Comparison of the cytotoxic actions of hypoxia and endotoxin in the perfused cat liver.

The isolated cat liver perfused at a constant flow with Krebs-Henseleit solution containing low-molecular-weight dextran was employed to ascertain the direct effects of hypoxia or endotoxin on hepatic integrity. Hypoxia resulted in large increases in circulating lactate dehydrogenase (LDH) activity and in amino-nitrogen concentration, whereas endotoxin at a dose of 0.75 microgram/gm liver wet weight resulted in only small changes in these variables after 150 minutes of perfusion. Perfusion pressure and perfusate pH did not change significantly in response to either intervention. Both hypoxia and endotoxin significantly compromised lysosomal stability as evidenced by large increases in circulating levels of cathepsin D, large increases in the nonsedimentable fraction of tissue cathepsin D (ie, increased percentage of free activity), and changes in the ultrastructural appearance of liver lysosomes associated with enhanced fragility (eg, swelling, increased vacuolization). Both interventions also significantly impaired phagocytosis by reticuloendothelial cells within the liver. However, neither intervention altered BSP clearance, indicative of a lack of effect on parenchymal cell clearance. These findings indicate that both endotoxin and hypoxia induce direct cellular damage within the liver; however, endotoxin exerted a more selective action on lysosomes, whereas hypoxia produced more of a diffuse cytotoxic effect.