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Abstract

In liver transplantation, it is currently hypothesized that nonparenchymal cell damage and/or activation is the major cause of preservation-related graft injury. Because parenchymal cells (hepatocytes) appear morphologically well preserved even after extended cold preservation, their injury after warm reperfusion is ascribed to the consequences of nonparenchymal cell damage and/or activation. However, accumulating evidence over the past decade indicated that the current hypothesis cannot fully explain preservation-related liver graft injury. We review data obtained in animal and human liver transplantation and isolated perfused animal livers, as well as isolated cell models to highlight growing evidence of the importance of hepatocyte disturbances in the pathogenesis of normal and fatty graft injury. Particular attention is given to preservation time-dependent decreases in high-energy adenine nucleotide levels in liver cells, a circumstance that (1) sensitizes hepatocytes to various stimuli and insults, (2) correlates well with graft function after liver transplantation, and (3) may also underlie the preservation timedependent increase in endothelial cell damage. We also review damage to bile duct cells, which is increasingly being recognized as important in the long-lasting phase of reperfusion injury. The role of hydrophobic bile salts in that context is particularly assessed. Finally, a number of avenues aimed at preserving hepatocyte and bile duct cell integrity are discussed in the context of liver transplantation therapy as a complement to reducing nonparenchymal cell damage and/or activation. (Liver Transpl 2001;7: 381-400.)A lthough the use of University of Wisconsin (UW) solution has permitted an increase in mean preservation time, the incidence of graft dysfunction still persists, 1,2 contributing significantly to a more than 20% per year mortality rate for patients in liver transplantation centers in the United States. 3 In addition, when storage time exceeds 10 to 12 hours, such late posttransplantation complications as biliary strictures occur in more than 25% of liver transplant recipients. [4][5][6] To prevent or minimize graft dysfunction and posttransplantation complications, it is essential to fully understand the importance of individual liver cell types in graft injury induced by cold storage and reperfusion. Insight into the cellular and molecular basis of these injuries will lead to the development of better intervention strategies, which is very important because graft dysfunction results in increased morbidity and enhances mortality rates. 7,8 Moreover, up to 30% of patients with graft dysfunction need retransplantation as early as within the first 3 months after transplantation, 2,7,8 which increases the demand on an already short pool of donor organs.According to morphological studies, cold preservation leads to injuries of nonparenchymal cells, whereas liver parenchymal cells appear well preserved. It is currently hypothesized that sinusoidal endothelial cell impairment, 9-11 activatio...