Progress in Reye syndrome: epidemiology, biochemical mechanisms and animal models.
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Adolescent↗
Biomedical subjects
L Kilpatrick-Smith
Publications and source records attributed to L Kilpatrick-Smith.
Serum acid proteolytic activity in Reye syndrome.
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Humans↗
Enhanced endotoxin effects in plasma fibronectin-deficient rats.
Immunoreactive plasma fibronectin depletion has been associated with the presence of collagen-fibronectin complexes in patients after trauma and in animal models of traumatic and burn injuries. However, the role of plasma fibronectin in the development of sepsis after traumatic and burn injuries in patients is unknown. Treatment of patients and animals with purified human plasma fibronectin ameliorates some of the clinical and metabolic effects of systemic endotoxemia. We report that the induction of immunoreactive plasma fibronectin deficiency by gelatin infusion is associated with enhanced effects of intraperitoneal Escherichia coli endotoxin injection. We have observed a significant increase in the concentrations of ammonia in plasma of treated rats compared with those in control rats administered the same dose of endotoxin.
Ammonia↗
Endotoxin-induced changes in nitrogen metabolism.
Intraperitoneal administration of a sublethal dose of E. coli endotoxin to fasted rats produced within 12 hrs a rise in plasma ammonia, urea, glutamine, glutamate and aspartate as compared to controls. At this time, hepatic ureagenesis also increased as did the levels of glutamate, glutamine, aspartate, alanine and asparagine. However, liver glucose and ketone levels were unchanged. Hepatic [ATP]/[ADP] ratios declined in endotoxin-treated animals and there was an oxidation of mitochondrial pyridine nucleotides and a reduction of cytosolic pyridine nucleotides. The results suggest that impairment of nitrogen metabolism is an early effect of endotoxemia.
Amino Acids↗
Cellular effects of endotoxin in vitro: mobility of endotoxin in the plasma membrane of hepatocytes and neuroblastoma cells.
Lipopolysaccharide labeled with fluorescein isothiocyanate (FITC-LPS) was used to examine interactions between endotoxin and plasma membrane in isolated rat hepatocytes and mouse neuroblastoma NB41A3 cells. At the same endotoxin to cell ratio, hepatocytes bound more toxin than did neuroblastoma cells. At a dose of 12 micrograms/mg dry wt, a bound mobile fraction of between 60 and 75% of FITC-LPS was found on hepatocytes at 25 degrees C with a lateral diffusion coefficient (D) of 4.0 X 10(-9) cm2/s. In neuroblastoma cells, the mobile fraction was larger (85-90%), with D 1.0 X 10(-8) cm2/s. D was temperature-dependent between 10 and 37 degrees C and increased from 1.8 X 10(-9) to 1.0 X 10(-8) cm2/s in hepatocytes and from 9.4 X 10(-9) to 1.9 X 10(-8) cm2/s in neuroblastoma cells. In both types of cell, nonviable (cells which did not exclude Trypan blue) as compared to viable cells showed different recovery patterns and 100% of the probe molecules were mobile. These results suggest that: (1) endotoxin binding to mammalian cells consists of two subpopulations with different mobilities; (2) binding of the immobile fraction is dependent on cellular integrity; and (3) the differences in binding, lateral mobility, and size of the immobile fraction in hepatocytes and neuroblastoma cells may be due to variations in membrane composition and/or number of binding sites.
Animals↗
Cellular effects of endotoxin in vitro. II. Reversibility of endotoxic damage.
Administration of Escherichia coli endotoxin to NB41A3 neuroblastoma cells in culture produced decreases in 1) intracellular [ATP]/[ADP], 2) flux through pyruvate dehydrogenase (PDH), and 3) total intracellular calcium. These effects were reversible if endotoxin was washed off within 10-15 min, but not if it remained in contact with the cells for 30 min or more. Minor, reversible morphological and functional alterations occurred during the initial phase, but after 30-min exposure to the toxin, the damage was irreversible. A model is proposed in which early, reversible weak binding of endotoxin to the plasma membrane partially blocks inward calcium flux, lowering the intracellular [Ca2+] and consequently the PDH phosphatase activity which activates the PDH complex. If endotoxin is removed at this stage, these processes are reversed and the cell recovers. If not, the toxin becomes irreversibly incorporated into the cell with consequent damage to the plasma membrane and organelles, which leads to massive ion movements resulting in cellular hydration with ultimate disruption of mitochondria and cell death.
Adenosine Diphosphate↗
Cellular effects of endotoxin in vitro. I. Effect of endotoxin on mitochondrial substrate metabolism and intracellular calcium.
Intramitochondrial substrate metabolism was examined in cultured neuroblastoma NB41A3 cells exposed to endotoxin in order to elucidate possible causes for the changes in [ATP]/[ADP][Pi] and [NAD+]/[NADH] reported by us previously in these cells [1]. Flux through pyruvate dehydrogenase (PDH), measured with [1-14C]-pyruvate, was inhibited by 54% within 10 min in endotoxin-treated cells (0.99 nmol/min/mg dry wt vs 0.46 nmol/min/mg dry wt). In contrast, flux through 2-oxoglutarate dehydrogenase, measured with [1-14C]-glutamate was unaltered (0.79 nmol/min/mg dry wt). Dichloroacetate, an inhibitor of PDH kinase, restored flux through PDH to control levels. In endotoxin-treated cells, only 44% of the total PDH complex was in the active (nonphosphorylated) form as compared to 72% in control cells. Equilibrium uptake studies with 45Ca2+ and atomic absorption measurements showed that intracellular [Ca2+] in endotoxin-treated cells was about 20% lower than in control cells. It is postulated that binding of endotoxin to the plasma membrane triggers a sequence of events that lead to an initial decline in intracellular calcium concentration and that this latter event may be responsible for the inhibition of PDH phosphatase and consequent conversion of the complex to its inactive phosphorylated form.
Animals↗