Abstract
Administration of a sublethal concentration of E. coli 0111:B4 endotoxin (E) to fasted Sprague-Dawley rats results in Reye syndrome-like metabolic (hyperammonemia, elevated serum lactate, and free fatty acids), hepatic histologic (microvesicular fat deposition) and mitochondrial ultrastructural (pleomorphism and swelling with matrix disruption) changes (Yoder et al, Infect. Immun, in press). In this study, we assessed hepatic alterations in energy production, ammonia metabolism, and determined the amino acid concentration profile in E (0.2 mg/kg) or placebo (5% dextrose in water) treated (C) 250g Sprague-Dawley rats (N=5 each group). At 1, 4 or 12 hrs following E or placebo IP injection, the liver was freeze-clamped. There were no significant differences in metabolic parameters detectable at the 1 hr time point. At 4 and 12 hrs, however, ATP/ADP declined by 25% (p<0.01), [lactate] increased by 50% (p < 0.001), and [urea] increased 67% (p < 0.001) in E compared to C rats. In addition, mitochondrial [NAD+]/[NADH] increqased whereas cytosolic [NAD+]/[NADH] decreased in E compared to C rats. Two-fold increases (P<0.005) in [glutamate], [alanine] and [glutamine] and a 55% decrease in [citruilinel (p<.0.05) were measured in E compared to C animals. These results indicate that a sublethal dose of E disrupts hepatic aerobic energy production, increases glycolysis and proteolysis, and impairs ammonia clearance in the fasted rat. Since the metabolic derangements reported in this study are similar to those observed in patients with Reye syndrome, the current findings lend further support to the relevance of our sublethal endotoxin rat model.
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Kilpatrick-Smith, L., Yoder, M., Douglas, S. et al. 1220 ALTERED HEPATIC ENERGY, AMMONIA, AND AMINO ACID METABOLISM IN THE SUBLETHAL ENDOTOXIN RAT MODEL OF REYE SYNDROME. Pediatr Res 19, 314 (1985). https://doi.org/10.1203/00006450-198504000-01250
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DOI: https://doi.org/10.1203/00006450-198504000-01250