PROTECTIVE EFFECTS OF A RECOMBINANT N-TERMINAL FRAGMENT OF BACTERICIDAL PERMEABILITY-INCREASING PROTEIN ON ENDOTOXIC-SHOCK IN CONSCIOUS RABBITS

Endotoxin (lipopolysaccharide, LPS) can induce shock, multiple organ f ailure, and death. A recombinant N-terminal fragment of bactericidal/p ermeability increasing protein, rBPI(23), binds with high affinity to gram-negative bacterial LPS and neutralizes its biological activity. W e sought to determine the effect of rBPI(23) on LPS-induced respirator y dysfunction and cardiovascular depression in conscious rabbits. Rabb its were injected with Escherichia coli 0113 IFS (6 mu g/kg) and treat ed with rBPI(23) (2 mg/kg), vehicle, or control protein after recovery from surgery performed to implant catheters for hemodynamic assessmen ts and intravenous injections. LPS challenge caused respiratory dysfun ction including tachypnea, significant decreases in arterial O-2 tensi on (Po-2), arterial oxygen content, and an increase in alveolar-arteri al O-2, gradient (A-aDo(2)). LPS administration also resulted in profo und and prolonged decreases in mean arterial blood pressure and cardia c index. Treatment with rBPI(23) prevented LPS-induced respiratory dys function and significantly ameliorated the cardiovascular depression. 5 of 16 LPS-challenged animals died of respiratory failure and acidosi s, whereas none died in the rBPI(23) treated group (p = .11). The resu lts demonstrate that rBPI(23) protects animals against LPS-induced car diopulmonary depression in endotoxic shock.