lessening the carotid artery intima-media thickness(P<0.01),but it was in balance with TCMG and WMG in reducing the carotid plaques in quantities(P>0.05).
Conclusions:The research shows that the treatment of the therapy of tonifying the kidney and activating blood and dissipating phlegm combined with the Atorvastatin calcium can reduce AS plaque fibrous cap degradation and stabilize AS plaque,so it can achieve better block or delay progression of vulnerable plaques for action,and for individual patients it also can reverse the AS plaque,thus effectively reduce CHD patients with acute cardio-cerebro vascular events.The above functions mainly take effect through the following several aspects,such as the apparent improvement of angina pectori effect and the TCM symptoms scores,the significant effect of the obvious effective rateand total effective rate of angina curative effect,electrocardiogram(ECG) curative effect and the total effective rates of TCM syndromes,decreaseing the level of the serum TC,TG and LDL-C,and rising HDL-C,decreaseing the level of five inflammatory factors,lessening the carotid artery intima-media thickness and the carotid plaques in quantities.We can conclude that it may be one mechanism of treatment of AS by the therapy of tonifying the kidney and activating blood and dissipating phlegm,by adjusting the body lipid and inflammatory factor levels.This study opens a new direction for the treatment of AS disease by combination of TCM with western medicine and provide a scientific,objective and strong theoretical basis.
2 Animal Experimental Study
Objective：The study investigates the mechanism of the inflammatory factors of the AS plaques of experimental rabbit models by therapy of tonifying the kidney and activating blood and dissipating phlegm,and to discuss the advantages of combination of TCM with western medicine in the treatment of AS and stabilizing AS plaques.The above functions mainly take effect through the following several aspects,including influence on the levels of lipid and lipoprotein,such as TC,TG,HDL-C and LDL-C and the five inflammatory factors,such as Fg,hs-CRP,IL-18,MCP-1 and MMP-9.
Methods：The study selected 50 healthy male purebred rabbits of New Zealand,2weeks after feeding observation adaptability,all rabbits were randomly divided into 5 groups,Blank Control Group(BCG),Model Group(MG),Traditional Chinese Medicine Group (TCMG),West Medicine Group(WMG),Zhong Xi Group(ZXG).There were 10 rabbits in every groups,and the later four groups were made into model.Besides the BCG rabbits were feed with the ordinary food,the other four groups were all established AS model through combined method,which was feeding high-lipid diet and injecting bovine serum albumin(BSA) via rabbit's ear vein to cause autoimmune endothelial injury.MG rabbits were just given high-lipid diet to bulid the modle,not given any drug treatment.MG and other three treatment groups were feed with high-lipid diet for about 12 weeks.Compared with BCG group after becoming successful model,the treatment groups of TCMG,WMG and ZXG were treated by intragastric administration for 12 weeks,which were respectively given by decoction of tonifying the kidney and activating blood and dissipating phlegm,Atorvastatin calcium and combination of TCM with western medicine.After the treatment,at 20 weekend, three treatment groups' rabbits were observed on the levels of the blood lipid and lipoprotein, and five serum inflammatory factors.The pathological morphology of AS aorta were observed,including macroscopic observation,examined by Hematoxylin-Eoin(HE) staining,immunohistochemical study(MCP-1 and MMP-9) and transmission electron microscopy.And we also calculated the positive cells express percentage of MCP-1 and MMP-9.The numerical values were expressed by mean±standard deviation(X±S) and statistical analyzed with the soft ware of SPSS 15.0.The quantitative data was analysised by t-test and Variance analysis.The independent sample t-test was used in comparison among groups, paired sample t-test was used in comparison before and after treatment,and Variance analysis was ued in pairwise comparison between groups.The enumeration data was analysised by Chi-square test. Chi-square test was used in rate comparison.
Results:
(1) The detected results of lipid and lipoprotein: Compared with BCG,the level of TC,TG,HDL-C and LDL-C of the other four groups increased significantly(P< 0.01).Compared with MG,the level of the serum TC,TG and LDL-C of three treatment groups all decreased significantly and the level of HDL-C increased obviously(P<0.01 or P< 0.05).Compared between each treatment groups,the group of ZXG was superior to the groups of TCMG and WMG in decreaseing the level of the serum TC,TG and LDL-C,and rising HDL-C(P<0.05或P<0.01).And compared with TCMG,the group of WMG was superior to the TCMG in decreaseing the level of the serum TC,TG and LDL-C,and rising HDL-C(P<0.05).
(2) The detected results of the five inflammatory factors:Compared with BCG before the treatment,the level of Fg、hs-CRP、IL-1、MCP-1 and MMP-9 of the other four groups increased significantly(P<0.01).The level of the five inflammatory factors,such as Fg、hs-CRP、IL-18、MCP-1 and MMP-9, declined significantly compared between before and after the treatment within the three groups(P<0.01 or P< 0.05).Compared between each treatment groups,with MG,the level of the five inflammatory factors of the three treatment groups declined significantly(P<0.01).The group of ZXG was superior to the groups of TCMG and WMG indecreaseing the level of five inflammatory factors(P< 0.01).And compared with TCMG,the group of WMG was superior to the TCMG in decreasing the level of the hs-CRP(P<0.05),but the other four indicators had no differences(P>0.05).
(3) The comparison of the positive cells express percentage of MCP-1 and MMP-9:Compared with BCG,the positive cells express percentage of MCP-1 and MMP-9 in the other four groups increased significantly(P< 0.01).Compared with MG,the percentage of the three treatment groups all decreased obviously(P<0.01 or P<0.05).The group of ZXG was superior to the groups of TCMG and WMG in decreaseing the positive cells express percentage of MCP-1 and MMP-9(P<0.01),but had no differences between TCMG and WMG(P> 0.05).
Conclusions:
(1) It is a successful method to establish rabbits AS model through feeding high-lipid diet and injecting bovine serum albumin via rabbit's ear vein.
(2) The research shows that the treatment of the therapy of tonifying the kidney and activating blood and dissipating phlegm combined with the Atorvastatin calcium may be superior to the groups of TCMG and WMG in improving the level of the lipid and lipoprotein.We can conclude that it may be one mechanism of treatment of AS and stabilizing AS plaque by adjusting the body lipid levels.
(3) The therapy of tonifying the kidney and activating blood and dissipating phlegm combined with the Atorvastatin calcium may be superior to the groups of TCMG and WMG in decreasing the levels of five inflammatory factors and the positive cells express percentage of MCP-1 and MMP-9.We can draw the conclusion that the combination of TCM with western medicine can achieve better block or delay progression of vulnerable plaques.The above functions mainly take effect through the following several aspects,such as restraining the levels of inflammatory factors of rabbits's AS plaque,reducing AS plaque fibrous cap degradation and stabilizing AS plaque.We can infer that the levels of inflammatory factors may be a important element to decide plaque ulnerability.
(4) Kidney deficiency combined with phlegm and blood stasis is one of the most important pathogenesis,which can influence the occurrence and development of AS.The combination therapy mode of tonifying the kidney and activating blood and dissipating phlegm combined with the Atorvastatin calcium can have effcet from different angles and more targets on regulating the levels of blood lipid,decreaseing the levels of inflammatory factors,restraining AS plaque fibrous cap degradation and protecting vascular endothelial cells function,and so on.Thus it can achieve better block or delay progression of vulnerable plaques for action,and effectively reduce the corresponding to the incidence of adverse events. So we infer that it can restrain the relevant inflammatory factors of AS patients through the therapy of tonifying the kidney and activating blood and dissipating phlegm.
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