Abstract
Ischemia/reperfusion (I/R) injury is a main cause of primary dysfunction or non-function after liver transplantation (LTx). Recent evidence indicates that an increase in nitric oxide (NO) production after LTx is associated with I/R injury. The aim of this study was to demonstrate that low-dose FK506 in combination with aminoguanidine (AGH), which leads to a reduction of NO levels, has a protective effect by reducing I/R associated injury after LTx. Fortyone DA-(RT1av1) rats served as donors and recipients for syngenic orthotopic arterialised LTx. They were divided into 4 groups: controls without pre-/treatment (I), pre-/treatment with high-dose FK506 (II), pre-/treatment with AGH only (III), and pre-/treatment with low-dose FK506 in combination with AGH (IV). After LTx the laboratory parameters and liver biopsy were performed. The levels of transaminase (ALT) in groups I, II and III were significantly higher on day 3 after LTx compared to group IV (p = 0.001, p = 0.001, p = 0.000). In group IV the I/R-associated liver necrosis rate was reduced significantly. Our results demonstrated that a combined dual pharmacological pretreatment (group IV) reduced I/R injury of the graft after LTx in a rat model.
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Carden, D. L. and Granger D. N., Pathophysiology of ischemiareperfusion injury. J. Pathol., 190(3), 255–256 (2000).
Cicco, G., Panzera, P. C., Catalano, G., and Memeo, V., Microcirculation and reperfusion inury in organ transplantation. Adv. Exp. Med. Biol., 566, 363–373 (2005).
Corbett, J. A. and McDaniel, M. L., Selective inhibition of inducible nitric oxide synthase by aminoguanidine. Methods Enzymol., 268, 398–408 (1996).
Crenesse, D., Laurens, M., Heurteaux, C., Cursio, R., Saint-Paul, M. C., Schmid-Aliana, A., and Gugenheim, J., Rat liver ischemia-reperfusion-induced apoptosis and necrosis are decreased by FK506 pretreatment. Eur. J. Phramacol., 473(2–3), 177–184 (2003).
Fondevila, C., Busuttil, R. W., and Kupiec-Weglinski, J. W., Hepatic ischemia/reperfusion inury — a fresh look. Exp. Mol. Pathol., 74(2), 86–93 (2003).
Gong, J. P., Tu, B., Wang, W., Peng, Y., Li, S. B., and Yan, L. N., Protective effect of nitric oxide induced by ischemic preconditioning on reperfusion injury of rat liver graft. World J. Gastroenterol., 10(1), 73–76 (2004).
Kaibori, M., Sakitani, K., Oda, M., Kamiyama, Y., Masu, Y., Nishizawa, M., Ito S., and Okumara, T., Immunosuppressant FK506 inhibits inducible nitric oxide synthase gene expression at a step of NF-kappaB activation in rat hepatocytes. J. Hepatol., 30(6), 1138–1345 (1999).
Kaizu, T., Ikeda, A., Nakao, A., Takahashi, Y., Tsung, A., Kohmoto, J., Toyokawa, H., Shao, L., Bucher, B. T., Tomiyama, K., Nalesnik, M. A., Murase, N., and Geller, D. A., Donor graft adenoviral iNOS gene transfer ameliorates rat liver transplant preservation inury and improves survival. Hepatology, 43(3), 464–473 (2006).
Kitagawa, K., Matsumoto, M., and Tagaya, M., “Ischemic tolerance” phenomenon found in the brain. Brain Res., 528, 21 (1990).
Kuo, P. C., Alfrey, E. J., Abe, K. Y., Huie, P., Sibley, R. K., and Dafoe, D. C., Cellular localization and effect of nitric oxide synthesis in a rat model of orthotopic liver transplantation. Transplantation, 61(2), 305–312 (1996).
Lee, S., Charters, A. C., Chandler, J. G., and Orloff, M. J., A technique for orthotopic liver transplantation in the rat. Transplantation, 16(6), 664–669 (1973).
Lemasters, J. J., Peng, X. X., Bachmann, S., Currin, R. T., Gao, W., and Thurman, R. G., Dual role of Kupffer cell activation and endothelial cell damage in reperfusion injury to livers stored for transplantation surgery. J. Gastroenterol. Hepatol., 10(1), 84–87 (1995).
Novotny, A. R., Emmauel, K., Maier, S., Westerholt, A., Weighardt, H., Stadler, J., Bartels, H., Schwaiger, M., Siewert, J. R., Holzmann, B., Heidecke, C. D., Cytochrome P450 activity mirrors nitric oxide levels in postoperative sepsis: predictive indicators of lethal outcome. Surgery, 141(3), 376–384 (2007).
Sakr, M., Zetti G., and McClain, C., Protective effect of FK506 pretreatment against renal ischemia/reperfusion injury in rats. Transplantation, 53, 987 (1992).
Stolz, D. B., Ross, M. A., Ikeda, A., Tomiyama, K., Kaizu, T., Geller, D. A., and Murase, N., Sinusoidal endothelial cell repopulation following ischemia/reperfusion injury in rat liver transplantation. Hepatology, 46(5), 1464–75 (2007).
Worrall, N. K., Chang, K., Suau, G. M., et al., Inhibition of inducible nitric oxide synthase prevents myocardial and systemic vascular barrier dysfunction during early cardiac allograft rejection. Circ. Res., 78(5), 769–779 (1996).
Worrall, N. K., Boasquevisque, C. H., Botney, M. D., Misko, T. P., Sullivan, P. M., Ritter, J. H., Ferguson, T. B., and Patterson, G. A., Inhibition of inducible nitric oxide synthase ameliorates functional and histological changes of acute lung allograft rejection. Transplantation, 63(8), 1095–1101 (1997).
Yang, C. W., Ahn, H. J., Han, H. J., Kim, W. Y., Li, C., Shin, M. J., Kim, S. K., Park, J. H., Kim, Y. S., Moon, I. S., and Bang, B. K., Pharmacological preconditioning with lowdose cyclosporine or FK506 reduces subsequent ischemia/reperfusion injury in rat kidney. Transplantation, 72(11), 1753–1759 (2001).
Yin, D. P., Sankary, H. N., Chong, A. S., Ma, L. L., Shen, J., Foster, P., and Williams, J. W., Protective effect of ischemic preconditioning on liver preservation-reperfusion injury in rats. Transplantation, 66(2), 152–157 (1998).
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Hüser, N., Doll, D., Altomonte, J. et al. Graft preconditioning with low-dose tacrolimus (FK506) and nitric oxide inhibitor aminoguanidine (AGH) reduces ischemia/reperfusion injury after liver transplantation in the rat. Arch. Pharm. Res. 32, 215–220 (2009). https://doi.org/10.1007/s12272-009-1138-9
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DOI: https://doi.org/10.1007/s12272-009-1138-9