Effect of a recombinant endotoxin-neutralizing protein on endotoxin shock in rabbits

This is the authors' abstract. We don't add key points for this paper.

Limulus anti-lipopolysaccharide factor, an 11.8-kilodalton peptide isolated from amebocytes of Limulus polyphemus inhibits the biologic activities of endotoxin in vitro, including gelation of Limulus amebocyte lysate. A recombinant version of Limulus anti-lipopolysaccharide factor, termed endotoxin neutralizing protein, has now been expressed in yeast. Endotoxin-neutralizing protein was evaluated for its potential prophylactic and therapeutic effects in rabbits challenged with Escherichia coli endotoxin. Design: Controlled animal trial. Setting: Animal research laboratory. Subjects: A total of 112 New Zealand white rabbits were studied. Interventions: Rabbits were challenged with an LD80 dose of E. coli endotoxin (100 μg/kg); control animals (n = 52) were treated with saline solution at the time of endotoxin challenge; experimental animals received endotoxin-neutralizing protein 2.5 mg/kg prechallenge (n = 20), 5.0 mg/kg prechallenge (n = 20), or 5.0 mg/kg 30 mins postchallenge (n = 20). Measurements and Main Results: Rabbits treated with endotoxin-neutralizing protein before endotoxin challenge maintained stable mean arterial pressures and arterial pH and bicarbonate values which were significantly higher than controls during a 6–hr observation period. Geometric mean serum endotoxin concentrations were significantly lower in animals treated before endotoxin challenge as compared with controls measured at 30 mins and hourly after endotoxin challenge. Animals treated with endotoxin-neutralizing protein 30 mins after challenge had significantly lower geometric mean serum endotoxin concentrations measured 60 mins and hourly after challenge. Geometric mean serum tumor necrosis factor concentrations were lower in all treated animals compared with controls, but significantly so only in animals treated with endotoxin-neutralizing protein 2.5 mg/kg before endotoxin challenge. Survival to 24 hrs was significantly improved compared with controls in rabbits treated with endotoxin-neutralizing protein 2.5 mg/kg prechallenge (85% vs. 29%, p < .001), and with endotoxin-neutralizing protein 5.0 mg/kg prechallenge (90% vs. 29%, p < .001); animals treated with endotoxin-neutralizing protein 5.0 mg/kg postchallenge demonstrated improved survival compared with controls (55% vs. 29%, p = .055), although not significantly so. Conclusions: Endotoxin-neutralizing protein attenuates the toxic effects ofE. coli endotoxin in rabbits and improves survival, even when administered after endotoxin challenge. Endotoxin-neutralizing protein deserves further evaluation as a potential therapy for Gram-negative sepsis. (Crit Care Med 1994; 22:1211–1218)