TY - JOUR
T1 - Glycosylated recombinant human tumor necrosis factor binding protein-1 reduces mortality, shock, and production of tumor necrosis factor in rabbit Escherichia coli sepsis
AU - Porat, R.
AU - Paddock, H. N.
AU - Schwaitzberg, S. D.
AU - Connolly, R. J.
AU - Wilkens, T.
AU - Dasch, J. R.
AU - Gascon, M. P.
AU - Hutchison, J. S.
AU - Ythier, A.
AU - Wallach, D.
AU - Dinarello, C. A.
PY - 1995
Y1 - 1995
N2 - Objective: To examine the effect of glycosylated recombinant human tumor necrosis factor binding protein-1 (r-hTNF binding protein-1), the extracellular domain of the tumor necrosis factor receptor p55 produced in mammalian cells, in a rabbit model of circulatory shock due to Escherichia coli. Design: Prospective, randomized, controlled trial. Setting:University hospital research laboratory.Subjects: Eighteen female, New Zealand white rabbits. Interventions: Anesthetized rabbits, infused with E. coli (109 organisms/kg), were pretreated with either r-hTNF binding protein-1 or saline. Mean arterial pressure, central venous pressure, cardiac output, and heart rate were recorded every 20 mins for 1 hr before, and for 4 hrs after, the infusion of E. coli. Blood samples were obtained at 1-hr intervals for platelet count and white blood cell count, r-hTNF binding protein-1, and tumor necrosis factor (TNF) measurements. Measurements and Main Results: Administration of r-hTNF binding protein-1 resulted in improvement of mean arterial pressure, cardiac output, and systemic vascular resistance, as compared with the vehicle-treated group (p < .05). Treatment with r-hTNF binding protein-1 was associated with 100% survival, as compared with 55.6% of the saline-treated rabbits (p < .05). Approximately 85% of r-hTNF binding protein-1 was cleared from the circulation 1 hr after the bolus injection (from 171 ± 27 μg/mL at time = 0, to 27 ± 4 μg/mL at 60 mins, decreasing to 6 ± 2 mg/mL for the next 3 hrs). The r-hTNF binding protein-1-treated rabbits had lower serum TNF bioactivity during the first 2 hrs (p < .01). The decreased bioactivity of TNF was confirmed by a specific radioimmunoassay for rabbit TNF. However, at 4 hrs, the vehicle-treated rabbits had lower serum bioactive TNF concentrations (p < .05). The decrease in TNF concentrations in the r-hTNF binding protein-1-treated rabbits resulted from decreased production and, in part, from carry-over of r-hTNF binding protein-1 into the bioassay. Conclusions: Treatment with r-hTNF binding protein-1 improved hemodynamic variables and survival of E. coli-challenged rabbits. Administration of r-hTNF binding protein-1 suppressed bioactivity of TNF in the circulation of these rabbits, and the production of TNF as well.
AB - Objective: To examine the effect of glycosylated recombinant human tumor necrosis factor binding protein-1 (r-hTNF binding protein-1), the extracellular domain of the tumor necrosis factor receptor p55 produced in mammalian cells, in a rabbit model of circulatory shock due to Escherichia coli. Design: Prospective, randomized, controlled trial. Setting:University hospital research laboratory.Subjects: Eighteen female, New Zealand white rabbits. Interventions: Anesthetized rabbits, infused with E. coli (109 organisms/kg), were pretreated with either r-hTNF binding protein-1 or saline. Mean arterial pressure, central venous pressure, cardiac output, and heart rate were recorded every 20 mins for 1 hr before, and for 4 hrs after, the infusion of E. coli. Blood samples were obtained at 1-hr intervals for platelet count and white blood cell count, r-hTNF binding protein-1, and tumor necrosis factor (TNF) measurements. Measurements and Main Results: Administration of r-hTNF binding protein-1 resulted in improvement of mean arterial pressure, cardiac output, and systemic vascular resistance, as compared with the vehicle-treated group (p < .05). Treatment with r-hTNF binding protein-1 was associated with 100% survival, as compared with 55.6% of the saline-treated rabbits (p < .05). Approximately 85% of r-hTNF binding protein-1 was cleared from the circulation 1 hr after the bolus injection (from 171 ± 27 μg/mL at time = 0, to 27 ± 4 μg/mL at 60 mins, decreasing to 6 ± 2 mg/mL for the next 3 hrs). The r-hTNF binding protein-1-treated rabbits had lower serum TNF bioactivity during the first 2 hrs (p < .01). The decreased bioactivity of TNF was confirmed by a specific radioimmunoassay for rabbit TNF. However, at 4 hrs, the vehicle-treated rabbits had lower serum bioactive TNF concentrations (p < .05). The decrease in TNF concentrations in the r-hTNF binding protein-1-treated rabbits resulted from decreased production and, in part, from carry-over of r-hTNF binding protein-1 into the bioassay. Conclusions: Treatment with r-hTNF binding protein-1 improved hemodynamic variables and survival of E. coli-challenged rabbits. Administration of r-hTNF binding protein-1 suppressed bioactivity of TNF in the circulation of these rabbits, and the production of TNF as well.
KW - bacteria
KW - critical illness
KW - cytokines
KW - endotoxin
KW - hemodynamics
KW - radioimmunoassay
KW - receptors
KW - sepsis
KW - septic shock
KW - tumor necrosis factor
UR - http://www.scopus.com/inward/record.url?scp=0029036170&partnerID=8YFLogxK
U2 - 10.1097/00003246-199506000-00014
DO - 10.1097/00003246-199506000-00014
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C2 - 7774220
AN - SCOPUS:0029036170
SN - 0090-3493
VL - 23
SP - 1080
EP - 1089
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 6
ER -