四氯化碳致急性肝损伤的原理

四氯化碳致急性肝损伤的原理及模型建立

一些肝毒索已经成功地应用于肝衰竭的诱导。目前常用的肝毒素主要有

D．Gal、醋氨酚、CCl4等。D．Gal肝损伤模型的病理改变与人类病毒性肝炎的

病理改变较为接近，肝外毒性不明显，剂量范围易控制，但有潜在的不可逆

性，同时因为D．Gal价格昂贵，大型动物猪或犬建立模型时所用剂量较大，重

复率并不十分理想，也无临床相关的药物中毒，所以限制了它在大型动物造模

方面的应用。CCl4是一种对肝细胞有严重毒性作用的化学物质。目前认为其导致肝损伤

的主要机制与四氯化碳自身和其自由基代谢产物有关，、CCl4在肝内经细胞色素

P450 2El代谢产生毒性代谢产物。CCl4自身的溶酶作用可导致肝细胞损伤，

但这仅限于高浓度的CCl4。CCl4的自由基导致肝损害的过程被认为是主要的机

制。榍文海等报道用杂种犬，将cache与等量花生油混合溶液，以0．9ml／kg一

次腹腔注射建立犬暴发性肝功能衰竭模型。结果，注射CCl4后犬里进行性肝功

能衰竭表现，第72 h血丙氨酸转氨酶、总胆红素、血氨明显升高，凝血酶原时

间延长，血糖降低，(均P<0．01)；脑电图检查出现异常波型。第7d病理检查显

示：肝细胞大片溶解坏死，网状支架大部分存在，肝细胞轻度增生。暴发性肝

功能衰竭形成率为93．0％。动物48～96h死亡率73．O％，14d内肝损害明显恢复。

动物一般表现，实验室及组织学检查表明，整个动物染毒过程，近似于人类的

急性暴发性肝功能衰竭过程。本模型具有以下特点：①动物受损后，经充分的

时间，可以恢复到用药前水平，模型具有可逆性；②受损动物以72h为死亡高

峰，第5d开始恢复，终点十分明确；③实验动物肝功能衰竭时间与死亡时间有

一定间隔，具有适用性和可控制性；④CCl4经济可行，注意保护，对实验人员

毒性不大，较为安全。

亚急性和慢性毒性：动物吸入400ppm，7小时/天，5天/周，173天，部分动物127天后勤部死亡，肝肾肿大，肝脂肪变性，肝硬化，肾小管上皮退行性病变。

Keywords:

•antioxidants;

•caspases;

•carbon tetrachloride;

•liver damage;

•chondroitin-4-sulphate;

•NF-κB;

•oxidative stress;

•free radicals

Background and purpose:

Reactive oxygen species (ROC) are the main causes of carbon tetrachloride (CCl

)-induced acute liver injury. Chondroitin-4-sulphate (C4S) is known to

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inhibit lipid peroxidation through antioxidant mechanisms. Activation of nuclear factor (NF)-κB and caspases may strongly intensify inflammation and cell damage, in addition to that directly exerted by ROS. We investigated

whether treatment with C4S, besides exerting antioxidant activity, was able to

-induced liver injury in mice.

modulate NF-κB and apoptosis activation in CCl

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Experimental approach:

. Varying doses Acute hepatitis was induced in mice by an i.p. injection of CCl

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injection. 24 h of C4S were administered i.p. 1 h before, 6 and 12 h after CCl

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injection, the mice were killed for biochemical and histological after CCl

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analysis.

Key results:

CCl

injection produced: marked elevation of alanine aminotransferase and

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aspartate aminotransferase; hepatic membrane lipid peroxidation, assayed by 8-isoprostane levels; and depletion of reduced glutathione and superoxide dismutase. CCl

also decreased NF-κB translocation and IkBα, and increased

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gene expression of mRNA and protein of metalloproteases (MMP)-2 and -9, and of pro- and cleaved forms of caspases-3 and -7. There was also increased