A novel endotoxin antagonist attenuates tumor necrosis factor-α secretion

Peter S. Dahlberg, Robert D. Acton, Richard J. Battafarano, Marc E. Uknis, Craig A. Ratz, Jennifer W. Johnston, Judith R. Haseman, Beulah H. Gray, David L. Dunn

Research output: Contribution to journalArticle

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-α (TNF-α) secretion, 2) have bactericidal activity against gram-negative bacteria, and 3) protect mice from a lethal lipopolysaccharide (LPS) challenge. Unfortunately, peptides have a short half-life 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-α secretion and 2) to decrease plasma endotoxin and TNF-α levels following an i.v. injection of E. coli 0111:B4 LPS. BG38-KLH inhibited cultured macrophage TNF-α secretion in response to LPS derived from four pathogenic strains of gram-negative bacteria in a dose dependent manner (>90% inhibition at 50 μg/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-α 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.

Original languageEnglish (US)
Pages (from-to)44-48
Number of pages5
JournalJournal of Surgical Research
Volume63
Issue number1
DOIs
StatePublished - Jun 1996
Externally publishedYes

ASJC Scopus subject areas

  • Surgery

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    Dahlberg, P. S., Acton, R. D., Battafarano, R. J., Uknis, M. E., Ratz, C. A., Johnston, J. W., Haseman, J. R., Gray, B. H., & Dunn, D. L. (1996). A novel endotoxin antagonist attenuates tumor necrosis factor-α secretion. Journal of Surgical Research, 63(1), 44-48. https://doi.org/10.1006/jsre.1996.0220