Abstract
Animal models of hepatic fibrosis provide a means to study the cell and molecular mediators of fibrosis in a serial manner during both progression and recovery.
Several approaches to induction of fibrosis have been described. Of these, CCl4 intoxication in rats and mice is probably the most widely studied. In addition, the CCl4 model is the best characterized with respect to histological, biochemical, cell, and molecular changes associated with the development of fibrosis. CCl4 can be given intraperitoneally or by oral gavage; it induces zone III necrosis and hepatocyte apoptosis with associated hepatic stellate cell activation and tissue fibrosis. With repetitive dosing CCl4 can be used to induce bridging hepatic fibrosis (4 wk of twice-weekly dosing), cirrhosis (8 wk of twice-weekly dosing) and advanced micronodular cirrhosis (12 wk of twice-weekly dosing). In addition, for each of these models spontaneous recovery from fibrosis can be studied after cessation of dosing. Mechanistic studies using gene knockout and transgenic animals can also be established using CCl4. Together these models have provided unparalleled insights into the mechanisms underlying hepatic fibrosis.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ala-Kokko, L., Stenback, F., and Ryhanen, L. (1989) Preventative effect of malotilate on dimethylnitrosamina-induced liver fibrosis in rats. J. Lab. Clin. Med. 113, 177–183.
Cameron, G. R. and Karunaratne, W. A. E. (1936) Carbon tetrachloride cirrhosis in relation to liver regeneration. J. Pathol. Bacteriol. 42, 1–21.
Igarashi, S., Hatahara, T., and Nagai, Y. (1986) Anti-fibrotic effects of Malotilate on liver fibrosis induced by carbon tetrachloride in rats. Jpn J. Exp. Med. 56, 235–245.
Madden, J. W., Gertman, P. M., and Peacock, E. E. (1970) Dimethylnitrosamine induced hepatic cirrhosis — a new canine model of an ancient human disease. Surgery 68, 260–268.
Marrione, T. G. (1949) Factors influencing the collagen content in experimental cirrhosis. Am. J. Pathol. 25, 273–285.
Martinez-Hernandez, A. (1985) The hepatic extracellular matrix 11 Electron immunohistochemical studies in rats with CCl4 induced cirrhosis. Lab. Invest. 53, 166–186.
Nakamura, N., Fusamoto, H., and Koizumi, T. (1975) The effects of aminoacetonitrile and its derivative on components of hepatic connective tissue in rats with chronic hepatic injury. Acta Hepatogastroenterol. 22, 78–84.
Rojkind, M. and Dunn, M. A. (1979) Hepatic fibrosis. Gastroenterology 76, 849–863.
Rubin, E., Hutterer, F., and Popper, H. (1963) Cell proliferation and fibrous formation in chronic carbon tetrachloride intoxication. Am. J. Pathol. 42, 715–728.
Zimmerman, H. (1976) Experimental hepatotoxicity, in Experimental Production of Disease, Part 5: Liver. (Eiciler, O., ed.), Springer-Verlag, Berlin: pp. 1–120.
Ballardini, G., Degli, E. S., and Bianchi, F. B. (1983) Correlation between Ito cells and fibrogenesis is in an experimental model of hepatic fibrosis. A sequential stereological study. Liver 3, 58–63.
Dunn, M. A., Rojkind, M., and Warren, K. S. (1977) Distribution of Ito cells in experimental hepatic fibrosis. J. Clin. Invest. 59, 666–674.
Yokoi, Y., Namihisa, T., Matsuzaki, K., Miyazaki, A., and Yamaguchi, Y. (1988) Distribution of Ito cells in experimental hepatic fibrosis. Liver 8, 48–52.
Issa, R., Williams, E., Trim, N., et al. (2001) Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors. Gut 48, 548–557.
Tams, E. G. (1957) Morphological and functional changes in the livers of rats after ligation and excision of the common bile duct. Am. J. Pathol. 33, 13–27.
Tsukamoto, H., Matsuoka, M., and French, S. W. (1990) Experimental models of hepatic fibrosis: A review. Semin. Liver Dis. 10, 56–65.
Tamayo, R. P. (1983) Is cirrhosis of the liver experimentally produced by CCl4 an adequate model of human cirrhosis? Hepatology 3, 112–120.
Maher, J. J. and McGuire, R. F. (1990) Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo. J. Clin. Invest. 86, 1641–1648.
Iredale, J. P., Benyon, R. C., Arthur, M. J. P., et al. (1996) Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis. Hepatology 24, 176–184.
Iredale, J. P., Benyon, R. C., Pickering, J., et al. (1998) HSC apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J. Clin. Invest. 102, 538–549.
Issa, R., Zhou, X., Trim, N., et al. (2003) Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4 induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocytes regeneration. FASEB J. 17(1), 47–49.
Wright, M. C., Issa, R., Smart, D. E., et al. (2001) Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology 121, 685–698.
Oakley, F., Trim, N., Constandinou, C. M., et al. (2003) Hepatocytes express nerve growth factor during liver injury: evidence for paracrine regulation of hepatic stellate cell apoptosis. Am. J. Pathol. 163(5), 1849–1858.
Zengdun, S., Wakil, A. E., and Rockey, D. C. (1994) Strain specific differences in mouse hepatic wound healing are mediated by divergent T. helper cytokine responses. Proc. Natl. Acad. Sci. USA 94(20), 10663–10668.
Iredale, J. P. (2003) Cirrhosis: new research provides a basis for rational and targeted treatments. BMJ 327(7407), 143–147.
Acknowledgments
The authors gratefully acknowledge the support of the MRC UK (Snr Clinical Fellowship to JPI), The Childrens Liver Disease Foundation (project grant to JPI), and the Welcome Trust (Clinical Fellowship to NH).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Humana Press Inc.
About this protocol
Cite this protocol
Constandinou, C., Henderson, N., Iredale, J.P. (2005). Modeling Liver Fibrosis in Rodents. In: Varga, J., Brenner, D.A., Phan, S.H. (eds) Fibrosis Research. Methods in Molecular Medicine, vol 117. Humana Press. https://doi.org/10.1385/1-59259-940-0:237
Download citation
DOI: https://doi.org/10.1385/1-59259-940-0:237
Publisher Name: Humana Press
Print ISBN: 978-1-58829-479-1
Online ISBN: 978-1-59259-940-0
eBook Packages: Springer Protocols