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Melior Discovery fibrosis

Liver Fibrosis
The two most commonly used models of experimental hepatic fibrosis are induced chemically (carbon tetrachloride; CCl4) or by bile duct ligation (BDL). CCl4 causes hepatocyte damage, necrosis, inflammation, and fibrosis after 4 weeks of treatment and over 8 weeks causes cirrhosis. In contrast, BDL stimulates the proliferation of biliary epithelial cells and oval cells causing proliferating bile ductules with an accompanying portal inflammation and fibrosis.

Liver fibrosis is a wound healing response to acute or chronic injury that results in the excessive deposition of extracellular matrix proteins, i.e., scar tissue. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension. In mice, liver fibrosis induced by carbon tetrachloride (CCl4) resembles important properties of human liver fibrosis including: inflammation, regeneration, and fiber formation. This model is commonly used to study acute liver injury, advanced fibrosis, as well as fibrosis reversal. Additionally the CCl4 induced liver fibrosis model is highly reproducible and therefore an excellent candidate for drug screening.

  

 

                                                 

 

Figure 1. Bodyweights. After the first two doses, animals receiving 5% CCl4 had a significant drop in body weight at day 4. Though these animals continued to grow, they remained 2-5% smaller than their vehicle counterparts. Data are mean ± SEM; *p<0.05 compared to vehicle control.

 

 

                                             

Figure 2. AST levels and ALT levels. Aspartate transaminase (AST) and alanine transaminase (ALT) are commonly measured clinical biomarkers of liver health. Both AST and ALT levels were significantly elevated in CCl4 administered animals for the entire duration of the study, suggesting that liver damage has occurred. Data are mean ± SEM; *p<0.05 compared to vehicle control.

 

                                                         

 

 

Figure 3. PSR Area Percentage and Staining. Picrosirius Red (PSR) staining is a commonly used histopathology technique to visualize collagen in tissue sections. The percentage of PSR detected in liver sections from animals receiving CCl4 was significantly higher than that of vehicle animals, suggesting that fibrosis has been achieved. Sections of liver were also scored for pathology (0= no finding, 1= minimal, 2= mild, 3= moderate, 4= marked, 5= severe). Data are mean ± SEM; **p<0.01 compared to vehicle control.

 

                                                            

 

Figure 4. Hydroxyprline(week4). Hydroxyproline (4-hydroxyproline, Hyp) is a common nonproteinogenic amino acid. Hydroxyproline in tissue hydrolysates is an indirect measure of the amount of collagen present. In line with the results of PSR collagen staining, hepatic Hyp content levels in CCl4-treated animals were significantly higher than vehicle treated animals. Data are mean ± SEM; *p<0.05 compared to vehicle control.

 

 

                                                        

 

Figure 5. Liver weight and Histopathology. The right lobe of the liver was weighed prior to homogenization; livers of the CCl4 group were significantly heavier than those of vehicle animals. This may be related to the hypertrophy and increased swelling found in the pathological analysis.  Data are mean ± SEM; ****p<0.0001 compared to vehicle control.

 

These data support the findings that liver fibrosis by administration of CCl4 has been accomplished.

 

 

If you are interested in learning more about Liver Fibrosis, please contact models@meliordiscovery.com to start the conversation.