No abstract

In livers excised for transplantation, sinusoidal endothelium appears especially vulnerable to injury during organ preservation in the cold and subsequent reperfusion. The degree of endothelial cell injury correlates with functional impairment of the graft following transplantation. The mechanism of injury remains obscure, but endothelial cell damage has been described as coagulative necrosis secondary to irreversible physico-chemical damage. We investigated whether endothelial cell death is caused by apoptosis rather than by necrosis. Tissue from rat livers stored for varying periods in cold (1ЊC) Euro-Collins solution and then reperfused for 1 hour at 37ЊC were studied for evidence of apoptosis by detection of DNA fragmentation using the in situ terminal deoxynucleotidyl transferase d-uridine triphosphate nick end labeling (TUNEL) assay, DNA gel electrophoresis, and by transmission electron microscopy (EM). DNA fragmentation of the type characteristic of apoptosis was identified in 49.7% ؎ 2.2% of sinusoidal lining cells after 8 hours of ischemia ؉ reperfusion (viable graft) vs. 70.7% ؎ 4.3% after 16 hours ؉ reperfusion (nonviable graft) (P F .001). No such fragmentation was observed after cold preservation without reperfusion or in unpreserved, reperfused livers. EM demonstrated changes characteristic of apoptosis exclusively in endothelial cells. The study suggests that the apoptosis of sinusoidal endothelial cells is a pivotal mechanism of preservation injury in liver transplantation. (HEPATOLOGY 1998;27:1652-1660

Interleukin-6 (IL-6) is an acute reactant cytokine with anti-thought to be the most important risk factor for postoperative inflammatory properties, which has been found to prevent complications in patients undergoing liver resection 1,2 and it injury in a model of acute hepatitis in mice through downregu-is an important cause of primary nonfunction of liver allolation of tumor necrosis factor alpha (TNF-a); to correlate grafts. [3][4][5] The potential mediators involved in WI/Rp injury inversely with markers of hepatocellular injury in patients are numerous, 6-8 and include acute phase reactant cytokines with liver ischemia; and to initiate liver regeneration in mice. and polymorphonuclear neutrophils (PMN). 3,9 Better underIn this study, we investigated the role of IL-6 in rodent models standing of the pathogenesis of WI/Rp injury of the liver and of hepatic warm ischemia/reperfusion (WI/Rp) injury. IL-6-the availability of an agent that could alleviate Rp injury deficient mice (0/0) were subjected to hepatic WI and com-would have important clinical implications. pared with C57BL/6 mice, as well as IL-6 0/0 mice pretreated Interleukin-6 (IL-6) is an acute phase reactant cytokine with recombinant IL-6 (rIL-6). The effects of rIL-6 following with pleiotropic biological effects. This cytokine plays a cenvarious periods of ischemia were further studied in models of tral role in hematopoiesis, host defense, and inflammation. 10 hepatic ischemia in rats. IL-6 0/0 mice had increased reperfu-IL-6 has been found to have potent anti-inflammatory propsion injury as assessed by transaminase levels and a tissue erties, particularly in preventing injuries related to endotoxenecrosis scoring system when compared with controls, an ef-mia. 11,12 In a rat model of endotoxin-induced tracheal injury, fect prevented by pretreatment with rIL-6. Similarly, rats pre-recombinant IL-6 (rIL-6) was found to significantly prevent treated with rIL-6 had reduced reperfusion injury and better neutrophil infiltration and reduce other markers of inflamsurvival than controls in each respective WI group. Tissue mation. 11 TNF-a expression measured by Northern blot analysis andAlthough the liver is an important source of IL-6 and the serum C-reactive protein (CRP) levels, a marker of inflamma-primary site for its clearance, 13 the role of IL-6 in liver disease tion, were significantly reduced in animals pretreated with is unclear. In an acute hepatitis model in mice, rIL-6 was rIL-6. Administration of antibodies to TNF-a reproduced the found to confer a high degree of hepatoprotection when given beneficial effect of rIL-6. Hepatocyte proliferation, as assessed before the induction of the injury. 14 This effect was thought by a scoring method for mitotic index and proliferating nuclear to be related to downregulation of tumor necrosis factor cell antigen staining, was markedly increased in rIL-6-treated alpha (TNF-a) production. In a recent prospective randomrats when compared with controls. In conclusion, this study ized study of hepatic vascular...