medigraphic.com
Órgano Oficial de la Asociación Mexicana de Hepatología

2006, Number 1

<< Back Next >>

Ann Hepatol 2006; 5 (1)

Pentoxifylline does not prevent neither liver damage nor early profibrogenic events in a rat model of non-alcoholic steatohepatitis

Vial P, Riquelme A, Pizarro M, Solís N, Madariaga JA, Aguayo G, Duarte I, Soza A, Accatino L, Arrese M

Language: English
References: 29
Page: 25-29
PDF size: 93.24 Kb.


Text Extraction

Background: Non-alcoholic steatohepatitis (NASH) is a metabolic disorder of the liver, which may evolve to fibrosis or cirrhosis. Pentoxifylline (PTX) has been postulated to act as an antifibrogenic agent able to inhibit hepatic stellate cell proliferation and collagen synthesis in vitro. Short-term studies suggest beneficial effects of PTX in experimental models of NASH. Aim: To study whether PTX can influence liver fibrogenesis in an animal model of NASH. Methods: To induce NASH, a choline-deficient diet (CDD) was given to Sprague-Dawley rats for 8 weeks. Rats were allocated to two experimental groups one receiving PTX (9 mg/kg/day) in drinking water. Control rats received a choline-supplemented diet. Biochemical and histological evaluation of fatty liver was performed by conventional techniques. In addition, mRNA levels of Pro-collagen I and transforming growth factor beta-1 were assessed by semi-quantitative RT-PCR and stellate cell activation by α-actin immunofluorescence stain. Results: After 8 weeks CDD induced a marked elevation of serum aminotransferases, a marked decrease in both hepatic and biliary glutathione and a severe fatty liver infiltration with mild histological inflammation and fibrosis. A significant increase in mRNA levels of both Pro-collagen I and TGFβ-1 was seen after CDD feeding. No differences were seen between rats receiving PTX and rats on CDD diet alone with regard to the biochemical, morphological or molecular alterations induced by the CDD. Conclusion: PTX does influence neither liver injury nor early profibrogenic events in the CDD model of NASH.


REFERENCES

  1. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003; 37: 1202-1219.

  2. Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease. CMAJ 2005; 172: 899-905.

  3. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-1231.

  4. Yoshioka Y, Hashimoto E, Yatsuji S, Kaneda H, Taniai M, Tokushige K, Shiratori K. Nonalcoholic steatohepatitis: cirrhosis, hepatocellular carcinoma, and burnt-out NASH. J Gastroenterol 2004; 39: 1215-1218.

  5. Cortez-Pinto H, Camilo ME. Non-alcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH): diagnosis and clinical course. Best Pract Res Clin Gastroenterol 2004; 18: 1089-1104.

  6. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123: 134-140.

  7. Portincasa P, Grattagliano I, Palmieri VO, Palasciano G. Nonalcoholic steatohepatitis: recent advances from experimental models to clinical management. Clin Biochem 2005; 38: 203-217.

  8. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998; 114: 842-845.

  9. Day C, Saksena S. Non-alcoholic steatohepatitis: Definitions and pathogenesis. J Gastroenterol Hepatol 2002; 17 Suppl 3: S377-S384.

  10. Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002; 16: 663-678.

  11. Videla LA, Rodrigo R, Orellana M, Fernandez V, Tapia G, Quinones L, Varela N, et al. Oxidative stress-related parameters in the liver of nonalcoholic fatty liver disease patients. Clin Sci (Lond) 2004; 106: 261-268.

  12. Diehl AM. Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease. Clin Liver Dis 2004; 8: 619-638.

  13. Crespo J, Cayon A, Fernandez-Gil P, Hernandez-Guerra M, Mayorga M, Dominguez-Diez A, Fernandez-Escalante JC, et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 2001; 34: 1158-1163.

  14. Desmouliere A, Xu G, Costa AM, Yousef IM, Gabbiani G, Tuchweber B. Effect of pentoxifylline on early proliferation and phenotypic modulation of fibrogenic cells in two rat models of liver fibrosis and on cultured hepatic stellate cells. J Hepatol 1999; 30: 621-631.

  15. Bahra PS, Rainger GE, Wautier JL, Nash GB. Effects of pentoxifylline on the different steps during adhesion and transendothelial migration of flowing neutrophils. Cell Biochem Funct 2001; 19: 249-257.

  16. Preaux AM, Mallat A, Rosenbaum J, Zafrani ES, Mavier P. Pentoxifylline inhibits growth and collagen synthesis of cultured human hepatic myofibroblast-like cells. Hepatology 1997; 26: 315-322.

  17. Raetsch C, Jia JD, Boigk G, Bauer M, Hahn EG, Riecken E-O, Schuppan D. Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis. Gut 2002; 50: 241-247.

  18. Koppe SW, Sahai A, Malladi P, Whitington PF, Green RM. Pentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet. J Hepatol 2004; 41: 592-598.

  19. Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99: 2365-2368.

  20. Satapathy SK, Garg S, Chauhan R, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99: 1946-1952.

  21. Hironaka K, Sakaida I, Uchida K, Okita K. Correlation between stellate cell activation and serum fibrosis markers in choline-deficient Lamino acid-defined diet-induced rat liver fibrosis. Dig Dis Sci 2000; 45: 1935-1943.

  22. Kawaguchi K, Sakaida I, Tsuchiya M, Omori K, Takami T, Okita K. Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. Biochem Biophys Res Commun 2004; 315: 187-195.

  23. Anderson ME. Determination of glutathione and glutathione disulfide in biological samples. Methods Enzymol 1985; 113: 548-555.

  24. Washington K, Wright K, Shyr Y, Hunter EB, Olson S, Raiford DS. Hepatic stellate cell activation in nonalcoholic steatohepatitis and fatty liver. Hum Pathol 2000; 31: 822-828.

  25. Honda H, Ikejima K, Hirose M, Yoshikawa M, Lang T, Enomoto N, Kitamura T, et al. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology 2002; 36: 12-21.

  26. Windmeier C, Gressner AM. Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis. Gen Pharmacol 1997; 29: 181-196.

  27. Tarcin O, Avsar K, Demirturk L, Gultepe M, Oktar BK, Ozdogan OC, Baloglu H, et al. In vivo inefficiency of pentoxifylline and interferon-alpha on hepatic fibrosis in biliary-obstructed rats: assessment by tissue collagen content and prolidase activity. J Gastroenterol Hepatol 2003; 18: 437-444.

  28. Diehl AM. Lessons from animal models of NASH. Hepatol Res 2005.

  29. Koteish A, Diehl AM. Animal models of steatosis. Semin Liver Dis 2001; 21: 89-104.




2020     |     www.medigraphic.com