ORIGINAL ARTICLE

JOP. J Pancreas (Online) 2005; 6(4):316-324.

Pancreatic Fibrosis in Rats and Its Response to Antioxidant Treatment

Gonzalo de las Heras-Castaño1, María Teresa García-Unzueta2, Agustín Domínguez-Diez3, María Dolores Fernández-González2, Ana María García-de la Paz4, Marta Mayorga-Fernández5, Fidel Fernández-Fernández5

1Departament of Gastroenterology, 2Departament of Clinical Biochemistry, 3Departament of General Surgery II, 4Departament or Pharmacy, 5Departament of Pathology, Hospital Universitario 'Marqués de Valdecilla'. Santander, Spain

ABSTRACT

Context Oxidative stress plays a role in the development of pancreatic fibrosis.

Objectives In the present study, we hypothesized that the administration of an antioxidant complex could ameliorate cerulein and cyclosporin A pancreatic fibrosis, assessed by changes in oxidative stress and a histopathological study in an experimental rat model.

Animals Four groups of ten rats each. In Group A, the rats served as controls and were treated with intraperitoneal saline solution. In Group B, six courses of cerulein pancreatitis were induced at weekly intervals. In Group C, the rats received cyclosporin A the day before and the day on which pancreatitis was induced in Group B. In Group D, the rats were treated as in Group C but also received antioxidants. All rats were sacrificed at the seventh week.

Main outcome measures The presence of fibrosis was evaluated according to a scoring system. Glutathione peroxidase was utilized as an indicator of oxidative stress and total antioxidant status as an indicator of total antioxidant tissue capacity.

Results The rats in Groups B and C showed more pancreatic fibrosis than those in Groups A and D (90%, 70%, 0%, and 20%, respectively). The glutathione peroxidase increased in Group B (455±196 mU/g protein) and Group C (243±206 mU/g protein) with respect to those in Group A (137±80 mU/g protein) and Group D (135±105 mU/g protein). Total antioxidant status was significantly higher in Groups B (1.41±0.96 mmol/g protein) and D (1.28±0.09 mmol/g protein) with respect to Groups A (0.10±0.06 mmol/g protein) and C (0.15±0.09 mmoL/g protein).

Conclusion The administration of cerulein and cyclosporin A caused fibrosis, whereas antioxidant administration showed preventive effects regarding cerulein and cyclosporin A-induced pancreatic fibrosis.

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References

  1. Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, et al. Periacinar stellate-shaped cells in rat pancreas: Identification, isolation and culture. Gut 1998; 43:128-33. [More details]

  2. Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998; 115:421-32. [More details]

  3. Apte MV, Phillips PA, Fahmy RG, Darby SJ, Rodgers SC, McCaughan GW, et al. Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells. Gastroenterology 2000; 118:780-94. [More details]

  4. Rose P, Fraine E, Hunt LP, Acheson DW, Braganza JM. Dietary antioxidants and chronic pancreatitis. Hum Nutr Clin Nutr 1986; 40:151-64. [More details]

  5. Braganza JM, Schofield D, Snehalatha C, Mohan V. Micronutrient antioxidant status in tropical compared with temperate-zone chronic pancreatitis. Scand J Gastroenterol 1993;28:1098-104. [More details]

  6. Yadav S, Day JP, Mohan V, Snehalatha C, Braganza JM. Selenium and diabetes in the tropics. Pancreas 1991; 6:528-33. [More details]

  7. Braganza JM. The pathogenesis of chronic pancreatitis. QJM 1996; 89:243-50. [More details]

  8. Morris-Stiff GJ, Bowrey DJ, Oleesky D, Davies M, Clark GW, Puntis MC. The antioxidant profiles of patients with recurrent acute and chronic pancreatitis. Am J Gastroenterol 1999; 94:2135-40. [More details]

  9. Uden S, Schofield D, Miller PF, Day JP, Bottiglier T, Braganza JM. Antioxidant therapy for recurrent pancreatitis: Biochemical profiles in a placebo-controlled trial. Aliment Pharmacol Ther 1992; 6:229-40. [More details]

  10. De las Heras Castaño G, Garcia de la Paz A, Fernandez MD, Fernandez Forcelledo JL. Use of antioxidants in the treatment of the pain in chronic pancreatitis. Rev Esp Enferm Dig 2000; 92:375-80. [More details]

  11. Mathew P, Wyllie R, Van Lente F, Steffen RM, Kay MH. Antioxidants in hereditary pancreatitis. Am J Gastroenterol 1996; 91:1558-62. [More details]

  12. Braganza JM, Thomas A , Robinson A. Antioxidants to treat chronic pancreatitis in childhood. Case report and possible implications for pathogenesis. Int J Pancreatol 1988; 3:209-16. [More details]

  13. Matsumura N, Ochi K, Ichimura M, Mizushima T, Harada H , Harada M. Study on free radicals and pancreatic fibrosis. Pancreatic fibrosis induced by repeated injections of superoxide dismutase inhibitor. Pancreas 2001; 22:53-7. [More details]

  14. Niederau C, Ferrell LD, Grendell JH. Caerulein-induced acute necrotizing pancreatitis in mice: protective effects of proglumide, benzotript, and secretin. Gastroenterology 1985; 88:1192-204. [More details]

  15. Goerelick FS, Adler G , Kem HF. Cerulein induced pancreatitis. In: Go VLW, DiMagno EP, Gardner JP, Lebenthal E, Reber HA, Scheele GA(eds). The Pancreas: Biology, Pathobiology, and Disease. 2nd ed. New York, NY, USA: Raven Press, 1993:501-26. [More details]

  16. Elsasser HP, Adler G, Kern HF. Fibroblast structure and function during regeneration from hormone-induced acute pancreatitis in the rat. Pancreas 1989; 4:169-78. [More details]

  17. Gress TM, Müller-Pillasch F, Yamaguchi H, Adler G, Menke A. Expression and activation of extracellular-matrix degrading proteases and tissue-inhibitors of metalloproteinases during regeneration from acute cerulein-induced pancreatitis (Abstract). Pancreas 1996; 13:438. [More details]

  18. Muller-Pillasch F, Gress TM, Yamaguchi H, Geng M, Adler G, Menke A. The influence of Transforming Growth Factor ß1 on the expression of genes coding for matrix metalloproteinases and tissue inhibitors of metalloproteinases during regeneration from cerulein-induced pancreatitis. Pancreas 1997; 15:168-75. [More details]

  19. Neuschwander-Tetri BA, Burton FR, Presti ME, Britton RS, Janney CG, Garvin PR, et al. Repetitive self-limited acute pancreatitis induces pancreatic fibrogesis in the mouse. Dig Dis Sci 2000; 45:665-74. [More details]

  20. Wisner J, Green D, Ferrell L, Renner I. Evidence for a role of oxygen derived free radicals in the pathogenesis of cerulein induced acute pancreatitis in rats. Gut 1988; 29:1516-23. [More details]

  21. Schoenberg MH, Buchler M, Gaspar M, Stinner A, Younes M, Melzner I, et al. Oxygen free radicals in acute pancreatitis of the rat. Gut 1990; 31:1138-43. [More details]

  22. Urunuela A, Sevillano S, de la Mano AM, Manso MA, Orfao A , De Dios I. Time-course of oxygen free radical production in acinar cells during acute pancreatitis induced by pancreatic duct obstruction. Biochim Biophys Acta 2002; 1588:159. [More details]

  23. Elsasser HP, Haake T, Grimmig M, Adler G, Kern HF. Repetitive cerulein-induced pancreatitis and pancreatic fibrosis in the rat. Pancreas 1992; 7:385-90. [More details]

  24. Woods JS, Kavanagh TJ, Corral J, Reese AW, Diaz D, Ellis ME. The role of glutathione in chronic adaptation to oxidative stress studies in a normal rat kidney epithelial (NRK52E) cell model of sustained up regulation of glutathione biosynthesis. Toxicol Appl Pharmacol 1999; 160:207-16. [More details]

  25. Mari M, Wu D, Nieto N, Cederbaum AI. CYP2E1-dependent toxicity and upregulation of antioxidant genes. J Biomed Sci 2001; 8:52-8. [More details]

  26. Wittel UA, Bachem M, Siech M. Oxygen radical production precedes alcohol-induced acute pancreatitis in rats. Pancreas 2003; 26:e74-80. [More details]

  27. Adler G, Hupp T , Kern HF. Course and spontaneous regression of acute pancreatitis in the rat. Virchows Arch A Pathol Anat Histol 1979; 382:31-47. [More details]

  28. Vaquero E, Molero X, Salas A , Malagelada JR. Myofibroblast proliferation, fibrosis, and defective pancreatic repair by cyclosporin in rats. Gut 1999; 45:269-77. [More details]

  29. Van Gossum A, Closset P, Noel E, Cremer M , Neve J. Deficiency in antioxidant factors in patients with alcohol-related chronic pancreatitis. Dig Dis Sci 1996; 41:1225-331. [More details]

  30. Casini A, Galli A, Pignalosa P, Frulloni L, Grappone C, Milani S, et al. Collagen type I synthesized by pancreatic periacinar stellate cells (PSC) co-localizes with lipid peroxidation-derived aldehydes in chronic alcoholic pancreatitis. J Pathol 2000; 192:81-9. [More details]

  31. Apte MV, Wilson JS. Stellate cell activation in alcoholic pancreatitis. Pancreas 2003; 27:316-20. [More details]

  32. Gomez JA, Molero X, Vaquero E, Alonso A, Salas A, Malagelada JR. Vitamin E attenuates biochemical and morphological features associated with the development of chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2004; 287:G162-9. [More details]

  33. Johnson DW, Saunders HJ, Johnson FJ, Huq SO, Field MJ, Pollock CA. Fibrogenic effects of cyclosporin A on the tubulointerstitium: role of cytokines and growth factors. Exp Nephrol 1999; 7:470-8. [More details]

Keywords Antioxidants; Caerulein; Cyclosporine; Fibrosis; Oxidative Stress; Pancreas, Pancreatitis; Therapeutics

Correspondence Gonzalo de las Heras-Castaño: gherasc@ono.com