EFFECTS OF SUBLETHAL DOSES OF ENDOTOXIN AND ASPIRIN (ASA) ON RAT HEPATIC ENERGY METABOLISM: AN ANIMAL MODEL OF REYE SYNDROME

Abstract

The administration of a sublethal dose of endotoxin (LPS) to fasted rats results in biochemical and histopathological perturbations similar to Reye Syndrome (RS), ie. hyperammonemia, elevated serum lactate and free fatty acids, and hepatic microvesicular fat deposition and swollen mitochondria in the absence of cellular necrosis (Yoder et al, Infect. Immun., 1985). In this study, hepatic energy metabolism was assessed in freeze clamped liver samples (12 hrs post treatment) obtained from (250-300 gm Sprague-Dawley) rats which had received an intraperitoneal injection of placebo-5% dextrose (C), 0.25mg LPS/kg (LPS), placebo + 1hr later 50mg ASA/kg (ASA) or 0.25mg LPS/kg + 1hr later 50 mg ASA/kg (LPS/ASA). In both LPS and LPS/ASA, ATP/ADP declined by 31% (p<0.005), [total ketones] decreased by 40% (p<0.0005) and [acetyl CoA] declined by 37% (p<0.005) as compared to C and ASA. In LPS/ASA, there were increases in [isovaleryl CoA], [isobutyryl CoA] and [B-methylcrotonyl CoA] as compared with ASA (60%, p<0.01) and LPS (90%, p<.005). These results suggest inhibition of fatty acid oxidation and abnormal branch chain amino acid (BCAA) oxidation and are analogous to data obtained in patients with RS showing hyperammonemia, compromised FA oxidation and accumulation of intermediates of BCAA oxidation. Accumulation of BCAA intermediates with LPS/ASA is a possible mechanism for the potentiation of RS by ASA. These findings provide further biochemical evidence that a sublethal dose of LPS administered to fasted rats produces an animal model of RS, (Supported by NS 17752)

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