Role of bactericidal permeability-increasing protein in the treatment of gram-negative pneumonia.
BACKGROUND
Gram-negative infections are a major cause of morbidity and death. Bactericidal permeability-increasing protein (BPI) is an endotoxin-neutralizing protein that also exhibits potent bactericidal activity. This study compared the efficacy of a 23 kd recombinant N-terminal fragment of BPI (rBPI23) with that of antiendotoxin antibody E5 in a model of gram-negative sepsis.


METHODS
Sixty Swiss-Webster mice (Carworth farm) received an intratracheal inoculation of Escherichia coli (7 x 10(6) colony-forming units) and were randomized to three groups (20 per group). Starting immediately after inoculation, the groups received either rBPI23 (4 mg/kg intravenously every 2 hours for four doses), E5 (11 mg/kg intravenously every 24 hours for two doses), or an isotype control antibody B55 (11 mg/kg intravenously every 24 hours for two doses) and were followed up for survival. In a second survival study, 40 mice received the same intratracheal inoculation of E. coli and were randomized to two groups. Starting 2 hours after inoculation, the groups received either rBPI23 (4 mg/kg intravenously every 2 hours for four doses) or E5 (8 mg/kg intravenously every 12 hours for four doses) and were followed up for survival. In a third study, mice received an intratracheal inoculation of 3 x 10(6) colony-forming units E. coli, a sublethal dose, and were killed to determine pulmonary and blood clearance of bacteria.


RESULTS
rBPI23 conferred significantly greater protection from death than either E5 or B55 when started immediately (95% survival vs 20% and 10%, respectively; p < 0.001) or 2 hours after inoculation (65% survival vs 25% for E5; p < 0.05). Both pulmonary and vascular clearance of bacteria was enhanced significantly by treatment with rBPI23.


CONCLUSIONS
rBPI23 may be a novel therapeutic agent in the management of gram-negative sepsis.
Kelly
C J
CJ
Division of Surgical Oncology, Hospital of the University of Pennsylvania, Philadelphia 19104.
Cech
A C
AC
Argenteanu
M
M
Gallagher
H
H
Shou
J
J
Minnard
E
E
Daly
J M
JM
D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000627:therapeutic use*; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D008168:Lung / Q000382:microbiology; D008565:Membrane Proteins; D051379:Mice; D010446:Peptide Fragments / Q000627:therapeutic use*; D011014:Pneumonia / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000627:therapeutic use
D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C021623:bactericidal permeability increasing protein