Skip to main content
SpringerLink
Log in

Granulocyte-Colony Stimulating Factor Administration Ameliorates Liver Regeneration in Animal Model of Fulminant Hepatic Failure and Encephalopathy

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

It has previously been shown that recombinant granulocyte-colony stimulating factor (rG-CSF) accelerates and enhances hepatocyte proliferation in partially hepatectomized rats. In the present study, we examined the effect of rG-CSF administration on liver injury, regeneration, and survival outcome in an experimental rat model of fulminant hepatic failure (FHF) and encephalopathy induced by repeated injections of thioacetamide (TAA). FHF was induced in adult male Wistar rats by three consecutive intraperitoneal injections of TAA, at intervals of 24 hr. The animals were also injected with either saline or rG-CSF. Serum biochemical parameters and blood ammonia levels, liver histology, stage of hepatic encephalopathy, and survival were statistically significantly improved in TAA-intoxicated and rG-CSF-treated rats compared to TAA-intoxicated and saline-treated ones. Furthermore, rG-CSF not only ameliorated the histologically evident liver injury in a statistically significant manner but also enhanced the proliferative capacity of the hepatocytes. Our data confirm the beneficial effect of rG-CSF administration in this animal model of FHF and encephalopathy, supporting evidence for a possible use of rG-CSF as supportive therapy in the management of FHF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. O'Grady J, Schalman SW, Williams R: Acute liver failure: redefining the syndrome. Lancet 324:273–275, 1993

    Google Scholar 

  2. Lee WR: Acute liver failure. N Engl J Med 329:1867–1872, 1993

    Google Scholar 

  3. Ferenci P: Treatment of hepatic encephalopathy. Indian J Gastroenterol 20(suppl 1):C90-C94, 2001

    Google Scholar 

  4. Blei AT: Diagnosis and treatment of hepatic encephalopathy. Baillieres Best Pract Res Clin Gastroenterol 14:959–974, 2000

    Google Scholar 

  5. Riordan SM, Williams R: Acute liver failure: targeted artificial and hepatocyte-based support of liver regeneration and reversal of multiorgan failure. J Hepatol 32(suppl 1):63–76, 2000

    Google Scholar 

  6. VanThiel DH, Brems J, Nadir A, Idilman R, Colantoni A, Holt D, Edelstein S: Liver transplantation for fulminant hepatic failure. J Gastroenterol 36:1–4, 2001

    Google Scholar 

  7. Zimmermann C, Ferenci P, Pifl C, Yurdaydin C, Ebner J, Lassmann H, Roth E, Hortnagl H: Hepatic encephalopathy in thioacetamide induced acute liver failure in rats: characterization of an improved model and study of amino acid-ergic neurotransmission. Hepatology 9:594–601, 1989

    Google Scholar 

  8. Larsen FS, Knudsen GM, Pulson OB, Vilstrup H: Cerebral blood flow autoregulation is absent in rats with thioacetamide-induced hepatic failure. J Hepatol 21:491–495, 1994

    Google Scholar 

  9. Bruck R, Aeed H, Shirin H, Matas Z, Zaidel L, Avni Y, Halpern Z: The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure. J Hepatol 31:27–38, 1999

    Google Scholar 

  10. Chieli E, Malvaldi G: Role of the microsomal FAD-containing monooxygenase in the liver toxicity of thioacetamide S-oxide. Toxicology 31:41–52, 1984

    Google Scholar 

  11. Porter WR, Neal RA: Metabolism of thioacetamide and thioacetamide S-oxide by rat microsomes. Drug Metab Dispos 6:379–388, 1978

    Google Scholar 

  12. Fleig WE: Liver specific growth factors. Scand J Gastroenterol 23(suppl 151):31–36, 1988

    Google Scholar 

  13. Bergley C, Lopez A, Nicola N, Warren D, Vadas M, Sanderson C, Metcalf D: Purified colony-stimulating factors enhance the survival of human neutrophils and eosinophils in vitro: A rapid and sensitive microassay for colony-stimulating factors. Blood 68:162–166, 1986

    Google Scholar 

  14. Clark SC, Kammer R: The hematopoietic colony-stimulating factors. Science 236:1229–1237, 1987

    Google Scholar 

  15. Ichinose Y, Hara N, Ohta M, Aso H, Chikama H, Kawasaki M, Kubota I, Shimizu T, Yagawa K: Recombinant granulocyte colony-stimulating factor and lipopolysaccharide maintain the phenotype of and superoxide anion generation by neutrophils. Infect Immun 58:1647–1652, 1990

    Google Scholar 

  16. Avalos B, Gasson J, Hedvat C, Quan S, Baldwin G, Weisbart R, Williams R, Golde D, DiPersio J: Human granulocyte colony-stimulating factor: biologic activities and receptor characterization on hematopoietic cells and small cell lung cancer cell lines. Blood 75:851–857, 1990

    Google Scholar 

  17. Goergen I, Hartung T, Leist M, Niehoerster M, Tiegs G, Uhlig S, Weitzel F, Wendel A: Granulocyte colony-stimulating factor treatment protect rodents against lipopolysaccharide-induced toxicity via suppression of systemic tumor necrosis factor-α. J Immunol 149:918–924, 1992

    Google Scholar 

  18. Michalopoulos GK, DeFrances MC: Liver regeneration. Science 276:60–66, 1997

    Google Scholar 

  19. Theocharis S, Margeli A, Goutas N, Horti M, Karkadaris C, Kittas C: G-CSF administration enhances hepatocytes regeneration after partial hepatectomy in rats. J Hepatol 23(suppl 1):150, 1995

    Google Scholar 

  20. Theocharis SE, Agapitos EV, Margeli AP, Goutas N, Kittas C, Davaris P: Effect of two forms of granulocyte colony-stimulating factor on hepatic regeneration after 70 % partial hepatectomy in rats. Clin Sci 92:315–320, 1997

    Google Scholar 

  21. Margeli A, Theocharis S, Skaltsas S, Skopelitou A, Kittas C, Mykoniatis M, Varonos D: Effect of cadmium pretreatment on liver regeneration after partial hepatectomy in rats. Arch Toxicol 68:85–90, 1994

    Google Scholar 

  22. Theocharis S, Margeli A, Goutas N, Horti M, Karkadaris C, Kittas C: Granulocyte-colony stimulating factor administration reverses cadmium associated inhibition of hepatocyte regeneration. Eur J Gastroenterol Hepatol 8:805–809, 1996

    Google Scholar 

  23. Diehl AM, Rai RM: Regulation of signal transduction during liver regeneration. FASEB J 10:215–227, 1996

    Google Scholar 

  24. Theocharis S, Margeli A, Kittas C, Delladetsima J: Granulocyte-colony stimulating factor administration enhances hepatocytes regeneration in glactosamine-induced liver injury in rats. Hepatology 24(4Pt 2):467A, 1996

    Google Scholar 

  25. Theocharis S, Margeli A, Kittas C: Effect of granulocyte colony-stimulating factor administration on tissue regeneration due to thioacetamide-induced liver injury in rats. Dig Dis Sci 44:1990–1996, 1999

    Google Scholar 

  26. Margeli A, Manolis E, Skaltsas S, Tsarpalis K, Mykoniatis M, Theocharis S: Hepatic Stimulator Substance activity in an animal model of fulminant hepatic failure and encephalopathy. Dig Dis Sci 47:2170–2178, 2002

    Google Scholar 

  27. Geller D: A rat model of hepatic encephalopathy due to fulminant hepatic failure: the role of supportive therapy. In Advances in Ammonia Metabolism and Hepatic Encephalopathy. PB Soeters, IHP Wilson, AJ Meijer, E Holm (eds). Amsterdam, Elsevier Science Publishers, 1988, pp 213–217

    Google Scholar 

  28. International Federation of Clinical Chemistry: Committee on standards, Enzyme Panel. Clin Chem 24:720–721, 1978

    Google Scholar 

  29. Moss DW, Henderson AR, Kachmar JF: Enzymes, In Textbook of Clinical Chemistry. NW Tietz (ed). Philadelphia, WB Saunders, 1995, pp 706–713

    Google Scholar 

  30. Rock RC, Walker WG, Jennings CD: Nitrogen metabolites and renal function. In Textbook of Clinical Chemistry. NW Tietz (ed). Philadelphia, WB Saunders, 1995, pp 1268–1271

    Google Scholar 

  31. Balisteri WF, Shaw LM: Liver function. In Textbook of Clinical Chemistry. NW Tietz (ed). Philadelphia, WB Saunders, 1995, pp 1411–1412

    Google Scholar 

  32. Munro HN, Fleck A: Recent developments in the measurement of nucleic acids in biological materials. Analyst 91:78–88, 1966

    Google Scholar 

  33. Richards GM: Modifications of the diphenylamine reaction giving increased sensitivity and simplicity in the estimation of DNA. Anal Biochem 57:369–376, 1974

    Google Scholar 

  34. Kahn D, Svanas G, Eagopn P, Makowka L, Podesta L, Chapchap P, Starzl TE, van Thiel DH: Effect of an anti-androgenic H2 receptor antagonist on hepatic regeneration in rats. J Lab Clin Med 112:232–239, 1988

    Google Scholar 

  35. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275, 1951

    Google Scholar 

  36. Mullen KD: Evaluation of the suitability of galactosamine-induced fulminant hepatic failure as a model of hepatic encephalopathy in the rat and rabbit. In Advances in Ammonia Metabolism and Hepatic Encephalopathy. PB Soeters, JHP Wilson, AJ Meijer, E Holm (eds). Amsterdam, Eisevier Science Publishers, 1988, pp 205–211

    Google Scholar 

  37. Meng ZH, Dyer K, Billiar TR, Tweardy DJ: Distinct effects of systemic infusion of G-CSF vs. IL-6 on lung and liver inflammation and injury in hemorrhagic shock. Shock 14:41–48, 2000

    Google Scholar 

  38. Vollmar B, Messner S, Wanner GA, Hartung T, Menger MD: Immunomodulatory action of G-CSF in a rat model of endotoxin-induced liver injury: an intravital microscopic analysis of Kupffer cell and leukocyte response. J Leukoc Biol 62:710–718, 1997

    Google Scholar 

  39. Fiuza C, Salcedo M, Clemente G, Tellado JM: Granulocyte colony-stimulating factor improves deficient in vitro neutrophil transendothelial migration in patients with advanced liver disease. Clin Diagn Lab Immunol 9:433–439, 2002

    Google Scholar 

  40. Rolando N, Clapperton M, Wade J, Panetsos G, Mufti G, Williams R: Granulocyte colony-stimulating factor improves function of neutrophils from patients with acute liver failure. Eur J Gastroenterol Hepatol 12:1135–1140, 2000

    Google Scholar 

Download references

Authors
  1. Stamatios E. Theocharis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lila J. Papadimitriou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zoi P. Retsou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandra P. Margeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sotirios S. Ninos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John D. Papadimitriou
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Theocharis, S.E., Papadimitriou, L.J., Retsou, Z.P. et al. Granulocyte-Colony Stimulating Factor Administration Ameliorates Liver Regeneration in Animal Model of Fulminant Hepatic Failure and Encephalopathy. Dig Dis Sci 48, 1797–1803 (2003). https://doi.org/10.1023/A:1025463532521

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1025463532521

Search

Navigation