ROLE OF BACTERICIDAL PERMEABILITY-INCREASING PROTEIN IN THE TREATMENTOF GRAM-NEGATIVE PNEUMONIA

Background. Gram-negative infections are a major cause of morbidity an d death. Bactericidal permeability-increasing protein (BPI) is an endo toxin-neutralizing protein that also exhibits potent bactericidal acti vity. This study compared the efficacy of a 23 kd recombinant N-termin al fragment of BPI (rBPI23) with that of antiendotoxin antibody E5 in a model of gram-negative sepsis. Methods. Sixty Swiss- Webster mice (C arworth farm) received an intratracheal inoculation of Escherichia col i (7 X 10(6) colony-forming units) and were randomized to three groups (20 per group). Starting immediately after inoculation, the groups re ceived either rBPI23 (4 mg/kg intravenously every 2 hours for four dos es), E5 (11 mg/kg intravenously every 24 hours for two doses), or an i sotype control antibody B55 (11 mg/kg intravenously every 24 hours for two doses) and were followed up for survival. In a second survival st udy, 40 mice received the same intratracheal inoculation of E. coli an d were randomized to two groups. Starting 2 hours after inoculation, t he 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 d oses) and were followed up for survival. In a third study, mice receiv ed an intratracheal inoculation of 3 X 10(6) colony-forming units E. c oli, a sublethal dose, and were killed to determine pulmonary and bloo d clearance of bacteria. Results. rBPI23 conferred significantly great er protection from death than either E5 or B55 when started immediatel y (95% survival vs 20% and 10%, respectively; p < 0.001) or 2 hours af ter inoculation (65% survival us 25% for E5; p < 0.05). Both pulmonary and vascular clearance of bacteria was enhanced significantly by trea tment with rBPI23. Conclusions. rBPI23 may be a novel therapeutic agen t in the management of gram-negative sepsis.