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. 1996 Jun;63(1):44-8.
doi: 10.1006/jsre.1996.0220.

A Novel Endotoxin Antagonist Attenuates Tumor Necrosis Factor-Alpha Secretion

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A Novel Endotoxin Antagonist Attenuates Tumor Necrosis Factor-Alpha Secretion

P S Dahlberg et al. J Surg Res. .

Abstract

Twenty-seven amino acid peptides with sequences corresponding to a proposed endotoxin binding region of bactericidal permeability increasing protein (BPI):1) inhibit lipopolysaccharide induced macrophage tumor necrosis factor-alpha (TNF-alpha) secretion, 2) have bactericidal activity against gram-negative bacteria, and 3) protect mice from a lethal lipopolysaccharide (LPS) challenge. Unfortunately, peptides have a short halflife in vivo. Therefore, we have chemically conjugated the BPI based peptide, BG38, to a larger carrier protein, keyhole limpet hemocyanin (KLH), and characterized its ability: 1) to inhibit LPS induced macrophage TNF-alpha secretion and 2) to decrease plasma endotoxin and TNF-alpha levels following an i.v. injection of E. coli 0111:B4 LPS. BG38-KLH inhibited cultured macrophage TNF-alpha secretion in response to LPS derived from four pathogenic strains of gram-negative bacteria in a dose dependent manner (>90% inhibition at 50 microgram/ml, P < 0.05 Student's t test). BG38-KLH also decreased serum endotoxin (>90%, P < 0.05 Student's t test) and peak TNF-alpha levels (>30% inhibition, P < 0.05 Student's t test) following E. coli LPS challenge in a murine gram-negative bacterial sepsis model. Novel endotoxin antagonists based upon a small domain of BPI represent promising reagents for the treatment of serious gram-negative bacterial infections.

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