Mecanismos de protección del precondicionamiento isquémico en el trasplante hepático de injertos esteatósicos
ABSTRACT: Despite the significant improvement during the last decade, the dramatic shortage of organs for transplantation obliges us to consider use of steatotic grafts, which are more vulnerable to hepatic ischemia-reperfusion (I/R) injury than non-steatotic livers. The use of steatotic livers is associated with an increased risk of primary non-function or dysfunction after transplantation. Several hypotheses have been put forward to explain why steatotic livers are more liable to I/R injury than normal livers. These include increases in: oxidative stress, neutrophil infiltration, microcirculatory alterations and release of tumor necrosis factor ? (TNF) from Kupffer cell activation. Recently, it has been reported that ischemic preconditioning, based on brief episodes of ischemia and reperfusion, protects steatotic livers undergoing normothermic ischemia. Results obtained suggest that ATP preservation induced by ischemic preconditioning may be central to the protection of steatotic liver against the hepatic I/R injury. NO and AMPK are candidates for mediating ischemic preconditioning. In the present work we examined: (1) whether preconditioning protects against hepatic and lung damage associated with steatotic liver transplantation and the effect of preconditioning on the mechanisms involved in the increased vulnerability of fatty livers to hepatic I/R. Evaluate the role of NO in ischemic preconditioning; (2) Whether AMPK and NO are involved in the benefits of ischemic preconditiong on energy metabolism in steatotic liver transplantation. Steatotic and non-steatotic liver grafts were similar in their blood flow, neutrophil accumulation, and TNF release after transplantation. Neither the increased vulnerability of fatty livers of Zucker rats to hepatic I/R injury associated with liver transplantation nor the protection conferred by preconditioning could be explained by changes in hepatic blood flow, neutrophil accumulation, and TNF release after transplantation under the conditions evaluated. However, in the presence of steatosis, lipid peroxidation injury increased. Preconditioning reduced the xanthine accumulation and percentage of xanthine oxidase seen in steatotic liver grafts during cold ischemia, and conferred protection against liver and lung damage following transplantation. The benefits of preconditioning could be mediated by nitric oxide. NO reduce the deleterious effects of ROS and modulate XDH/XOD activity, thus protecting steatotic livers against hepatic I/R injury. Preconditioning, through AMPK activation, induce NO synthesis. Pharmacological strategies based in pretreatment with AMPK activators or NO donors could protect against I/R injury associated with non-steatotic liver transplantation. However, the effective dose of exogenous NO may differ in both steatotic and non-steatotic livers.The injurious effects of exogenous donors on hepatic injury and oxidative stress in steatotic grafts were associated with increase nitrotyrosine levels. The results of nitrotyrosines suggest that peroxynitrite is a predominant form of ROS in steatotic grafts. This could explain, at least partially, the increased vulnerability of steatotic grafts to I/R injury and the injurious effects of exogenous NO on steatotic liver transplantation.
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Advisor:Peralta Uroz, Carmen; Roselló Catafau, Joan
School:Universitat de Barcelona
Source Type:Master's Thesis
Keywords:fisiologia divisió iii
Date of Publication:09/21/2005