Human neutrophil bactericidal/permeability-increasing protein reduces mortality rate from endotoxin challenge

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Abstract
Objectives To study the toxicology and pharmacology of the endotoxin-neutralizing agent, bactericidal/permeability-increasing protein. Design Prospective, randomized, placebo-controlled laboratory study. Setting Academic research laboratory. Subjects CD-1 mice (n = 259); Sprague Dawley rats (n = 26); New Zealand White rabbits (n = 19). Interventions Pharmacokinetics of intravenously injected bactericidal/permeability-increasing protein was assessed in mice. Toxicology was tested in mice and rats. Efficacy of intravenously administered bactericidal/permeability-increasing protein as an endotoxin-neutralizing agent was tested in mice, rats, and rabbits. Measurements and Main Results Administration of a single 10-mg/kg bolus injection of bactericidal/permeability-increasing protein resulted in no alterations in hematologic, renal, or hepatic function, activity level, or weight gain in animals observed over a 7-day study period. A single bolus injection (10 mg/kg) of bactericidal/permeability-increasing protein protected 15 of 16 mice from a lethal endotoxin challenge (mortality rate 1/16 [6.25%]) compared with a 100% (16/16) mortality rate in the saline-treated controls (p < .001). Bactericidal/permeability-increasing protein administered up to 1 hr after endotoxin provided significant protection against lethal endotoxin challenge. Furthermore, bactericidal/permeability-increasing protein reduced the induration and dermal necrosis observed in the localized dermal Shwartzman reaction. Conclusions Bactericidal/permeability-increasing protein is a potent antiendotoxin that neutralizes endotoxin in vivo and prevents mortality in animal models of lethal endotoxemia. (Crit Care Med 1994; 22:553–558)

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