动物模型,肝衰竭 z-bo 2020-08-07 549

　　(1) Replication method Adult rats, fasting for 12 hours, are injected with D-Galactosamine (D-Gal) into the abdominal cavity at a dose of 1.2 to 1.8 g/kg body weight. Or adult dogs or large white pigs, underwent general anesthesia, catheterization in the left external jugular vein (used for drug delivery and blood sampling), femoral artery catheterization to monitor blood pressure, and a micro-sensor inserted into the top of the skull to measure intracranial pressure ( ICP), then dissolve D-Gal in 5% glucose injection and inject it into the blood vessel from the external jugular vein at a dose of 0.5-1.5 g/kg body weight. After administration, continuously observe the general condition of the model animals, record the time of death of poisoning, and measure blood pressure, pulse, body temperature, intracranial pressure and other physiological indicators throughout the process, and draw blood regularly for blood and biochemical routine tests and liver and kidney functions For the determination, after the model animal died or was put to death, the liver, heart, lung, kidney and other organs and tissues were taken for pathological examination.

　　(2) Model characteristics: After 12 hours of administration, the model rats showed listlessness, decreased activity, and yellow urine; 30 hours later, their responsiveness to external stimuli decreased, and gradually entered a state of lethargy, with varying degrees of endotoxemia and liver Stage I and II manifestations of sexual encephalopathy; serum ALT was significantly elevated at 12h after administration, then gradually decreased, and returned to normal at 14d; while ALT increased, TBIL, BUN and NH3 levels increased, PT prolonged, and GLU The level drops, the main amino acid content in the plasma increases, and the ratio of branched chain amino acids/aromatic amino acids (BCAA/AAA) decreases. The change trend of the main amino acid content in brain tissue is similar to that in plasma, but the content of aspartic acid and glutamic acid decreases ; At 40h after administration, the EEG frequency slowed down, the amplitude increased, and typical three-phase wave changes appeared; at 48h, a large number of hepatocytes were necrotic, the cytoplasm was vacuolated, the structure of the liver cord was unclear, and the central vein of the liver lobule Obviously dilated congestion; at 7d, liver cells were still necrotic, and there was inflammatory cell infiltration in the portal area. The model rats began to die at 2d, and the survival rate was 20%-30% at 14d. After 18 hours of administration to model pigs, ALT, AST, ALP, LDH, TBIL, cholic acid (TB), NH3, tumor necrosis factor-a (TNF-a) began to increase; 18-24 hours later, the arterial blood ketone body ratio ( AKBR) and GLU gradually decreased, blood indigo green retention rate also increased with time, blood pressure was basically stable, but intracranial pressure increased significantly; autopsy showed that all model animals had light red ascites 5001000ml, liver cirrhosis and shrinkage, and Hemorrhages were scattered in many places, with large necrosis of hepatocytes and hemorrhage, but some live hepatocytes were still seen in the central area of the liver lobules, and no obvious lesions were seen in the remaining organs. The average survival time of model pigs was: 66h for the 0.75g/kg body weight group and 43h for the 1.0g/kg body weight group. The symptoms of model dogs after administration were basically the same as those of model pigs.

　　(3) Comparative medicine D-Gal is an amino sugar, which is metabolized in the liver through the galactose pathway. It has strong liver-specific toxicity and can cause severe hepatocyte necrosis. The main mechanism of action is: specific binding with uridine triphosphate (UTP) to form uridine diphosphate galactosamine (UDP-Gal), and at the same time through phosphorylation to form galactosamine 1 phosphate to inhibit uridine diphosphate glucose (UDPG) ) Pyrophosphatase, resulting in a decrease in UTP content and a severe decrease in UDPG, thereby inhibiting the synthesis of nucleic acid, protein and glycogen in liver cells, destroying the integrity of the liver cell membrane system, causing large doses of Ca influx, leading to liver cell necrosis. In addition, it can also aggravate liver cell damage by causing endotoxemia, depleting glutathione, and activating liver macrophages to release TNF-a. D-Gal is used to replicate acute liver failure models. The most commonly used animals are rats, but also dogs and pigs. The former is usually administered by intraperitoneal injection with a dose between 1.2 and 2.3 g/kg body weight, while the latter is administered by intravenous injection with a dose of 0.5 to 1.5 g/kg body weight. The dosage of D-Gal is significantly related to the nature, degree, and survival time of animal liver injury. The selection of anesthetics and the length of fasting before the experiment will also affect the development of liver toxicity. For example, the anesthetic halothane and D-Gal have a toxic synergistic effect, and fasting for 12 hours before the experiment can increase the liver toxicity of D-Gal. The main advantages of this model are threefold. First, the physical signs, physiological and biochemical indicators, and pathological characteristics of model animals are similar to clinical viral liver failure; second, it has a relatively specific toxic effect on liver tissue, except for only slight congestion or bleeding in the spleen and kidney tissues. , Has no obvious effect on other tissues; third, the model has a high replication success rate, good reproducibility, moderate survival time, and a certain reversibility, which is suitable for treatment research and efficacy evaluation for various experimental purposes. However, due to the high price of D-Gal, its application is limited, especially for model replication of large animals such as dogs or pigs. The large dosage requirements lead to excessive experimental expenses. This may be because the model is more common in rats. The main reason for animal objects.