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Human neutrophil bactericidal/permeability-increasing protein reduces mortality rate from endotoxin challenge: a
C J Fisher1, M N Marra, J E Palardy
1Cleveland Clinic Foundation, OH.
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.