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An N-terminal fragment of bactericidal/permeability-increasing protein protects against hemodynamic and metabolic derangements in rat Gram-negative sepsis

Department of Pharmacology, XOMA Corporation, Berkeley, California, USA

Cornell Mallari

Department of Pharmacology, XOMA Corporation, Berkeley, California, USA

Recombinant N-terminal fragments of bactericidal/permeability-increasing protein (BPI) are protective in acute models of endotoxemia or bacteremia. However, their usefulness in models utilizing slow infusion of bacteria has not been reported. Anesthetized rats were infused with Escherichia coli 07:K1 bacteria (5 x 109 cfu/h) for 2 h. Hemodynamics, glucose and lactate levels, tumor necrosis factor- (TNF) and endotoxin levels were measured for 210 min. The rats were treated with a 2 h infusion of RBPI₂₁ or thaumatin (10 mg/kg/h), a protein that does not bind endotoxin but is similar to rBPI₂₁ in molecular weight and isoelectric point. Control rats received only saline and vehicle. In animals treated with thaumatin, blood pressure, cardiac index and stroke volume declined rapidly (within 30 min). After 90 min glucose levels were significantly depressed whereas lactate was elevated. Endotoxemia (764 ± 353 ng/ml) was observed within 30 min. rBPI ₂₁ significantly reduced the cardiovascular depression observed after 30 min and abolished all hemodynamic responses by the end of the experiment. rBPI₂₁ significantly reduced hypoglycemia, elevated lactate levels, and endotoxin levels after 90 min. These results indicate that reduction of endotoxin levels resulting from RBPI₂₁ therapy leads to significant protection in this model of acute Gram-negative bacterial sepsis.

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