한국동물위생학회지 (Korean Journal of Veterinary Service)

  • 제26권4호
  • /
  • Pages.345-359
  • /
  • 2003
  • /
  • 3022-7372(pISSN)
  • /
  • 2287-7630(eISSN)
한국동물위생학회 (The Korean Society of Veterinary Service)
권호 표지

Alcohol-induced hepatic fibrosis in pig

  • Lee, Chang-Woo (Eastern branch, Gyeongbuk Veterinary Service Laboratory) ;
  • Jyeong, Jong-Sik (Gyeongbuk Veterinary Service Laboratory) ;
  • Lee, Cha-Soo (Colleage of Veterinary Medicine, Kyungpook National University) ;
  • Jeong, Kyu-Shik (Colleage of Veterinary Medicine, Kyungpook National University)
  • 발행 : 2003.12.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

A number of toxicants have been incriminated as a causing hepatic disease. Among many detrimental injury, alcohol has been noted for hepatitis, fatty liver, fibrosis, and hepatic cirrhosis. The purpose of this study was to develop animal model for hepatic fibrosis in pigs fed ethanol, and to search for a new anti-fibrogenic agent via this model. Twelve male Landrace pigs were divided into 3 groups of 4 animals each. Group 1, 2 and 3 were fed with active ceramic water only, ceramic water + liquid diet containing 15% ethanol and normal tap water + liquid diet containing 15% ethanol for 12 weeks, respectively. At week 12, all pigs were immediately sacrificed for collection each tissue and blood. Serologically, serum ALT and AST levels were significantly reversed in group 2, as compared to group 3. They were normal range in pigs of group 1. Microscopically, macrovesicular lipid droplets and moderate hepatocellular necrosis were evident in the tap water + ethanol fed group 3. However, the active ceramic water treated group 1 showed normal architecture. Moreover, in group 2, mild fatty changes and necrosis were observed in hepatocytes. Collagen fibers were increased in spaces surrounding periportal and interlobular connective tissues in the group 3 of tap water + ethanol, but collagen synthesis and its thickness of fibrotic septa connecting portal tracts were markedly reduced in the group 2 of ceramic water + ethanol. Myofibroblasts were detected mainly in the interlobular connective tissues of pig liver of group 3 treated ethanol and tap water. Few to no myofibroblasts were observed in groups 1 and 2. CYP2E1 was not or rarely detected in group 1 fed ceramic water. However, group 2 showed slightly activation of CYP2E1 in the area of pericentral vein, while CYP2E1 was significantly activated in group 3 fed tap water and ethanol. Based on the above data, we believe that we have developed a unique alcohol induced fibrosis model in pig, which will be useful in developing anti-fibrotic agents and drugs. Furthermore, the active ceramic water used in our study had an inhibitory and may be protective against ethanol induced hepatic toxicity and fibrosis.

키워드

참고문헌

  1. Lieber CS. 1993. Biochemical factors in alcoholic liver disease. Semin Liver Dis 13:136-153 https://doi.org/10.1055/s-2007-1007345
  2. Reinke LA, Lai EK, DuBose CM, et al. 1987. Reactive free radical generation in vitro in heart and liver of ethanol-fed rats correlation with radical formation in vitro. Proc Natl Acad Sci 84:9223~9227
  3. Cederbaum AI. 1989. Role of lipid peroxidation and oxidative stress in alcohol toxicity. Free Radic Biol Med 7:537-539 https://doi.org/10.1016/0891-5849(89)90029-4
  4. Ekstrom G, Ingelman-Sundberg M. 1989. Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P450. Biochem Pharmacol 38:1313-1318 https://doi.org/10.1016/0006-2952(89)90338-9
  5. Friedman SL. 1993. The cellular basis of hepatic fibrosis: Mechanism and treatment strategies. New England J Med 328:1828-1835 https://doi.org/10.1056/NEJM199306243282508
  6. Ramadori G, Knittel T, Saile B. 1998. Fibrosis and altered matrix synthesis. Digestion 59:372-375 https://doi.org/10.1159/000007518
  7. Schuppan D. 1990. Structure of extracellular matrix in normal and fibrotic liver: collagens and glycoproteins. Semin Liver Dis 10:1-10 https://doi.org/10.1055/s-2008-1040452
  8. Hahn E, Wick G, Pencev D, et al. 1980. Distribution of basement membrane proteins in normal and fibrotic human liver: collagen type IV laminin and fibronectin. Gut 21:63-71 https://doi.org/10.1136/gut.21.1.63
  9. Martinez-Hernandez A. 1984. The hepatic extracellular matrix. I. Electron immunohistochemical studies in normal rat liver. Lab Invest Med 51:57-69
  10. Irving MG, Roll FG, Huang S, et a1. 1984. Characterization and culture of sinusoidal endothelium from normal liver, lipoprotein uptake and collagen phenotype. Gastroenterology 87:1233-1247
  11. Ballardini G, Faccani A, Fallani M, et a1. 1985. Sequential behaviour of extracellular matrix glycoproteins in an experimental model of hepatic fibrosis. Virchows Arch B Cell Pathol Incl Mol Pathol 49:317-324 https://doi.org/10.1007/BF02912109
  12. Milani S, Herbst H, Schuppan D, et a1. 1990. Cellular localization of types I, III, and IV procollagen gene transcripts in normal and fibrotic human liver. Am J Pathol 137:59-70
  13. Schull MM, Ormsby I, Kier AB, et al. 1992. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359:693-699 https://doi.org/10.1038/359693a0
  14. Kulkarni AB, Karlsson S. 1993. Transforming growth factor beta-1 knockout mice. A mutation in one cytokine gene causes a dramatic inflammatory disease. Am J Pathol 143:3-9
  15. Gabbiani G, Hirschel BJ, Ryan GB, et al. 1972. Granulation tissue as a contractile organ: A study of structure and function. J Exp Med 135:719-733 https://doi.org/10.1084/jem.135.4.719
  16. Grinnell F. 1994. Fibroblasts, myofibroblasts and wound contraction. J Cell Biol 124:401-404 https://doi.org/10.1083/jcb.124.4.401
  17. Best CH, Hartroft WS, Lucas CC, et al. 1949. Liver damage produced by feeding alcohol or sugar and its prevention by choline. Br Med J 2: 1001-1006 https://doi.org/10.1136/bmj.2.4635.1001
  18. Lieber CS, Schmid R. 1961. The effect of chronic ethanol on fatty acid metabolism: Stimulation of hepatic fatty acid synthesis in vitro. J Clin Invest 40:394-399 https://doi.org/10.1172/JCI104266
  19. Jauhonen P, Baraona E, Miyakawa H, et al. 1982. Mechanism for selective perivenular hepatotoxicity of ethanol. Alcohol Clin Exp Res 6:350-357 https://doi.org/10.1111/j.1530-0277.1982.tb04990.x
  20. Lieber CS, DeCarli LM. 1970. Quantitative relationship between the amount of dietary fat and the severity of the alcoholic fatty liver. Am J Clin Nutr 23:474-478
  21. Lieber CS, Spritz N, DeCarli LM. 1969. Fatty liver produced by dietary deficiencies : Its pathogenesis and potentiation by ethanol. J Lipid Res 10:283-287
  22. Lefevre A, Adler H, Lieber CS. 1970. Effect of ethanol on ketone metabolism. J Clin Invest 49:1775-1782 https://doi.org/10.1172/JCI106395
  23. Lieber CS, DeCarli LM. 1974. An experimental model of alcohol feeding and liver injury in the baboon. J Med Primatol 3:153-163
  24. Joly JG, Feinman L, Ishii H, et al. 1973. Effect of chronic ethanol feeding on hepatic microsomal glycerophosphate acyltransferase activity. J Lipid Res 14:337-343
  25. Savolainen MJ, Baraona E, Pikkarainen P, et al. 1984. Hepatic triacylglycerol synthesizing activity in the baboon. J Lipid Res 25:813-820
  26. Savolainen MJ, Baraona E, Leo MA, et al. 1986. Pathogenesis of the hypertriglyceridemia at early stages of alcoholic liver injury in baboon. J Lipid Res 27:1073-1083
  27. Karsenty C, Baraona E, Savolainen MJ, et al. 1985. Effects of chronic ethanol intake on mobilization and excretion of cholesterol in baboons. J Clin Invest 75:976-986 https://doi.org/10.1172/JCI111799
  28. Knecht KT, Bradfort BU, Mason RP, et al. 1990. In vivo formation of a free radical metabolite of ethanol. Mol Pharmacol 38:26-30
  29. Morimoto M, Hagbjork AL, Wan YJ, et al. 1995. Modulation of alcoholic liver disease by cytochrome P4502E1 inhibitors. Hepatology 21:61O-617
  30. Kamimura S, Gaal K, Britton RS, et al. 1992. Increased 4-hydroxynonenal levels in experimental alcoholic liver disease: association of lipid peroxidation with liver fibrogenesis. Hepatology 16: 448-453 https://doi.org/10.1002/hep.1840160225
  31. Leonarduzzi G, Arkan MC, Basaga H, et al. 2000. Lipid peroxidation products in cell signalling. Free Radic Biol Med 28: 1370-1378 https://doi.org/10.1016/S0891-5849(00)00216-1
  32. Lieber CS. 1999. Prevention and treatment of liver fibrosis based on pathogenesis. Alcohol Clin Exp Res 23:944-949
  33. Friedman SL. 1997. Molecular mechanisms of hepatic fibrosis and principles of therapy. J Gastroenterol 32:424-430 https://doi.org/10.1007/BF02934504
  34. Bhunchet E, Wake K. 1992. Role of mesenchymal cell populations in porcine serum-induced rat liver fibrosis. Hepatology 16:1452-1473 https://doi.org/10.1002/hep.1840160623
  35. Gressner AM. 1994. Perisinusoidal lipocytes and fibrogenesis. Gut 35:1331-1333 https://doi.org/10.1136/gut.35.10.1331
  36. Abdel-Aziz G, Rescan PY, Clement B, et al. 1991. Cellular sources of matrix proteins in experimentally induced cholestatic rat liver. J Pathol 164:167-174 https://doi.org/10.1002/path.1711640211
  37. Andrade ZA, Guerret S, Fernandes AL. 1999. Myofibroblasts in schistosomal portal fibrosis of man. Mem Inst Oswaldo Cruz 94:87-93
  38. Nakano M, Lieber CS. 1982. Ultrastructure of initial stages of perivenular fibrosis in alcohol fed baboons. Am J Pathol 106:145-155
  39. Lieber CS. 2000. Alcohol and the liver: metabolism of alcohol and its role in hepatic and extrahepatic diseases. Mt Sinai J Med 67:84-94
  40. Ohnishi K, Lieber CS. 1977. Reconstitution of the microsomal ethanoloxidizing system: Qualitative and quantitative changes of cytochrome P-450 after chronic ethanol consumption. J Biol Chem 252:7124-7131
  41. Tsutsumi M, Lasker JM, Shimizu M, et al. 1989. The intralobular distribution of ethanol-inducible P4502E1 in rat and human liver. Hepatology 10:437-446 https://doi.org/10.1002/hep.1840100407
  42. Shaw S, Rubin KP, Lieber CS. 1983. Depressed hepatic glutathione and increased diene conjugates in alcoholic liver disease: Evidence of lipid peroxidation. Dig Dis Sci 28:585-589 https://doi.org/10.1007/BF01299917
  43. Lieber CS. 2000. Alcoholic liver disease : new insights in pathogenesis lead to new treatments. J Hepatol 32:113-128
  44. Weiner FR, Esposti SD, Zern MA. 1993. A role for cytokines as regulators of hepatic fibrogenesis. Gastroenterol Jpn 28:97-101
  45. Halsted CH, Villanueva JA, Devlin AM, et a1. 2002. Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig. Proc Natl Acad Sci USA 99:10072-10077 https://doi.org/10.1073/pnas.112336399
  46. Niemela O, Parkkila S, Yla-Herttuala S, et a1. 1995. Sequential acetaldehyde production, lipid peroxidation, and fibro genesis in micropig model of alcohol-induced liver disease. Hepatology 22:1208-1214
  47. Czaja M, Xu J, Alt E. 1995. Prevention of carbon tetrachloride-induced rat liver injury by soluble tumor necrosis factor receptor. Gastroenterology 108:1849-1854 https://doi.org/10.1016/0016-5085(95)90149-3
  48. Kershenobich D, Vargas F, Garcia-Tsao G, et al. 1988. Colchicine in the treatment of cirrhosis of the liver. N Engl J Med 318:1709-1713
  49. Li J, Kim CI, Leo MA, et al. 1992. Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in cultured lipocytes. Hepatology 15:373-381 https://doi.org/10.1002/hep.1840150303
  50. Lieber CS, Robins SJ, Li J, et al. 1994. Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon. Gastroenterology 106:152-159
  51. Navder KP, Baraona E, Lieber CS. 1997. Polyenylphosphatidylcholine attenuates alcohol-induced fatty liver and hyper-lipemia in rats. J Nutr 127:1800-1806
  52. Lieber CS, Leo MA, Aleynik SI, et al. 1997. Polyenylphosphatidylcholine decreases alcohol- induced oxidative stress in the baboon. Alcohol Clin Exp Res 21:375-379 https://doi.org/10.1111/j.1530-0277.1997.tb03776.x