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Liver Fibrosis and Cirrhosis

发布时间 2018-03-04
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         Liver Fibrosis and Cirrhosis

         

         Introduction


         Liver fibrosis results from chronic injury such as viral hepatitis (especially hepatitis B and C), alcohol abuse, drugs, metabolic diseases due to overload of iron or copper, congenital abnormalities or autoimmune attack of hepatocytes or bile duct epithelium. It is characterized by the encapsulation or replacement of injured tissue by a collagenous scar. Liver fibrosis is reversible, whereas cirrhosis, the later stage of fibrosis progression, featuring regenerative nodules surrounded by fibrous bands, is generally irreversible. Liver cirrhosis leads to an impaired liver function with an increased intrahepatic resistance (portal hypertension) and the development of hepatocellular carcinoma (HCC). 

         Carbon tetrachloride (CCl4)-induced hepatic fibrosis and cirrhosis in rodents is Liver Fibrosis and Cirrhosisa well-established and widely accepted experimental model for the study of liver fibrosis and cirrhosis. In many aspects it mirrors the pattern of human disease associated with toxic damage. For example, the α-SMA expression, Stellate cell activation and key matrix components including collagen-1, MMPs and their inhibitors TIMPs have been indicated in the pathogenesis of this model. CCl4 induction elicits a reproducible and predictable fibrotic response in liver, making it a valuable basis for preclinical pharmacology studies of anti-fibrotic and anti-cirrhotic therapeutics and the pathophysiology study of liver fibrosis-cirrhosis-HCC changes.     


         

         PharmaLegacy Models and Research Tools   


         

ModelAcute liver injury & fibrogenesis    model                                                                                                                                                                           Fibrosis and cirrhosis model

Animal

BALB/c mice

Wistar rats

Toxin

    CCl4

                                                 CCl4Bile duct ligation
Disease time

Onset Day 1-3, with recovery

Self-limiting injury:1 wkEarly fibrosis: 4 wks

Reversible fibrosis:6 wks

Early cirrhosis: 8 wks

Micronodular cirrhosis:12 wks


Onset 1-10 weeks, no recovery
Similarities to human disease

Acute injury with significant

hepatocellular necrosis

Chronic progression with fibrosis, cirrhosis, ascites and liver

 failure

Chronic progression with fibrosis, cirrhosis. Irreversible
CharacteristicsReliable; Ideal model for studying the effects on acute liver injury and early fibrotic changesThe duration required for cirrhosis mainly depends upon the CCl4 dosage. Liver carcinogenesis may develop due to the carcinogenic effect of CCl4 as well as CCl4-induced liver cirrhosis. Good for investigating hepatocarcinoma growth in the liver cirrhosis environmentRapid progression to cirrhosis. Short term for cholangitic injury; long-term for fibrosis/ cirrhosis
Primary endpoints

           Liver functions:  Serum ALT, AST, bilirubin, globulin and albumin 

Liver fibrogenic stress:  Hepatic hydroxyproline

          Histopathology:  Collagen by Sirius red staining, connective tissue by Masson’s trichrome staining, SMA-α an                                       d collagen IHC

                 Biomarkers:   Collagen I, collagen III, TGF-α, β by quantitative RT-PCR 

                        Ascites:   Incidence and volume

Additional endpoints

         Fibrosis biomarkers:   MMP, TIMP, HGF, TNF-α, cyclin by quantitative RT-PCR, Western blot, or ELISA

Hepatocyte regeneration:   IHC for PCNA, Ki67, BrdU 

                         Apoptosis:   TUNEL

Special endpointsTBARS, Hepatic glutathione, MDA content, Cytochrome P450 2E1Cyclooxygenase-2 (COX-2)

Related Capabilities



*MCD or high fat diet induced non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) 

*Bile duct ligation induced liver fibrosis and cirrhosis in mice

*Primary hepatic stellate cells culture system

Case Study - CCl4 -induced Liver Fibrosis and Cirrhosis Model




Liver fibrosis and cirrhosis induced by chronic injection of CCl4 in Wistar rats

The AST and ALT in blood are increased with the duration of administration; a number of biomarker expressions are significantly increased in the liver at the end of 8 weeks; the hyperplasic nodules, surrounded by the fibrous bands, that are positively stained by Sirius Red are clearly formed in the liver at 16 weeks, but are ameliorated by Compound A treatment. (n=6, *P<0.05, **P<0.01 vs Vehicle by Bonferroni multi-comparison test)


Liver Fibrosis and CirrhosisLiver Fibrosis and Cirrhosis

Liver Fibrosis and Cirrhosis

Liver Fibrosis and CirrhosisLiver Fibrosis and Cirrhosis


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