Nitric oxide and hepatic ischemia-reperfusion injury

A number of surgical maneuvers require a period of liver ischemia. On reperfusion, hepatic injury results from a failure of the microcirculation and an excessive inflammatory response. Within the liver, sinusoidal cells produce a basal level of nitric oxide from endothelial nitric oxide synthase activity. During the early reperfusion period, increased concentrations of cytokines and oxygen free radicals result in expression of the inducible form of nitric oxide synthase, via activation of nuclear transcription factor-kappaB, in hepatocytes and Kupffer cells. This results in increased production of nitric oxide after 4 to 6 h from the onset of reperfusion. Nitric oxide generation attenuates the inflammatory response by counteracting endothelin, reducing inflammatory cell activity and decreasing the expression of cytokines and adhesion molecules. In animal models, therapeutic strategies that increase endogenous nitric oxide concentrations in the liver significantly decrease reperfusion injury. Such treatment modalities may have important clinical implications for the future, particularly in view of the increasing use in hepatic transplantation programs of marginal donor livers with their greater susceptibility to ischemia-reperfusion injury.