Increased hepatic lysosomal activity in biliary cirrhosis originates from hepatocytes rather than from macrophages

Abstract

To investigate the potential role of lysosomes in cirrhosis, the activity of lysosomal enzymes was analyzed in rats with cirrhosis induced by bile-duct ligation. Twenty-eight days after surgery, the activity of lysosomal enzymes was markedly increased in the homogenate of cirrhotic livers (e.g. arylsulfatase 7 +/- SD 1 vs 17 +/- 3 nmol.min-1.mg-1 in controls and cirrhotics, respectively; p < 0.001). The corresponding plasma levels were also increased (arylsulfatase: 10 +/- 1 vs 25 +/- 9 pmol.min-1.mg-1; p < 0.01). In contrast, the activities of these enzymes in lysosomal fractions did not differ, suggesting an increase in number of lysosomes. The increased lysosomal activity correlated with severity of cirrhosis as assessed by the aminopyrine breath test and with cholestatic parameters but less with transaminases. Since macrophages, cells which are rich in lysosomes, could contribute to the increase in lysosomal enzyme content, these cells were estimated stereologically after being marked immunohistochemically with a monoclonal antibody against the rat macrophage membrane antigen ED2. ED2 positive cells were increased 2.7-fold in cirrhotic livers. This increase cannot account for the observed increase in hepatic lysosomal enzyme content. Furthermore, 1 week after bile-duct ligation, when there was cholestasis but not yet cirrhosis, lysosomal enzyme activities were already increased. These data support the idea that the increased hepatic lysosomal activity in biliary cirrhosis is of hepatocyte rather than of macrophage origin, and is presumably related to cholestasis.