EVIDENCE THAT ACTIVATION OF KUPFFER CELLS INCREASES OXYGEN-UPTAKE AFTER COLD-STORAGE

Fasting for long periods of time has previously been shown to increase survival following liver transplantation. The experiments reported he re were designed to study the mechanism of this phenomenon. Livers sto red in cold Euro-Collins solution for 16 hr were perfused subsequently for 3 hr. Oxygen uptake increased slowly reaching maximal values afte r about 80 min of reperfusion. This increase in oxygen uptake was sign ificantly greater in livers from fed rats (73 mu mol/g/hr) than in liv ers from either 4-day fasted rats (42 mu mol/g/hr) or from rats where Kupffer cells were inactivated by gadolinium chloride treatment (30 mu mol/g/hr). Thus, it is likely that the increase in oxygen uptake invo lves activation of Kupffer cells on reperfusion. Therefore, carbon upt ake, which is due predominantly to phagocytosis by Kupffer cells, was monitored in the perfused liver. Carbon uptake was increased significa ntly in livers from fed rats at 80 compared with 20 min of perfusion. Further, carbon uptake was diminished significantly by long-term fasti ng and gadolinium chloride treatment. These results indicate that oxyg en uptake increases in parallel with activation of Kupffer cells in li vers from fed rats and support the hypothesis that activated Kupffer c ells produce factors that stimulate oxygen uptake after cold storage. In further support of this hypothesis, the observed increase in oxygen uptake was diminished when the flow rate was increased. Because media tors would be diluted as the flow rate was increased, this result is c onsistent with the hypothesis that oxygen uptake depends on chemical m ediators released from Kupffer cells. When livers were perfused with i ndomethacin, a prostaglandin synthesis inhibitor, the increase in oxyg en uptake observed in fed rats was reduced by 34%. Further, in livers perfused under hypoxic conditions using a low-flow model, lactate dehy drogenase release in livers from fed rats (547 U/g/hr) was significant ly greater than in livers from 4-day fasted rats (397 U/g/hr), indicat ing that fasting increased tolerance to hypoxia. In conclusion, livers of fasted rats require less oxygen during reperfusion, most likely be cause activation of Kupffer cells on reperfusion is minimized. These f indings could explain why survival after transplantation is improved b y long-term fasting.