Environmental Atherosclerosis Studies

我们早期的研究清楚地表明，NIEHS优先化学品，二硫化碳（CS2）增强动脉粥样硬化，特别是在高脂血症的情况下，强烈表明需要将这种导致美国死亡的主要原因作为影响人类疾病的环境因素的化学测试和机制研究的终点。由于缺乏对这一领域的研究，在进行昂贵和耗时的研究之前，应该确定和测试动脉粥样硬化的适当动物模型。虽然存在禽类、犬、兔和啮齿类动物的动脉粥样硬化模型，但啮齿类动物在菌株表征、近交系的可用性、遗传操作的容易性和成本方面具有明显优势。动脉粥样硬化中的大量机械工作已经利用小鼠;特别是已经被基因工程改造的小鼠，使得参与脂质代谢的各种基因（即Apo-E和LDL受体）已经被破坏或改变，使得动物更容易发展动脉粥样硬化。小鼠的大部分血清脂质以高密度脂蛋白（HDL）的形式携带，几乎没有低密度脂蛋白（LDL），也不会发生动脉粥样硬化。然而，如果将一些菌株如C57 BL/6置于高脂饮食（HFD）中，则它们发展为高脂血症，脂蛋白出现在低密度和中密度带中，并且动物发展为局限于主动脉瓣下的主动脉根部的动脉粥样硬化。在该模型中，CS2主要在HFD动物中显著增强病变。对这种模式有一些批评。首先，动物对动脉粥样硬化具有很强的天然抵抗力，并且必须采用相当极端的饮食，这具有几种毒副作用，包括胆结石、肝阻塞和脾脏中的肉芽肿。其次，动脉粥样硬化的数量在数量上和解剖学上是有限的。第三，病变主要由泡沫细胞和细胞外脂质组成，没有增殖成分，因此不能反映更晚期人类疾病的组成。

Our earlier studies clearly demonstrating that an NIEHS priority chemical, carbon disulfide (CS2) enhanced atherosclerosis, especially in the setting of hyperlipidemia, strongly indicates the need to include this leading cause of death in the USA as an endpoint in chemical testing and mechanistic research into environmental factors influencing human disease. Because of the paucity of research into this area, appropriate animal models of atherosclerosis should be identified and tested before expensive and time consuming studies are undertaken. While there are avian, dog, rabbit, and rodent models of atherosclerosis, rodents have clear advantages in terms of strain characterization, availability of inbred strains, ease of genetic manipulation, and cost. A large amount of mechanistic work in atherosclerosis has utilized the mouse; especially mice that have been genetically engineered such that various genes involved in lipid metabolism (i.e. Apo-E and the LDL receptor) have been disrupted or altered making the animals more prone to the development of atherosclerosis. Mice carry most of their serum lipids in high density lipoproteins (HDL) and have virtually no low density lipoproteins (LDL) and develop no atherosclerosis. However, if some strains such as C57BL/6 are placed on a high fat diet (HFD) they develop hyperlipidemia, lipoproteins appear in the low and intermediate density bands, and the animals develop atherosclerosis limited to the aortic root under the aortic valves. This is the model in which CS2 significantly enhanced lesions mostly in animals on the HFD. There are several criticisms of this model. Firstly, the animals are very resistant to atherosclerosis naturally and a rather extreme diet has to be employed that has several toxic side effects including gallstones, hepatic obstruction, and granulomas in the spleen. Secondly, the amount of atherosclerosis is limited quantitatively and anatomically. Thirdly, the lesions consist mainly of foam cells and extra cellular lipid with no proliferative component and thus do not reflect the composition of more advanced human disease.