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.
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REFERENCES
O'Grady J, Schalman SW, Williams R: Acute liver failure: redefining the syndrome. Lancet 324:273–275, 1993
Lee WR: Acute liver failure. N Engl J Med 329:1867–1872, 1993
Ferenci P: Treatment of hepatic encephalopathy. Indian J Gastroenterol 20(suppl 1):C90-C94, 2001
Blei AT: Diagnosis and treatment of hepatic encephalopathy. Baillieres Best Pract Res Clin Gastroenterol 14:959–974, 2000
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
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
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
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
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
Chieli E, Malvaldi G: Role of the microsomal FAD-containing monooxygenase in the liver toxicity of thioacetamide S-oxide. Toxicology 31:41–52, 1984
Porter WR, Neal RA: Metabolism of thioacetamide and thioacetamide S-oxide by rat microsomes. Drug Metab Dispos 6:379–388, 1978
Fleig WE: Liver specific growth factors. Scand J Gastroenterol 23(suppl 151):31–36, 1988
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
Clark SC, Kammer R: The hematopoietic colony-stimulating factors. Science 236:1229–1237, 1987
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
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
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
Michalopoulos GK, DeFrances MC: Liver regeneration. Science 276:60–66, 1997
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
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
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
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
Diehl AM, Rai RM: Regulation of signal transduction during liver regeneration. FASEB J 10:215–227, 1996
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
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
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
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
International Federation of Clinical Chemistry: Committee on standards, Enzyme Panel. Clin Chem 24:720–721, 1978
Moss DW, Henderson AR, Kachmar JF: Enzymes, In Textbook of Clinical Chemistry. NW Tietz (ed). Philadelphia, WB Saunders, 1995, pp 706–713
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
Balisteri WF, Shaw LM: Liver function. In Textbook of Clinical Chemistry. NW Tietz (ed). Philadelphia, WB Saunders, 1995, pp 1411–1412
Munro HN, Fleck A: Recent developments in the measurement of nucleic acids in biological materials. Analyst 91:78–88, 1966
Richards GM: Modifications of the diphenylamine reaction giving increased sensitivity and simplicity in the estimation of DNA. Anal Biochem 57:369–376, 1974
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
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275, 1951
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
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
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
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
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
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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
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DOI: https://doi.org/10.1023/A:1025463532521