动物模型,肝硬化 z-bo 2020-08-07 560

　　(1) Replication method Adult male rats were injected intraperitoneally with 0.5% dimethylnitrosamine (DMNA) at a dose of 10 mg/kg body weight for 3 consecutive days a week, once a day, for 4 weeks. Or intraperitoneally inject thioacetamide (TAA) at a dose of 100 mg/kg body weight, double the first dose, and then 1 time/2 days for 13 consecutive weeks, or use distilled water to make a 0.03% solution of TAA as the only drinking for animals Water for 12 weeks of continuous feeding. Or choose adult mice and inject 10% D-galactosamine (DGA) intraperitoneally at a dose of 250 mg/kg body weight, once a day, 6 times a week for 6 months. After modeling, take whole blood and liver for biochemical and histomorphological examination.

　　(2) Model characteristics DMNA model was established for 2 to 4 weeks, serum alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) activity, serum total bilirubin (TBIL) ), total bile acid (TBA) and liver tissue hydroxyproline (Hyp) content increased, albumin (Alb) content decreased, liver tissue showed large areas of hemorrhage and necrosis, inflammatory cell infiltration, liver sinusoid wall cells and fibrous tissue Diffuse hyperplasia, forming thick complete intervals and pseudo-lobules. After 12 weeks of TAA modeling, serum growth hormone (GH) levels increased, insulin-like growth factor-I (IGF-I) levels decreased, and IGF-I mRNA expression levels in liver tissues also decreased. Liver tissues showed the formation of pseudolobules. After 6 months of DGA modeling, the model animals showed progressive bile duct hyperplasia and fibrous septum formation.

　　(3) Comparative Medicine Chemical substances including drugs are one of the important causes of liver damage and cirrhosis. Clinically, the mechanism of drug-induced liver disease varies from species to species and is very complex, but it is mainly divided into two types: direct cytotoxicity and idiosyncratic constitutional response. The liver damage caused by the former is generally predictable, specific to certain drugs and related to the dose of the drug, while the latter only occasionally occurs in some sensitive individuals, and it is difficult to predict whether it occurs or not, and has nothing to do with the dose. For example, isoniazid can cause mild and transient elevation of transaminase in 20% of patients, and then gradually develop chronic hepatitis and liver cirrhosis after one year of continuous use. Therefore, low-dose and long-term continuous use are often necessary prerequisites for drugs and chemicals to cause human liver cirrhosis, and it is also an important step in replicating animal models of liver cirrhosis. Long-term use of low-dose carcinogens can induce liver cirrhosis and liver cancer. Commonly used carcinogens for modeling mainly include: DMNA, diethylnitrosamine (DENA), TAA, etc. Since the liver is the main organ of its metabolism, once it enters the body, the damaged body parts are mainly liver cells. For example, DMNA is transformed into a strong alkylate by microsomal transformation, which can cause intracellular macromolecular damage. In the acute phase, it can cause necrosis and lipid change in the acinar zone 3, and in the chronic phase, liver fibrosis, cirrhosis and liver tumors are formed; among them, TAA Metabolism can generate electrophilic active group products, which can interfere with the transfer of RNA in the liver cell nucleus, affect protein synthesis and enzyme activity, increase nuclear DNA synthesis and mitosis, and promote the development of liver cirrhosis; small doses of TAA induce liver cell apoptosis High-dose causes lipid oxidation and central lobular necrosis, and liver fibrotic tissue changes are close to the performance of human cirrhosis; long-term use of DGA can also induce liver fibrosis, cirrhosis and liver cancer. DGA is not a pure liquid that directly kills liver cells, but an inductive agent that acts indirectly. After DGA enters the body, it can cause the capture of uridine triphosphate (UTP) in the liver, the synthesis of glycogen, RNA, glycoprotein, the depletion of glutathione, the activation of liver macrophages, and the massive release of TNF-a. Lead to functional and structural damage of liver cells, and induce liver tissue necrosis and liver cell apoptosis. DMNA, DENA, TA model features: easy to operate, stable model, can study the pathological process of liver cirrhosis portal hypertension and the mechanism of liver cirrhosis to liver cancer at the same time, but it is highly toxic, volatile, and the modelling rate is not high. DGA model features: dose-dependent, pathological changes are similar to viral hepatitis, can observe the pathological process of liver cirrhosis and portal hypertension and study the reversibility of liver fibrosis at the same time, the model has good repeatability, but the model dose is large and the cycle is long. Drugs are expensive, and animals are prone to liver failure and have a high mortality rate, which limits the popularization and wide application of this model.