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The Treatment with Antibody of TNF-α Reduces the Inflammation, Necrosis and Fibrosis in the Non-alcoholic Steatohepatitis Induced by Methionine- and Choline-deficient Diet

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Abstract

To assess the effects of anti-TNF-α antibody (infliximab) in experimental steatohepatitis induced by methionine- and choline-deficient (MCD) diet. The study included thirty rats. One group received normal rat food, and two groups received MCD diet. The treatment group received a single dose intra-peritoneal infliximab (4 mg/kg), at week 8. MCD diet increased levels of AST, ALT, TNF-α, TGF-β1, tissue and plasma MDA (p < 0.05 for each). Moreover, it led to steatosis, ballooning degeneration, inflammation, fibrosis and increased actin expression, histopathologically (p < 0.05 for each). In this experimental steatohepatitis anti-TNF-α antibody decreased the levels of AST, ALT, TGF-β1 and plasma and tissue MDA (p < 0.05 for each). Moreover, inflammation, necrosis, actin expression and fibrosis decreased in anti-TNF-α group compared to placebo group (p < 0.05 for each). This study indicates that anti-TNF-α antibody is effective on necrosis, inflammation and fibrosis in the experimental model of non-alcoholic steatohepatitis, induced by MCD diet.

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References

  1. Diehl, A. M. 1999. Nonalcoholic steatohepatitis. Semin. Liver Dis. 19:221–229.

    PubMed  CAS  Google Scholar 

  2. Ingue, F. Y., M. Z. Younossi, G. Marchosini, and T. A. McCullough. 2001. Clinical features and natural history of non-alcoholic steatosis syndromes. Semin. Liver Dis. 75:733–739.

    Google Scholar 

  3. Koteish, A., and A. M. Diehl. 2002. Animal models of steatohepatitis. Best Pract. Res. Clin. Gastroenterol. 16:679–690.

    Article  PubMed  CAS  Google Scholar 

  4. Harrison, S. A., S. Kadakia, K. Lang, and S. Schenker. 2002. Non-alcoholic steatohepatitis: what we know in the new millenium. Am. J. Gastroenterol. 97:2714–2724.

    PubMed  CAS  Google Scholar 

  5. Day, C. P., and O. F. James. 1998. Steatohepatitis: a tale of two ‘hits’? Gastroenterology 114:842–845.

    Article  PubMed  CAS  Google Scholar 

  6. Ikejima, K., Y. Takei, H. Honda, M. Hirose, M. Yoshikawa, Y. J. Zhang, T. Lang, T. Fukuda, S. Yamashina, T. Kitamura, and N. Sato. 2002. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 122:1399–1410.

    Article  PubMed  CAS  Google Scholar 

  7. Atzeni, F., P. Sarzi-Puttini, A. Doria, L. Iaccarino, and F. Capsoni. 2005. Potential off-label use of infliximab in autoimmune and non-autoimmune diseases: a review. Autoimmun. Rev. 4:144–152.

    Article  PubMed  CAS  Google Scholar 

  8. Markham, A., and H. M. Lamb. 2000. Infliximab: a review of its use in the management of rheumatoid arthritis. Drugs 59:1341–1359.

    Article  PubMed  CAS  Google Scholar 

  9. Czaja, M. J., J. Xu, and E. Alt. 1995. Prevention of carbon tetrachloride-induced rat liver injury by tumour necrosis factor receptor. Gastroenterology 108:1849–1854.

    Article  PubMed  CAS  Google Scholar 

  10. Hishinuma, I., J. Nagakawa, K. Hirota, K. Miyamoto, K. Tsukidate, T. Yamanaka, K. Katayama, and I. Yamatsu. 1990. Involvement of tumor necrosis factor-alpha in development of hepatic injury in galactosamine-sensitized mice. Hepatology 12:1187–1191.

    Article  PubMed  CAS  Google Scholar 

  11. Iimuro, Y., R. M. Gallucci, M. I. Luster, H. Kono, and R. G. Thurman. 1997. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. J. Hepatol. 26:1530–1537.

    Article  CAS  Google Scholar 

  12. Tilg, H., R. Jalan, A. Kaser, N. A. Davies, F. A. Offner, S. J. Hodges, O. Ludwiczek, D. Shawcross, H. Zoller, A. Alisa, R. P. Mookerjee, I. Graziadei, C. Datz, M. Trauner, D. Schuppan, P. Obrist, W. Vogel, and R. Williams. 2003. Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis. J. Hepatol. 38:419–425.

    Article  PubMed  CAS  Google Scholar 

  13. Leclercq, I. A., G. C. Farrell, J. Field, D. R. Bell, F. J. Gonzalez, and G. R. Robertson. 2000. CYP2EI and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J. Clin. Invest. 105:1067–1075.

    Article  PubMed  CAS  Google Scholar 

  14. Ustundag, B., I. H. Bahcecioglu, K. Sahin, S. Duzgun, S. Koca, F. Gulcu, and I. H. Ozercan. 2007. Protective effect of soy isoflavones and activity levels of plasma paraoxonase and arylesterase in the experimental nonalcoholic steatohepatitis model. Dig. Dis. Sci. 52:2006–2014.

    Article  PubMed  CAS  Google Scholar 

  15. Satoh, K., S. Takamatsu, S. Sakuta, S. Mizuno, H. Metoki, and M. Takamatsu. 1981. Augmented malondialdehyde production by platelets from patients with cerebrovascular disorders. Jpn. Circ. J. 45:1335–1341.

    PubMed  CAS  Google Scholar 

  16. Yagi, K.. 1984. Assay for blood plasma or serum. Methods Enzymol. 105:328–331.

    PubMed  CAS  Google Scholar 

  17. Ohkawa, H., N. Ohishi, and K. Yagi. 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95:351–358.

    Article  PubMed  CAS  Google Scholar 

  18. Brunt, E., C. Janney, A. M. Bisceglie, B. A. Neuschwander-Tetri, and B. R. Bacon. 1999. Nonalcoholic steatohepatitis; a proposal for grading and staging the histopathologic lesions. Am. J. Gastroenterol. 94:2467–2474.

    Article  PubMed  CAS  Google Scholar 

  19. Nanji, A. A., E. K. Yang, F. Fogt, S. M. H. Sadrzadeh, and A. J. Dannenberg. 1996. Medium chain triglycerides and vitamin E reduce the severity of established experimental alcoholic liver disease. J. Pharmacol. Exp. Ther. 277:1694–1699.

    PubMed  CAS  Google Scholar 

  20. Kirsch, R., V. Clarkson, E. G. Shephard, D. A. Marais, M. A. Jaffer, V. E. Woodburne, R. E. Kirsch, and P. L. Hall. 2003. Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J. Gastroenterol. Hepatol. 18:1272–1282.

    Article  PubMed  Google Scholar 

  21. Lee, K. S., S. J. Lee, H. J. Park, J. P. Chung, K. H. Han, C. Y. Chon, S. I. Lee, and Y. M. Moon. 2001. Oxidative stress effect on the activation of hepatic stellate cells. Yonsei Med. J 42:1–8.

    PubMed  CAS  Google Scholar 

  22. Liu, X. J., L. Yang, Y. Q. Mao, Q. Wang, M. H. Huang, Y. P. Wang, and H. B. Wu. 2002. Effects of the tyrosine protein kinase inhibitor genistein on the proliferation, activation of cultured rat hepatic stellate cells. World J. Gastroenterol. 8:739–745.

    PubMed  CAS  Google Scholar 

  23. Chawla, R. K., W. H. Watson, C. E. Eastin, E. Y. Lee, J. Schmidt, and C. J. McClain. 1998. S-adenosylmethionine deficiency and TNF-alpha in lipopolysaccharide-induced hepatic injury. Am. J. Physiol. 275:G125–129.

    PubMed  CAS  Google Scholar 

  24. Ghoshal, A. K., M. Ahluwalia, and E. Farber. 1983. The rapid induction of liver cell death in rats fed a choline-deficient methionine-low diet. Am. J. Pathol. 113:309–314.

    PubMed  CAS  Google Scholar 

  25. Hensley, K., Y. Kotake, and H. Sang. 2001. Dietary choline restriction causes complex I dysfunction and increased H(2)O(2) generation in liver mitochondria. Carcinogenesis 21:983–989.

    Article  Google Scholar 

  26. George, J., N. Pera, N. Phung, I. Leclercq, J. Yun Hou, and G. Farrell. 2003. Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis. J. Hepatol. 39:756–764.

    Article  PubMed  CAS  Google Scholar 

  27. Simeonova, P. P., R. M. Gallucci, T. Hulderman, R. Wilson, C. Kommineni, M. Rao, and M. I. Luster. 2001. The role of tumor necrosis factor-alpha in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride. Toxicol. Appl. Pharmacol. 177:112–120.

    Article  PubMed  CAS  Google Scholar 

  28. Crespo, J., A. Cayon, P. Fernandez-Gil, M. Hernandez-Guerra, M. Mayorga, A. Dominguez-Diez, J. C. Fernandez-Escalante, and F. Pons-Romero. 2001. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34:1158–1163.

    Article  PubMed  CAS  Google Scholar 

  29. Kugelmas, M., D. B. Hill, B. Vivian, L. Marsano, and C. J. McClain. 2003. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 38:413–419.

    Article  PubMed  CAS  Google Scholar 

  30. Satapathy, S. K., S. Garg, R. Chauhan, P. Sakhuja, V. Malhotra, B. C. Sharma, and S. K. Sarin. 2004. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am. J. Gastroenterol. 99:1946–1652.

    Article  PubMed  CAS  Google Scholar 

  31. Koppe, S. W., A. Sahai, P. Malladi, P. F. Whitington, and R. M. Green. 2004. Pentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet. J. Hepatol. 41:592–598.

    Article  PubMed  CAS  Google Scholar 

  32. Strieter, R. M., D. G. Remick, P. A. Ward, R. N. Spengler, J. P. Lynch, J. Larrick, and S. L. Kunkel. 1988. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem. Biophys. Res. Commun. 155:1230–1236.

    Article  PubMed  CAS  Google Scholar 

  33. Edwards, M. J., B. J. Keller, F. C. Kaufman, and R. G. Thurman. 1993. The involvement of kupffer cells in carbon tetrachloride toxicity. Toxicol. Appl. Pharmacol. 119:275–279.

    Article  PubMed  CAS  Google Scholar 

  34. Bissell, D. M., D. Roulot, and J. George. 2001. Transforming growth factor beta and the liver. Hepatology 34:859–867.

    Article  PubMed  CAS  Google Scholar 

  35. Li, Z., S. Yang, H. Lin, J. Huang, P. A. Watkins, A. B. Moser, C. Desimone, X. Y. Song, and A. M. Diehl. 2003. Probiotics and antibodies to TNF inhibit inflammatory activity and improve non-alcoholic fatty liver disease. J. Hepatol. 37:343–350.

    Article  CAS  Google Scholar 

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Correspondence to Suleyman Serdar Koca.

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Koca, S.S., Bahcecioglu, I.H., Poyrazoglu, O.K. et al. The Treatment with Antibody of TNF-α Reduces the Inflammation, Necrosis and Fibrosis in the Non-alcoholic Steatohepatitis Induced by Methionine- and Choline-deficient Diet. Inflammation 31, 91–98 (2008). https://doi.org/10.1007/s10753-007-9053-z

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  • DOI: https://doi.org/10.1007/s10753-007-9053-z

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