The role of bactericidal/permeability-increasing protein in the treatment of primate bacteremia and septic shock.
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.
Rogy
M A
MA
Department of Surgery, Cornell University Medical College, New York, New York 10021.
Oldenburg
H S
HS
Calvano
S E
SE
Montegut
W J
WJ
Stackpole
S A
SA
Van Zee
K J
KJ
Marra
M N
MN
Scott
R W
RW
Seilhammer
J J
JJ
Moldawer
L L
LL
D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides; D016470:Bacteremia / Q000628:therapy*; D001798:Blood Proteins / Q000627:therapeutic use*; D004927:Escherichia coli Infections / Q000628:therapy*; D015850:Interleukin-6 / Q000096:biosynthesis; D008565:Membrane Proteins; D009504:Neutrophils / Q000276:immunology; D010215:Papio; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D012772:Shock, Septic / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D015850:Interleukin-6; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C021623:bactericidal permeability increasing protein