Protective effect of a recombinant fragment of bactericidal/permeability increasing protein against carbohydrate dyshomeostasis and tumor necrosis factor-α elevation in rat endotoxemia

Endotoxin (lipopolysaccharide, LPS), a component of the gram-negative bacterial cell wall, induces carbohydrate dyshomeostasis and the release of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) when administered to experimental animals. Bactericidal/permeability increasing protein (BPI), a cationic protein found in human neutrophil granules, binds with high affinity to LPS and is capable of neutralizing its biological activity. The present study was designed to determine if a recombinant N-terminal fragment of BPI, rBPI 23, attenuates LPS-induced alterations in serum glucose, lactate, and TNF-α in rats. In anesthetized animals challenged with a 30 min infusion of Escherichia coli O111:B4 LPS (0.25 mg/kg), there was an early transient increase in serum levels of glucose followed by a drop to 60% of those found in saline control rats. A prolonged elevation in serum levels of lactate and transient, but marked, elevation of TNF-α were also observed following LPS infusion. These LPS-induced changes were inhibited significantly by simultaneous infusion of rBPI 23. Different dose-response profiles of rBPI 23 on LPS-induced alterations in glucose, lactate and TNF-α were observed. When rBPI 23 was infused 30 min after the initiation of LPS infusion, it significantly inhibited the alterations in glucose and lactate, but not TNF-α. The rise in TNF-α was reduced significantly with a 15 min delayed infusion of rBPI 23. A control protein failed to alter any responses to LPS. The results indicate that rBPI 23 can provide significant protection against the metabolic disturbances and TNF-α release associated with endotoxemia. In addition, the suggest that LPS-induced metabolic alterations in glucose and lactate are at least partially independent of TNF-α release.