The role of bactericidal/permeability-increasing protein in the treatment of primate bacteremia and septic shock.

Abstract

Human neutrophil azurophilic granules contain an approximately 55-kDa protein, known as bactericidal/permeability-increasing protein (BPI), which possesses a high-affinity binding domain for the lipid A component of lipopolysaccharide (LPS). The in vivo LPS neutralizing activity of exogenous BPI was studied in a model of lethal Escherichia coli bacteremia. Five baboons were treated with BPI (5 mg/kg bolus injection followed by a 95 micrograms/kg/min BPI infusion over 4 hr), while four additional animals received a genetically engineered variant of BPI (NCY103). Five animals received a placebo treatment and served as controls. Both wild-type rhBPI and NCY103 significantly (P < 0.05) decreased blood levels of LPS throughout an 8-hr evaluation period following live bacterial challenge. Two hours following E. coli administration, LPS levels peaked in the controls, at 6.86 +/- 3.22 ng/ml, whereas LPS levels were 3.39 +/- 2.1 ng/ml in the BPI group and 2.04 +/- 1.18 ng/ml in the NCY103 group. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 levels likewise were attenuated in the treatment groups, whereas circulating sTNFR I was significantly (P < 0.05) reduced only in the BPI group. Leukocytopenia and granulocytopenia were significantly (P < 0.02) lessened in the BPI group, by an average of 59% leukocytopenia and 65% granulocytopenia, respectively. This study supports the concept of E. coli LPS neutralization by BPI in vivo and demonstrates that a moderate (70%) reduction in peak LPS-LAL activity is sufficient to alter some hematologic and cytokine manifestations of bacteremia.

• Authors: M A Rogy, H S Oldenburg, S E Calvano, W J Montegut, S A Stackpole, K J Van Zee, M N Marra, R W Scott, J J Seilhammer, L L Moldawer
• Journal: Journal of clinical immunology (J Clin Immunol) Vol. 14 Issue 2 Pg. 120-33 (Mar 1994) ISSN: 0271-9142 [Print] Netherlands
• PMID: 8195314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Infective Agents
• Antimicrobial Cationic Peptides
• Blood Proteins
• Interleukin-6
• Membrane Proteins
• Receptors, Tumor Necrosis Factor
• Recombinant Proteins
• Tumor Necrosis Factor-alpha
• bactericidal permeability increasing protein

Topics

• Animals
• Anti-Infective Agents (therapeutic use)
• Antimicrobial Cationic Peptides
• Bacteremia (therapy)
• Blood Proteins (therapeutic use)
• Escherichia coli Infections (therapy)
• Interleukin-6 (biosynthesis)
• Membrane Proteins
• Neutrophils (immunology)
• Papio
• Receptors, Tumor Necrosis Factor (metabolism)
• Recombinant Proteins (therapeutic use)
• Shock, Septic (therapy)
• Tumor Necrosis Factor-alpha (biosynthesis)