Running title: Superoxide and Post-ischemic Liver Injury Address all correspondence to:

The objective of this study was to define the relationship among Kupffer cells (KCs), superoxide production, and tumor necrosis factor-D (TNF-D) expression in the pathophysiology of post-ischemic liver injury following short and long periods of ischemia. Using different forms of superoxide dismutase with varying circulating half-lives, a monoclonal antibody directed against mouse TNF-D, and NADPH oxidase deficient mice, we found that 45 or 90 minutes of partial (70%) liver ischemia and 6 hours of reperfusion (I/R) produced time-dependent increases in liver injury and TNF-D expression in the absence of neutrophil infiltration. Furthermore, we observed that hepatocellular injury induced by short periods of ischemia were not dependent upon formation of TNF-D but were dependent upon KCs and NADPH oxidase-independent production of superoxide. However, liver injury induced by extended periods of ischemia appeared to require the presence of KCs, NADPH oxidase-derived superoxide and TNF-D expression. We conclude that the sources for superoxide formation and the relative importance of TNF-D in the pathophysiology of I/R-induced hepatocellula