EFFECTS OF BACTERIAL ENDOTOXINS ON METABOLISM

Abstract

Cortisone acetate administered to mice at the same time as endotoxin significantly protected against lethality. Delaying the injection of cortisone after the endotoxin resulted in loss of protection; associated with this loss of protection was the failure of the hormone to induce liver tryptophan pyrrolase. Normal mice given only cortisone showed an increase in enzyme activity nearly three times that found for controls when assays were carried out either 4 or 17 hours after the hormone was given. Endotoxin-poisoned mice showed normal levels of enzyme activity when concurrent injection of cortisone was given but depressed levels of enzyme when the cortisone injection was delayed for only 1 hour or more. Enzyme induction or maintenance seems to be related to survival in endotoxin poisoning. The observation that inhibitors of enzyme (protein) synthesis potentiate the lethal action of endotoxin and prevent the protective effect of cortisone is in line with this. Inhibitors used were actinomycin D, ethionine, 2-thiouracil, and 8-azaguanine. Activity of liver tryptophan pyrrolase was lowered by endotoxin and elevated by cortisone. When given concurrently, normal enzyme activity was maintained. Chlor-amphenicol, an active inhibitor of protein synthesis in microorganisms but with limited effect in mammals, was without observable influence in these respects. 18 hours postinfection mice infected with Salmonella typhimurium, strain SR-11, given in an amount that caused first deaths on the 3rd day, had a lower than normal activity of tryptophan pyrrolase and responded to cortisone induction with a smaller increase in enzyme level than that found in control mice. Each is characteristic of endotoxin poisoning. 42 hours postinfection the mice were free of these signs of endointoxication, an observation in agreement with earlier experiments where other measures of endotoxin were employed.