Significant increase of Kuppfer cells associated with loss of Na+,K+-ATPase activity in rat hepatic allograft rejection.

Abstract

Cholestasis is a complication that occurs during the rejection of liver transplants. The aim of this study was to investigate the association of activated Kupffer cells (KCs) and Na+,K+-ATPase activity for taurocholate cotransport and bile canalicular (BC) Mg++-ATPase activity for hepatobiliary excretion in rat liver allograft. Quantitative analyses of KC number and size in relationship to enzyme activity of Na+,K+-ATPase and of BC Mg++-ATPase were conducted in rejected liver after allogenic transplantation and after prevention of rejection using cyclosporine. The animals were examined on the 10th postoperative day. In the rejection group, the number of KCs significantly increased more than fourfold in comparison with the number of KCs in the control livers. Some KCs were found in the sinusoids, but the majority were located in the space of Disse. Na+,K+-ATPase activity vanished from the basolateral plasma membrane, whereas BC Mg++-ATPase activity was restored in the apical domain. With immunosuppression, KCs showed the same behavior as in the control group, and activity of both ATPases was observed as strong electron-dense precipitates in basolateral and apical plasma membrane domains. In this study, we demonstrate that activated KCs migrate into the donor liver and release cytokines, which leads to the loss of Na+,K+-ATPase activity in the rejection group. BC Mg++-ATPase activity was not influenced by these mediators of activated macrophages. Since Na+,K+-ATPase is the cotransporter for hepatocyte taurocholate uptake, these data may contribute to understanding the mechanisms for cholestasis during hepatic allograft rejection.