Preservation of hepatic cell integrity by aprotinin in hypoxia

Abstract

Perfused cat livers subjected to 2.5 hr of hypoxia exhibited dramatic increases in perfusate cathepsin D and lactic acid dehydrogenase (LDH) activities, amino nitrogen concentrations, and a 60% depression in the clearance rate of carbon particles by the reticuloendothelial system (RES). Addition of aprotinin (250 KIU/ml) to the perfusate prior to hypoxia prevented the increases in circulating cathepsin D, LDH, and amino-nitrogen observed at 150 minutes. In addition, aprotinin prevented the reduction in carbon clearance during severe hypoxia. However, aprotinin had no effect on the percent free cathepsin D activity indicating that this agent did not directly prevent increases in lysosomal fragility occurring in response to hypoxia. Thus, addition of pharmacologic doses of aprotinin to the perfusate protected RES cells, and markedly reduced the release of cytoplasmic and lysosomal enzymes. The prevention of cell membrane dissolution appears to be a critical factor in hepatic preservation, and may be related to the inhibition of proteolysis by aprotinin. These effects may help explain the therapeutic effectiveness of this agent in shock and in myocardial ischemia.