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

Abstract

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-alpha (TNF-alpha) 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, rBPI23, attenuates LPS-induced alterations in serum glucose, lactate, and TNF-alpha 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 a transient, but marked, elevation of TNF-alpha were also observed following LPS infusion. These LPS-induced changes were inhibited significantly by simultaneous infusion of rBPI23. Different dose-response profiles of rBPI23 on LPS-induced alterations in glucose, lactate and TNF-alpha were observed. When rBPI23 was infused 30 min after the initiation of LPS infusion, it significantly inhibited the alterations in glucose and lactate, but not TNF-alpha. The rise in TNF-alpha was reduced significantly with a 15 min delayed infusion of rBPI23. A control protein failed to alter any responses to LPS. The results indicate that rBPI23 can provide significant protection against the metabolic disturbances and TNF-alpha release associated with endotoxemia. In addition, the results suggest that LPS-induced metabolic alterations in glucose and lactate are at least partially independent of TNF-alpha release.

• Authors: Y Lin, F R Kohn, A H Kung, W S Ammons
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 47 Issue 9 Pg. 1553-9 (Apr 29 1994) ISSN: 0006-2952 [Print] England
• PMID: 8185667 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Lactates
• Lipopolysaccharides
• Recombinant Proteins
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Bacteremia (prevention & control)
• Blood Glucose
• Carbohydrate Metabolism
• Lactates (blood)
• Lipopolysaccharides (administration & dosage, antagonists & inhibitors, pharmacology)
• Male
• Rats
• Rats, Sprague-Dawley
• Recombinant Proteins (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)