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CCl4-Induced Liver Fibrosis/Cirrhosis

Liver fibrosis results from chronic injury. It is caused by viral hepatitis (especially hepatitis B and C), alcohol abuse, drugs, metabolic diseases resulting from overload of iron or copper, congenital abnormalities, 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 impaired liver function with increased intrahepatic resistance (portal hypertension) and increased risk of hepatocellular carcinoma (HCC).

Carbon tetrachloride (CCl4)-induced hepatic fibrosis and cirrhosis in rodents is a 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, 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 pathophysiology studies of liver fibrosis-cirrhosis-HCC changes.

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Case Study - CCl4 -induced Liver Fibrosis and Cirrhosis Model

The aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in blood increase 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)


Efficacy Studies for Drug Compounds/Candidates:

·         serum biochemical endpoints

·         fibrotic grade evaluation in liver

·         quantification of fibrotic tissue in liver (Sirius red)

·         quantification of SMA-α positive cells

·         incidence and volume of ascites

Molecular Pharmacology for Proof of Concept Studies:

·         vitality of activated primary stellate cells

·         morphological alterations of the hepatocytes

·         hepatic hydroxyproline, hepatic/serum glutathione, malondialdehyde (MDA) content

·         expression of cyclins, PCNA, Ki67 and BrdU for regeneration of hepatocytes

Molecular Pharmacology for Proof of Concept Studies:

·         angiogenesis inhibitors

·         angiotensin receptor antagonists

·         vasoactive modulators

·         hepatic vasculature analysis by immunostaining of anti-vWF, VEGF-A, angiopoietin-1, angiopoietin-2, placental growth factor

·         VCAM-1, ICAM-1 expression; CD11b, CD3, CD31 expression

·         apoptosis of activated hepatic stellate cells

·         bio-marker analysis of involved signaling pathways

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