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.