Protective effect of a recombinant fragment of bactericidal/permeability increasing protein against carbohydrate dyshomeostasis and tumor necrosis factor-alpha 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-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.
Lin
Y
Y
Department of Pharmacology and Toxicology, XOMA Corporation, Berkeley, CA 94710.
Kohn
F R
FR
Kung
A H
AH
Ammons
W S
WS
D000818:Animals; D016470:Bacteremia / Q000517:prevention & control; D001786:Blood Glucose; D050260:Carbohydrate Metabolism; D007773:Lactates / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D001786:Blood Glucose; D007773:Lactates; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha