Marian N. Marra

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

Human neutrophil azurophilic granules contain an ∼55-kDa protein, known as bactericidal/permeabilityincreasing protein (BPI), which possesses a high-affinity binding domain for the lipid A component of lipopolysaccharide (LPS). Thein vivo LPS neutralizing activity of exogenous BPI was studied in a model of lethalEscherichia coli bacteremia. Five baboons were treated with BPI (5 mg/kg bolus injection followed by a 95 μg/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 followingE. 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-α) 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 ofE. coli LPS neutralization by BPIin vivo and demonstrates that a moderate (70%) reduction in peak LPS-LAL activity is sufficient to alter some hematologic and cytokine manifestations of bacteremia.