Protective effect of a recombinant amino-terminal fragment of bactericidal/permeability-increasing protein in experimental endotoxemia.
Bactericidal/permeability-increasing protein (BPI), a cationic protein found in neutrophil granules, binds with high affinity to gram-negative bacterial lipopolysaccharide (LPS) and can inhibit its actions in vitro. The in vivo efficacy of a recombinant 23-kDa amino-terminal LPS-binding fragment of BPI (rBPI23) was assessed in a mouse model of lethal endotoxemia. Systemic administration of rBPI23 protected actinomycin D-sensitized mice from lethal LPS (Escherichia coli O111:B4) challenge in a dose-dependent manner, with almost complete protection at the highest dose (10 mg/kg; 93% survival vs. 13% in vehicle-treated controls). Surviving rBPI23-treated animals did not show histopathologic signs of tissue damage evident in control animals that had died after LPS challenge. rBPI23 also attenuated the LPS-induced elevation in serum levels of tumor necrosis factor-alpha and interleukin-1 alpha, mediators believed to be involved in the pathogenesis of endotoxemia and sepsis. Thus, rBPI23 may be a potential new therapeutic agent for the treatment of gram-negative bacterial infection and sepsis.
Kohn
F R
FR
Dept. of Pharmacology and Toxicology, XOMA Corp., Berkeley, CA 94710.
Ammons
W S
WS
Horwitz
A
A
Grinna
L
L
Theofan
G
G
Weickmann
J
J
Kung
A H
AH
D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins / Q000627:therapeutic use*; D003609:Dactinomycin / Q000494:pharmacology; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D007375:Interleukin-1 / Q000097:blood; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D010446:Peptide Fragments / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C021623:bactericidal permeability increasing protein; D003609:Dactinomycin