Liver Fibrosis Models
Liver fibrosis is part of the general wound-healing response to liver damage of various origins and is characterized by the excessive accumulation of extracellular matrix (ECM) components. Liver fibrosis can be caused by a variety of stimuli (congenital, metabolic, infection, inflammatory, parasitic, vascular, toxins or drugs), but the molecular mechanisms underlying fibrosis are basically the same. The hepatic stellate cell (HSC) is the main cellular effector of this phenomenon and the major producer of scar ECM.
Fig.1 Changes in the hepatic architecture (A) associated with advanced hepatic fibrosis (B) (Bataller R. et al, 2005).
Liver fibrosis remains a major health problem as it has a high mortality rate and predisposes to portal hypertension, cirrhosis, liver failure, as well as hepatocellular carcinoma (HCC). Although our understanding of the pathogenesis of liver fibrosis has grown considerably over the last 20 years, effective antifibrotic agents are still lacking. Liver fibrosis models provide significant tools to study the processes underlying fibrogenesis, identify potential therapeutic targets, and develop novel therapies.
Liver Fibrosis Models Provided by Creative Animodel
There are several liver fibrosis models available induced by administration of hepatotoxins (CCl4, TAA), bile duct ligation, immunological mechanisms or transgenic technology. Creative Animodel has established three well-characterized animal liver fibrosis models:
• CCl4-induced model: CCl4 is metabolized by hepatocytes, giving rise to toxic trichloromethyl (CCl3) radicals, which mediate cytotoxic effects and eventually lead to massive centrilobular liver necrosis. The CCl4-induced model is a widely used and reliable animal model of hepatic fibrosis.
• TAA-induced model: Thioacetamide (TAA) is another well-established model of experimental liver fibrosis. TAA is bioactivated in the liver via oxidation processes leading to its S-oxide and the highly reactive S; S-dioxide, which is presumably responsible for TAA hepatotoxicity. Earlier studies suggested that TAA bioactivation involves the hepatic cytochrome P450 enzyme CYP2E2. The TAA-induced liver fibrosis model often serves as a second, independent approach to confirm data obtained from, for example, CCl4-treated animals.
• BDL-induced model: Surgical bile duct ligation (BDL) is the most commonly used to induce obstructive cholestatic injury. BDL stimulates the proliferation of biliary epithelial cells and oval cells causing proliferating bile ductules with an accompanying portal inflammation and fibrosis. This model allows a fast and reproducible way to inflict cholestatic liver injury and can be used in transgenic mice easily, allowing the investigation of cholestatic injury in many different study designs.
Model Characteristics and Pharmacology Evaluation
Relying on our multiple types of animal models, we offer a package of evaluation and validation measures to help evaluate the efficacy of your drug candidates in liver fibrosis disease, including but not limited to:
• Body weight, behavior, food intake, water intake, defecation.
• Liver weight and spleen weight, ascites measurement, portal vein pressure.
• Biomarker analysis.
• Histology analysis.
• Imaging studies.
• Liver biopsy for determining fibrosis score.
Creative Animodel offers several liver fibrosis models for screening, testing, and evaluation of new drugs and formulations. Our scientists will work closely with you to keep you apprised of project progress. Please feel free to contact us for further discussions.
1. Bataller R.; Brenner D A. Liver fibrosis[J]. Journal of clinical investigation, 2005, 115(2): 209.