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Evidence that both cyclosporin and azathioprine prevent warm ischemia reperfusion injury to the rat liver

  • Original Articles
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Transplant International

Abstract

The present work was undertaken to study whether the immunosuppressive agents cyclosporin (CyA) and azathioprine (AZA) ameliorate hepatic injury after warm ischemia. A temporary, normothermic liver ischemia was induced in female Sprague-Dawley rats. The rats were treated with CyA (10 mg/kg per day p.o.), AZA (8 mg/kg per day p.o.), or vehicles for 4 days before surgery. Seven-day survival rates after 60 min of ischemia improved significantly with CyA (76.2%, P<0.005) and AZA (78.6%, P<0.001) treatment, compared with 43.0% for the control group. The highest levels of serum aminotransferases in the treatment groups tended to be lower than those in the control group. The peak values for the percentage of liver necrosis, an indicator of the extent of hepatic necrosis, in the animals treated with CyA (26.1%±7.2%, mean±SEM) and AZA (32.1%±5.7%) were significantly lower than in the control group (47.4%±3.7%). Lipid peroxidative damage after reperfusion, assessed as the hepatic malondialdehyde (MDA) concentration, was significantly suppressed by pretreatment with CyA and AZA. Histological findings coincided with other parameters. This study demonstrates that both AZA and CyA have beneficial effects on normothermic liver ischemia in rats. It is suggested that the diminished lipid peroxidative damage with these agents might be one of the mechanisms responsible for this.

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References

  1. Arthur MJP, Kowalski-Saunders P, Wright R (1988) Effect of endotoxin on release of reactive oxygen intermediates by rat hepatic macrophages. Gastroenterology 95: 1588–1594

    Google Scholar 

  2. Carpenter MP (1981) Antioxidant effects on the prostaglandin endoperoxide synthetase product profile. Fed Proc 40: 189–194

    Google Scholar 

  3. Crompton M, Ellinger H, Costi A (1988) Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem J 255: 357–360

    Google Scholar 

  4. Decker K (1985) Eicosanoids, signal molecules of liver cells. Semin Liver Dis 5: 175–190

    Google Scholar 

  5. Francavilla A, Barone M, Todo S, Zeng Q, Porter KA, Starzl TE (1989) Augmentation of rat liver regeneration by FK 506 compared with cyclosporin. Lancet II: 1248–1249

    Google Scholar 

  6. Goldin H, Keisari Y (1989) The effect of cyclosporine on macrophage oxidative burst potential during graft-versus-host reactions in mice. Transplantation 47: 548–552

    Google Scholar 

  7. Goto S, Kim YI, Shimada T, Kawano K, Kobayashi M (1991) The effects of pretransplant cyclosporine therapy on rats grafted with twelve-hour cold-stored livers: with special reference to reperfusion injury. Transplantation 52: 615–621

    Google Scholar 

  8. Granger DN (1988) Role of xanthine oxidation in granulocytes in ischemia-reperfusion. Am J Physiol 255: H1269-H1275

    Google Scholar 

  9. Hayashi T, Nagasue N, Kohno H, Chang YC, Galizia G, Nakamura T (1989) Evidence that cyclosporine pretreatment protects lysosomal membrane in liver ischemia in dogs. Transplantation 47: 924–926

    Google Scholar 

  10. Howard TK, Klintmalm GBG, Cofer JB, Husberg BS, Goldstein RM, Gonwa TA (1990) The influence of preservation injury on rejection in the hepatic transplant recipient. Transplantation 49: 103–107

    Google Scholar 

  11. Kalayoglu M, Sollinger HW, Stratta RJ, D'Alessandro AM, Hoffmann RM, Pirsch JD, Belzer FO (1988) Extended preservation of the liver for clinical transplantation. Lancet I: 617–619

    Google Scholar 

  12. Kawano K, Kim YI, Kaketani K, Kobayashi M (1989) The beneficial effect of cyclosporine on liver ischemia in rats. Transplantation 48: 759–764

    Google Scholar 

  13. Kim YI, Calne RY, Nagasue N (1988) Cyclosporin A stimulates proliferation of the liver cells after partial hepatectomy in rats. Surg Gynecol Obstet 166: 317–332

    Google Scholar 

  14. Kim YI, Kawano K, Nakashima K, Goto S, Kobayashi M (1991) Alleviation of 3.5-hour warm ischemic injury of the liver in pigs by cyclosporine pretherapy. Transplantation 51: 731–733

    Google Scholar 

  15. Kim YI, Kawano K, Iwao Y, Ono M, Goto S, Kobayashi M, Egashira T (1992) Stimulation of liver regeneration by pretreatment with azathioprine as well as cyclosporine and FK506. Transplantation 53: 949–951

    Google Scholar 

  16. Kurokawa T, Kobayashi H, Nomani T, Harada A, Nakao A, Sugiyama S, Ozawa T, Takagi H (1992) Beneficial effects of cyclosporine on postischemic liver injury in rats. Transplantation 53: 308–311

    Google Scholar 

  17. Lefer AM (1985) Eicosanoids as mediators of ischemia and shock. Fed Proc 44: 275–280

    Google Scholar 

  18. Lowry OH, Rosebrough NJ, Lewis Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193: 265–275

    Google Scholar 

  19. Marubayashi S, Dohi K, Ochi K, Kawasaki T (1986) Role of free radicals in ischemic rat liver cell injury: prevention of damage by α-tocophirol administration. Surgery 99: 184–192

    Google Scholar 

  20. McCord JM (1985) Oxygen derived free radicals in post-ischemic tissue injury. N Engl J Med 312: 159–163

    Google Scholar 

  21. McKeown CMB, Edwards V, Phillips MJ, Harvery PRC, Petzunka CN, Strasberg SM (1988) Sinusoidal lining cell damage: the initial injury in cold preservation of liver allografts in the rat. Transplantation 46: 178–191

    Google Scholar 

  22. Miyagawa H, Yoshikawa T, Tanigawa T, Yoshida N, Sugino S, Kondo M, Nishikawa H, Kohno M (1988) Measurement of serum superoxide dismutase activity by electron spin resonance. J Clin Biochem Nutr 5: 1–7

    Google Scholar 

  23. Nathan CF (1987) Neutrophil activation on biological surfaces: massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes. J Clin Invest 80: 1550–1560

    Google Scholar 

  24. Nawroth PP, Stern DM (1986) Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 163: 740–745

    Google Scholar 

  25. Nordström G, Seeman T, Hasselgren PO (1985) Beneficial effect of allopurinol in liver ischemia Surgery 97: 679–684

    Google Scholar 

  26. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissue by thiobarbituric acid reaction. Anal Biochem 95: 351–358

    Google Scholar 

  27. Patel KD, Zimmerman GA, Prescott SM, McEver RP, McIntyre TM (1991) Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils. J Cell Biol 112: 749–759

    Google Scholar 

  28. Salvador M, Bunting S, Mullane K, Thorogood P, Vane JR (1977) Imidazole: a selective inhibitor of thromboxane synthetase. Prostaglandins 13: 611–618

    Google Scholar 

  29. Shaw BW, Wood RP (1989) Improved results with retransplantation of the liver. Transplant Proc 21: 2407–2408

    Google Scholar 

  30. Shiratori Y, Kawase T, Shiina S, Okano K, Sugimoto T, Teraoka H, Matano S, Matsumoto K, Kamii K (1988) Modulation of hepatotoxicity by macrophages in the liver. Hepatology 8: 815–821

    Google Scholar 

  31. Southard JH, Marsh DC, McAnulty JF, Belzer FO (1987) Oxygen-derived free radical damage in organ preservation: activity of superoxide dismutase and xanthine oxidase. Surgery 101: 566–570

    Google Scholar 

  32. Sraer J, Bens M, Ardaillou R (1989) Dual effects of cyclosporine A on arachidonate metabolism by peritoneal macrophages: phospholipase activation and partial thromboxane-synthase blockage. Biochem Pharmacol 38: 1947–1954

    Google Scholar 

  33. Starzl TE, Porter KA, Mazzaferro V, Todo S, Fung J, Francavilla A (1991) Hepatotrophic effects of FK506 in dogs. Transplantation 51: 67–70

    Google Scholar 

  34. Thurman RG, Lindert KA, Cowper KB, Koppele JM, Currin RT, Caldwell-Kenkel J, Tanaka Y, Gao W, Takei Y, Marzi I, Lemasters JJ (1991) Activation of Kupffer cells following liver transplantation. In: Wisse E, Knook DL, McCuskey RS (eds) Cells of the hepatic sinusoid. Kupffer Cell Foundation, The Netherlands, pp 358–363

    Google Scholar 

  35. Varani J, Bendelow MJ, Sealey DE, Kunkel SL, Gannon DE, Ryan US, Ward PA (1988) Tumor necrosis factor enhances susceptibility of vascular endothelial cells to neutrophil-mediated killing. Lab Invest 59: 292–295

    Google Scholar 

  36. Weisiger RA (1986) Oxygen radicals and ischemic tissue injury. Gastroenterology 90: 494–496

    Google Scholar 

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Authors and Affiliations

  1. Department of Surgery I, Oita Medical University, Hasama-cho, 879-55, Oita, Japan

    Katsunori Kawano, Yang Il Kim, Masayuki Ono, Shigeru Goto, Tetsuji Kai & Michio Kobayashi

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  1. Katsunori Kawano
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  2. Yang Il Kim
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  3. Masayuki Ono
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  4. Shigeru Goto
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  5. Tetsuji Kai
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  6. Michio Kobayashi
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Kawano, K., Kim, Y.I., Ono, M. et al. Evidence that both cyclosporin and azathioprine prevent warm ischemia reperfusion injury to the rat liver. Transplant Int 6, 330–336 (1993). https://doi.org/10.1007/BF00335970

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  • DOI: https://doi.org/10.1007/BF00335970

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