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Molecular Biology Reports

, Volume 38, Issue 3, pp 1687–1696 | Cite as

A natural process of cirrhosis resolution and deceleration of liver regeneration after thioacetamide withdrawal in a rat model

  • Ke Gu
  • Jian-Dong Zhao
  • Zhi-Gang Ren
  • Ning-Yi Ma
  • Song-Tao Lai
  • Jian Wang
  • Jin Liu
  • Guo-Liang Jiang
Article

Abstract

Characteristics of thioacetamide (TAA)-induced liver cirrhosis in rat was observed for 120 days after TAA withdrawal as part of the radiobiological study of partial liver irradiation on TAA-induced cirrhotic rats. The natural process focused on cirrhosis and regeneration was recorded as a baseline condition for the interpretation of the outcome of the partial liver irradiation study. Cirrhosis in rats was successfully induced by drinking 0.03% TAA water orally for 29 weeks with a modeling rate of 96%. After establishment of the cirrhosis model, the rats were observed for 120 days upon TAA withdrawal to investigate the dynamic changes of cirrhosis and regeneration. The following characteristics were observed: (1) Histological changes; (2) Liver functions; (3) Cirrhosis: trichrome stain, quantification of hydroxyproline in hydrolysed liver tissue and TGF-β1; (4) Liver regeneration: liver index, hepatocyte mitotic index (MI), hepatocyte proliferation index (PI) by flow cytometry, PCNA labeling index (LI) by IHC and expression of PCNA mRNA; and (5) Growth factors: serum HGF, VEGF, TGF-α, and IL-6. After TAA withdrawal, gradual improvement in liver functions was noted with decreases of ALT, AST, and ALP, and increase of PA. The resolution of cirrhosis was evident by histological improvement with attenuation of collagen fiber and decrease of TGF-β1 IHC index, and also decrease of trichrome stain and hydroxyproline content. However, cirrhosis was still existed on 120 days after TAA withdrawal. Significant deceleration of liver regeneration was demonstrated with TAA withdrawal, evidenced by decrease of MI and PI, reduced expression of PCNA mRNA and PCNA LI. In conclusion, upon TAA withdrawal hepatic cirrhosis was continuously resolved, but persisted up to 120 days, and liver regeneration was significantly decelerated.

Keywords

Thioacetamide Liver cirrhosis Liver regeneration 

Notes

Acknowledgments

This study was supported by the National Science Foundation of China (Grant no. 30800279) and in part by Grant 2004-826 from the Ministry of Public Health, People’s Republic of China. Authors thank Shiang Jiin Leaw, M.D. for her assistance in the English editing of this article.

References

  1. 1.
    Schuppan D, Afdhal NH (2008) Liver cirrhosis. Lancet 371:838–851CrossRefPubMedGoogle Scholar
  2. 2.
    Zhang HB, Wu J, Xian J et al (2008) Two approaches to construct mammalian expression vector of shRNA to reduce expression and replication of HBV in vitro. Mol Biol Rep 35:465–472CrossRefPubMedGoogle Scholar
  3. 3.
    Seeger C, Mason WS (2000) Hepatitis B virus biology. Microbiol Mol Biol Rev 64:51–68CrossRefPubMedGoogle Scholar
  4. 4.
    Müller A, Machnik F, Zimmermann T et al (1988) Thioacetamide-induced cirrhosis-like liver lesions in rats–usefulness and reliability of this animal model. Exp Pathol 34:229–236PubMedGoogle Scholar
  5. 5.
    Liu EH, Chen MF, Yeh TS et al (2007) A useful model to audit liver resolution from cirrhosis in rats using functional proteomics. J Surg Res 138:214–223CrossRefPubMedGoogle Scholar
  6. 6.
    Iredale JP, Benyon RC, Pickering J et al (1998) Mechanism of spontaneous resolution of rat liver fibrosis: hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 102:538–549CrossRefPubMedGoogle Scholar
  7. 7.
    Neuman RE, Logan MA (1950) The determination of hydroxyproline. J Biol Chem 184:299–306PubMedGoogle Scholar
  8. 8.
    Xiang Y, Lin G, Zhang QJ et al (2008) Knocking down Wnt9a mRNA levels increases cellular proliferation. Mol Biol Rep 35:73–79CrossRefPubMedGoogle Scholar
  9. 9.
    Waters NJ, Waterfield CJ, Farrant RD et al (2005) Metabonomic deconvolution of embedded toxicity: application to thioacetamide hepato- and nephrotoxicity. Chem Res Toxicol 18:639–654CrossRefPubMedGoogle Scholar
  10. 10.
    Torres MI, Fernandez MI, Gil A et al (1998) Dietary nucleotides have cytoprotective properties in rat liver damaged by thioacetamide. Life Sci 62:13–22CrossRefPubMedGoogle Scholar
  11. 11.
    Zimmermann T, Muller A, Machnik G et al (1987) Biochemical and morphological studies on production and regression of experimental liver cirrhosis induced by thioacetamide in Uje: WIST rats. Z Versuchstierkd 30:165–180PubMedGoogle Scholar
  12. 12.
    Yeh TS, Ho YP, Huang SF et al (2004) Thalidomide salvages lethal hepatic necro inflammation and accelerates recovery from cirrhosis in rats. J Hepatol 41:606–612CrossRefPubMedGoogle Scholar
  13. 13.
    Fontana L, Moreira E, Torres MI et al (1998) Dietary nucleotides correct plasma and liver microsomal fatty acid alterations in rats with liver cirrhosis induced by oral intake of thioacetamide. J Hepatol 28:662–669CrossRefPubMedGoogle Scholar
  14. 14.
    Fontana L, Moreira E, Torres MI et al (1996) Serum amino acid changes in rats with thioacetamide-induced liver cirrhosis. Toxicology 106:197–206CrossRefPubMedGoogle Scholar
  15. 15.
    David P, Alexandre E, Chenard-Neu MP et al (2002) Failure of liver cirrhosis induction by thioacetamide in Nagase analbuminaemic rats. Lab Anim 36:158–164CrossRefPubMedGoogle Scholar
  16. 16.
    Seong J, Han KH, Park YN et al (2003) Lethal hepatic injury by combined treatment of radiation plus chemotherapy in rats with thioacetamide-induced liver cirrhosis. Int J Radiat Oncol Biol Phys 57:282–288CrossRefPubMedGoogle Scholar
  17. 17.
    Li XN, Benjamin IS, Alexander B (2002) Reproducible production of thioacetamide-induced macronodular cirrhosis in the rat with no mortality. J Hepatol 36:488–493CrossRefPubMedGoogle Scholar
  18. 18.
    Issa R, Zhou XY, Constandinou CM et al (2004) Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking. Gastroenterology 126:1795–1808CrossRefPubMedGoogle Scholar
  19. 19.
    Bruck R, Genina O, Aeed H et al (2001) Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats. Hepatology 33:379–386CrossRefPubMedGoogle Scholar
  20. 20.
    Popov Y, Patsenker E, Bauer M et al (2006) Halofuginone induces matrix metalloproteinases in rat hepatic stellate cells via activation of p38 and NFкB. J Biol Chem 281:15090–15098CrossRefPubMedGoogle Scholar
  21. 21.
    Wang X, Chen Y, Lv L et al (2010) Inhibition of latent transforming growth factor-b1 activation by lentivirus-mediated short hairpin RNA targeting the CD36 gene in NR8383 cells. Mol Biol Rep 37:1649–1655CrossRefPubMedGoogle Scholar
  22. 22.
    Rube CE, Uthe D, Schmid KW et al (2000) Dose-dependent induction of transforming growth factor (TGF-) in the lung tissue of fibrosis-prone mice after thoracic irradiation. Int J Radiat Oncol Biol Phys 47:1033–1042CrossRefPubMedGoogle Scholar
  23. 23.
    Martin M, Lefaix JL, Delanian S (2000) TGF-β1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 47:277CrossRefPubMedGoogle Scholar
  24. 24.
    Schnur J, Ola′h J, Szepesi A et al (2004) Thioacetamide-induced hepatic fibrosis in transforming growth factor beta-1 transgenic mice. Eur J Gastroenterol Hepatol 16:127–133CrossRefPubMedGoogle Scholar
  25. 25.
    Gressner AM, Weiskirchen R, Breitkopf K et al (2002) Roles of TGF-b in hepatic fibrosis. Front Biosci 7:d793–d807CrossRefPubMedGoogle Scholar
  26. 26.
    Wolf HK, Michalopoulos GK (1992) Hepatocyte regeneration in acute fulminant and nonfulminant hepatitis: a study of proliferating cell nuclear antigen expression. Hepatology 15:707–713CrossRefPubMedGoogle Scholar
  27. 27.
    Margit Z (1996) Characterization of a cell cycle-dependent nuclear autoantigen. Mol Biol Rep 23:197–203CrossRefGoogle Scholar
  28. 28.
    Fausto N, Campbell JS, Riehle KJ (2006) Liver regeneration. Hepatology 43:s45–s53CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Ke Gu
    • 1
    • 3
  • Jian-Dong Zhao
    • 1
    • 3
  • Zhi-Gang Ren
    • 1
    • 3
  • Ning-Yi Ma
    • 1
    • 3
  • Song-Tao Lai
    • 1
    • 3
  • Jian Wang
    • 2
    • 3
  • Jin Liu
    • 1
    • 3
  • Guo-Liang Jiang
    • 1
    • 3
  1. 1.Department of Radiation OncologyFudan University Shanghai Cancer CenterShanghaiChina
  2. 2.Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
  3. 3.Department of Oncology, Shanghai Medical SchoolFudan UniversityShanghaiChina

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