Hepatic injury induced by ischemia/reperfusion of
The liver is highly susceptible to a number of pathological insults, including ischemia/reperfusion injury. We the liver is an important clinical problem that often have previously employed an animal model of hepatic follows circulatory shock with resuscitation, as well as ischemia/reperfusion injury, and have shown that this many types of liver surgery, including transplantation injury induces the production and release of hepatic-deand resection for tumor. Possible consequences include rived tumor necrosis factor a (TNF-a), which mediates, liver failure and/or multi-organ system failure, both of in part, local liver injury following hepatic reperfusion. which have high rates of morbidity and mortality. 1,2 In the present study, we have extended these previous Neutrophils have been shown to be responsible, in part, observations to assess whether an interrelationship exfor the pathophysiological changes that follow ischists between TNF-a and the neutrophil chemoattractant/ emia/reperfusion injury in many organs, including the activating factor, epithelial neutrophil activating protein, gut, 3-5 heart, 6,7 and soft tissues. 8,9 In addition, Jaeschke that may account for some of the pathology of neutrophilet al have recently shown that the neutrophil plays mediated ischemia/reperfusion-induced liver injury. We a central role in the development of the pathological observed that hepatic ischemia/reperfusion injury leads to: (1) a coincident increase in hepatic neutrophil seques-hepatic changes following hepatic ischemia/reperfusion tration, elevated serum alanine aminotransferase (ALT) injury. 10 These investigators showed a substantial delevels, and hepatic production of epithelial neutrophil accrease in the severity of hepatic injury in animals rentivating protein; (2) passive immunization with neutralizdered neutropenic before the initiation of hepatic isching antibodies to TNF-a resulted in significant suppresemia/reperfusion. These neutropenic animals also sion of hepatic-derived epithelial neutrophil activating showed an increase in hepatic adenosine triphosphate protein; and (3) neutralization of epithelial neutrophil aclevels and improved overall survival rate. 10 Interesttivating protein by passive immunization significantly atingly, the actual mechanisms responsible for neutrotenuated neutrophil sequestration in the liver and serum phil recruitment into the liver following hepatic isch-ALT levels. These findings support the notion that local emia/reperfusion injury remain to be defined.
expression of hepatic epithelial neutrophil activating
Using an animal model of hepatic ischemia/reperfuprotein produced in response to TNF-a is an important sion injury, our laboratory has previously shown that mediator of the local neutrophil-dependent hepatic inhepatic ischemia/reperfusion injury causes the producjury associated with hepatic ischemia/reperfusion. (HEP-ATOLOGY 1996;23:506-514.) tion and release of tumor necrosis factor a (TNF-a), which is important in the development of the subsequent liver injury. 11,12 While TNF-a was initially reported to be a neutrophil chemotaxin, 13 recent studies Abbreviations: TNF-a, tumor necrosis factor a; GRO-a, growth related oncohave shown that recombinant TNF-a is not directly gene; IL, interleukin; ENA-78, epithelial neutrophil activating protein; ALT, chemotactic for neutrophils. 14,15 These findings suggest