节点文献
“以脾论治，内清外柔”法对高血脂致动脉粥样硬化家兔脂质代谢及血管内皮功能影响的实验研究
【作者】 李曦明；
【导师】 周学文；
【作者基本信息】 辽宁中医学院 ， 中医内科学， 2005， 博士
【摘要】 背景:动脉粥样硬化是多因素疾病,病因复杂。大量的流行病学研究表明,动脉粥样硬化导致的冠心病和脑卒中仍是世界范围内,尤其是工业化国家人群的两大主要死亡原因。我国自20世纪50年代以来,主要疾病死亡率和死亡原因的构成都发生了很大变化。心脑血管疾病死亡人数占总死亡人数的比例也由1957年的12.07%升高到1997年的39.4%,动脉粥样硬化(AS)的发病机理一直是医学领域内的重要研究课题。经过科学家们百余年的努力,虽对动脉粥样硬化发病学中的很多环节有了较为深入的了解,但其确切的始动原因尚未清晰和确定。有关动脉粥样硬化的发病机理学说甚多,如脂质浸润学说、血栓源学说、血液动力学学说、中层平滑肌细胞增生学说、内膜损伤学说及受体缺失学说等,现逐渐明确动脉粥样硬化的发病机理是一个复杂的、综合性的较长过程。尽管每个学说都存在各自的局限性,但了解各学说的主要观点及创立依据和背景,对于了解动脉粥样硬化的病变发展过程和指导预防治疗都有很大的益处,目前比较有影响的动脉粥样硬化发病学说,有几大假说,分别是血栓形成学说,脂质浸润学说、炎症学说、氧化学说和损伤反应假说等。目前治疗血脂异常、动脉硬化的药物,除少数中药外,绝大多数均来自国外或合资企业,其专利权仍属国外,价格昂贵,而且这些药物对肝、肾功能会产生一定的影响,不利于长期服用。研制毒副作用小,疗效显著、具有多靶点综合治疗效应的中药复方制剂,不仅具有广泛的市场需求,也必将带来巨大的社会效益和经济效益。本实验所用中药脂脉康是辽宁中医学院附属医院内科周学文教授的临床经验处方,在临床上应用数年,在对高脂血症及动脉硬化的防治上已取得了很好的疗效,同时周学文教授在治疗法则上提出了“以脾论治,内清外柔”治疗高脂血症及动脉粥样硬化病的思想,为指导中医药治疗本病开辟了一条新的途径。本研究从基础医学出发探讨中药脂脉康防治动脉硬化的作用机制,按照比较公认的动脉粥样硬化的发病机制从多角度探讨中药防治动脉粥样硬化的作用机理。 目的:通过建立新西兰家兔高脂血症模型,探讨高脂血症与动脉粥样硬化的关系;通过对家兔血脂、免疫及基因指标的检测,探讨脂脉康方剂降低血脂,抑制动脉粥样硬化发展的机理,并同血脂康、辛伐他汀进行比较,为脂脉康在临床的进一步应用提供理论依据,同时阐明“以脾论治,内清外柔”防治高脂血症及动脉粥样硬化的学术思想。 方法:1、通过喂饲高脂饲料,建立高脂血症家兔模型;2、分别通过六组实验观察脂脉康对动脉粥样硬化家兔血脂水平,血清载脂蛋白,主动脉及内皮细胞形态学,免疫功能,肝细胞LDLR基因表达,平滑肌细胞凋亡及Bcl-2和Fas蛋白表达的影响。 结果:1通过喂饲高脂饲料后的家兔血脂检测结果及主动脉病理变化,表明已成功建立高脂血症家兔模型;2、脂脉康可有效降低血脂水平。3、通过电镜及光镜观察血管内皮细胞和腹主动脉病理形态,表明脂脉康具有较好的防止内皮细胞损伤,减轻血管内膜脂斑形成的作用。4、通过对C反应蛋白、可溶性细胞闯粘附分子-1的检测,表明脂脉康方剂可调节家兔的免疫功能5、脂脉康可有效上调肝细胞低密度脂蛋白受体基因的表达6、脂脉康可通过调节Bcl-2和Fas蛋白的表达而影响平滑肌细胞的凋亡,从而达到抗AS的作用。 结论:脂脉康方剂能在导致高脂血症及动脉粥样硬化形成的多种环节上从整体水平及基因分子水平等多层次、多环节、多靶点调整机体脂质代谢和动脉血管内皮细胞及血管平滑肌细胞的功能,在高脂血症及动脉硬化的防治中可起重要作用。
【Abstract】 Background: The Atherosclerosis (AS) is multi-factors disease, causes of which is so complicated. A great deal of Epidemiology research express that the diseases as cerebral apoplexy and coronary heart disease caused by atherosclerosis are still the main causes of death throughout the world, especially in industrialized countries. Since 1950’ s , a great change had been taken place in the constituent of mortality rate and death. Deaths rate of cardiovascular disease (CVD) present 12.07 in 1957, and 39. 4% in 1997, the mechanism of AS had long been studied as an important research subject in the medical field. Through the scientists’ efforts, some main sectors of the mechanism of AS had been intensive understood, but the initiation factor are still uncertain. At present, there existed a number of theories of AS, which had been accepted, such as lipid infiltration theory, Embolization theory, inflammation theory, oxidizing reaction theroy, damaging reaction theory, receptor deficiency etc. it has been increasingly recognized that the progress of AS is a complicated and synthetic process. In addition to a handful of Chinese herbal medicines, there are also some drugs which can treat dyslipidemia and AS, and the majority of which comes from abroad or joint ventures, their patent right still didn’ t belonged to us, the price were expensive, and those medicines will produce certain influence to the function of liver and kidney, and be inimical to use in a long period of time. So the need for Chinese compound preparation with low side effect, high efficacy, multi-target was increasing. The experiment was preformed by "Zhi-mai-kang" prescription, which developed by Professor Zhouxuewen, it had been used in clinic for long time, and a satisfactory curative effect had been achieved. On the basis of clinic practice, Professor Zhou brought forward the theory of dealing with the treatment of dyslipdemia and AS of spleen and clearing interior and softening exterior. On the base of accepted mechanism of AS, the theory provided a new way in treating the disease in TCM, from different angles to probe into the effective mechanism of Zhimaikan prescription. Objects:1 To probe into the relationship between hyperlipidemia and AS with the hyperlipidemia models of New Zealand rabbits.2 To probe into the mechanism of inhibiting AS with Zhimaikan, by detecting the blood-lipid, immune marker, genetic marker etc, and compared with XuezhiKang and simvastain. In TCM, to bring out the meaning of the theorythat treatment of dyslipdemia and as of spleen and clearing interior and softening exterior. Methods:1. To establish hyperlipideraia models of New Zealand rabbits by high-lipid forage breeding.2. A series of experiments were respectively carried out. In those experiments, certain indices was observed, such as the pathological changes in endarterium and liver.3. To study the effects of ZHI-MAI-KANG by detecting the levels of Oreactive protein and intercellular adhesion molecule-1 by ELISA.4. To study the effects of ZHI-MAI-KANG by detecting the levels the gene of lowdensity lipoprotein receptor through hybridization in situ.5. To study the influence to apoptosis of VSMC by investigating the expression of Bcl-2 and fas gene with flow cytometry.Results: the result of this study indicated that the model was made successfully, and zhimaikan had the ability to decrease level of blood-lipid, prevent endothelial damage, mitigate formation of plaque on intima vasorum, modulate immunologic function, up-regulate the expression of LDL receptor gene on liver cell, influence apoptosis of VSM cell by interfering expression of Bcl-2 and Fas genes. Conclusions:Zhimaikan have an ability of regulating metabolism of blood-lipid, anti-AS and regulating function of artery endotheliocyte and smooth muscle cell. It’ s function is based on the muti-levels, mutli-links, mutli-targets.