GLYCOSYLATED RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR BINDING PROTEIN-1 REDUCES MORTALITY, SHOCK, AND PRODUCTION OF TUMOR-NECROSIS-FACTOR INRABBIT ESCHERICHIA-COLI SEPSIS

Objective: To examine the effect of glycosylated recombinant human tum or necrosis factor binding protein-1 (r-hTNF binding protein-1), the e xtracellular domain of the tumor necrosis factor receptor p55 produced in mammalian cells, in a rabbit model of circulatory shock due to Esc herichia coli. Design: Prospective, randomized, controlled trial. Sett ing: University hospital research laboratory. Subjects: Eighteen femal e, New Zealand white rabbits. Interventions: Anesthetized rabbits, inf used with E. coli (10(9) organisms/kg), were pretreated with either r- hTNF binding protein-1 or saline. Mean arterial pressure, central veno us pressure, cardiac output, and heart rate were recorded every 20 min s for 1 hr before, and for 4 hrs after, the infusion off. coli. Blood samples were obtained at 1-hr intervals for platelet count and white b lood 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 pressu re, cardiac output, and systemic vascular resistance, as compared with the vehicle-treated group (p < .05). Treatment with r-hTNF binding pr otein-1 was associated with 100% survival, as compared with 55.6% of t he saline-treated rabbits (p <.05). Approximately 85% of r-hTNF bindin g protein-1 was cleared from the circulation 1 hr after the bolus inje ction (from 171 +/- 27 mu g/mL at time = 0, to 27 +/- 4 mu g/mL at 60 mins, decreasing to 6 +/- 2 mu g/mL for the next 3 hrs), The r-hTNF bi nding protein-1-treated rabbits had lower serum TNF bioactivity during the first 2 hrs (p <.01). The decreased bioactivity of TNF was confir med by a specific radioimmunoassay for rabbit TNF. However, at 4 hrs, the vehicle-treated rabbits had lower serum bioactive TNF concentratio ns (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. C onclusions: Treatment with r-hTNF binding protein-1 improved hemodynam ic variables and survival of E. coli-challenged rabbits. Administratio n of r-hTNF binding protein-1 suppressed bioactivity of TNF in the cir culation of these rabbits, and the production of TNF as well.