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 compone nt of lipopolysaccharide (LPS). The in vivo LPS neutralizing activity of exogenous BPI was studied in a model of lethal Escherichia coli bac teremia. Five baboons were treated with BPI (5 mg/kg bolus injection f ollowed by a 95 mug/kg/min BPI infusion over 4 hr), while four additio nal animals received a genetically engineered variant of BPI (NCY103). Five animals received a placebo treatment and served as controls. Bot h wild-type rhBPI and NCY103 significantly (P < 0.05) decreased blood levels of LPS throughout an 8-hr evaluation period following live bact erial challenge. Two hours following E. coli administration, LPS level s peaked in the controls, at 6.86 +/- 3.22 ng/ml, whereas LPS levels w ere 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 ci rculating 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 o f E. coli LPS neutralization by BPI in vivo and demonstrates that a mo derate (70%) reduction in peak LPS-LAL activity is sufficient to alter some hematologic and cytokine manifestations of bacteremia.