动物造模,药效评价,肝硬化 z-bio 2024-08-22 454

　　(1) Method of replication: Adult male rats were intraperitoneally injected with 0.5% dimethylnitrosamine (DMNA) at a dose of 10mg/kg body weight for 3 consecutive days per week, once a day, for a total of 4 weeks. Alternatively, thioacetamide (TAA) can be administered intraperitoneally at a dose of 100mg/kg body weight, doubling the first dose and once every 2 days for 13 consecutive weeks. Alternatively, TAA can be mixed with distilled water to form a 0.03% solution as the only drinking water for animals and fed continuously for 12 weeks. Alternatively, adult mice can be selected and intraperitoneally injected with 10% D-galactosamine (DGA) at a dose of 250mg/kg body weight, once a day, six times a week, for six consecutive months. After modeling, whole blood was extracted and liver was harvested for biochemical and histopathological examination.

　　(2) Model characteristics: After 2-4 weeks of DMNA modeling, serum alanine aminotransferase (ALT), gamma glutamyltranspeptidase (GGT), alkaline phosphatase (ALP) activity, serum total bilirubin (TBIL), total bile acid (TBA), and liver tissue hydroxyproline (Hyp) content increased, while albumin (Alb) content decreased. The liver tissue showed extensive bleeding and necrosis, inflammatory cell infiltration, and diffuse proliferation of sinusoidal wall cells and fibrous tissue, forming thick complete septa and pseudolobules. 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 tissue also decreased. Liver tissue showed the formation of pseudolobules. After 6 months of DGA modeling, the model animals showed progressive bile duct hyperplasia and fibrous septa formation.

　　(3) Comparative medicine, including chemical substances such as drugs, is one of the important causes of liver damage and cirrhosis. In clinical practice, the mechanism of drug-induced liver disease varies by variety and is very complex, but it is mainly divided into two types: direct cytotoxicity and specific constitutional response. The liver damage caused by the former is generally foreseeable, specific to certain drugs, and dose-dependent, while the latter only occasionally occurs in certain sensitive individuals and is difficult to predict whether it occurs or not, regardless of the dosage. Isoniazid can cause mild and transient elevation of transaminase in 20% of patients, which gradually develops into chronic hepatitis and cirrhosis after continuous use for one year. Therefore, low-dose and long-term continuous use are often necessary prerequisites for drugs and chemicals to induce human cirrhosis, and are also important steps in replicating animal models of cirrhosis. Low dose and long-term use of carcinogens can induce cirrhosis and liver cancer. The commonly used carcinogens in mold making include DMNA, diethylnitrosamine (DENA), TAA, etc. As the liver is the main organ for metabolism, once it enters the body, the damaged body parts are mainly liver cells. For example, DMNA undergoes microsomal transformation to form strong alkylates, which can cause damage to intracellular macromolecules. In the acute phase, it can lead to necrosis and lipid changes in acinar zone 3, while in the chronic phase, it can cause liver fibrosis, cirrhosis, and liver tumors; Among them, TAA can generate electrophilic active group products through metabolism, which can interfere with RNA transfer in liver cell nuclei, affect protein synthesis and enzyme activity, increase nuclear DNA synthesis and mitosis, and promote the development of liver cirrhosis; Low doses of TAA induce hepatocyte apoptosis, while high doses lead to lipid oxidation and central necrosis of the lobules, resulting in liver fibrosis tissue changes similar to those observed in human cirrhosis; Long term use of low-dose DGA can also induce liver fibrosis, cirrhosis, and liver cancer. DGA is not the original plasma that directly kills liver cells, but an indirect inductive toxin. After entering the body, DGA can cause the capture of uridine triphosphate (UTP) in the liver, hinder the synthesis of glycogen, RNA, and glycoproteins, deplete glutathione, activate liver macrophages, release a large amount of TNF-a, leading to functional and structural damage to liver cells, and inducing liver tissue necrosis and apoptosis. Characteristics of DMNA, DENA, and TA models: easy to operate, stable, and capable of simultaneously studying the pathological process of portal hypertension in liver cirrhosis and the mechanism of liver cirrhosis to liver cancer transformation. However, they are highly toxic, volatile, and have a low modeling rate. Characteristics of DGA model: It is dose-dependent, with pathological changes similar to viral hepatitis. It can simultaneously observe the pathological process of portal hypertension in cirrhosis and study the reversibility of liver fibrosis. The model has good repeatability, but the modeling dose is large, the cycle is long, the drug price is expensive, and animals are prone to liver failure and high mortality rate, which limits the popularity and widespread application of this model.