PEG-BP-30 Monotherapy Attenuates the Cytokine-Mediated Inflammatory Cascade in Baboon Escherichia coli Septic Shock

• Published in: The Journal of surgical research 1995-07, Vol.59 (1), p.153-158
• Main Authors: Espat, N.J., Cendan, J.C., Beierle, E.A., Auffenberg, T.A., Rosenberg, J., Russell, D., Kenney, J.S., Fischer, E., Montegut, W., Lowry, S.F., Copeland, E.M., Moldawer, L.L.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cytokines - physiology; Escherichia coli Infections - blood; Escherichia coli Infections - drug therapy; Escherichia coli Infections - physiopathology; Female; General aspects; Hemodynamics - drug effects; Human infectious diseases. Experimental studies and models; Infectious diseases; Inflammation - drug therapy; Interleukins - blood; Male; Medical sciences; Papio; Polyethylene Glycols - therapeutic use; Receptors, Tumor Necrosis Factor - physiology; Recombinant Proteins - therapeutic use; Shock, Septic - blood; Shock, Septic - drug therapy; Shock, Septic - physiopathology; Tumor Necrosis Factor-alpha - analysis
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.1995.1147

Septic shock following gram-negative infection is a leading cause of mortality in critically ill patients, accounting for nearly 200,000 deaths a year. The exaggerated production of tumor necrosis factor-α (TNFα) is known to contribute to hemodynamic collapse and the hematological dyscrasia associated with gram-negative sepsis. Although previous studies have shown TNFα antibodies and TNF immunoadhesins to be effective in experimental gram-negative sepsis, we postulated that administration of a novel construct of two modified soluble p55 receptors linked to polyethylene glycol (PEG-BP-30) would also attenuate the hemodynamic and hematologic alterations to lethal Escherichia coli septic shock in nonhuman primates. Nine adult female and male baboons ( Papio anubis), weighing 10-17 kg, were anesthetized and invasively monitored. The nine animals were randomized to receive either 0.2 mg/kg body wt PEG-BP-30 ( n = 3), 5.0 mg/kg body wt PEG-BP-30 ( n = 3), or placebo ( n = 3). One hour after pretreatment, animals were infused with 5-10 × 10 10 CFU/kg of live E. coli iv and vital signs were recorded for the next 8 hr. Arterial blood was drawn for baseline parameters and throughout the study to obtain total and differential white blood cell and platelet counts and cytokine levels (TNFα, IL- 1β, IL-6, IL-8). E. coli bacteremic baboons receiving only placebo demonstrated a significant fall in mean blood pressure and leukopenia. Two of the three animals expired. In contrast, five of the six baboons receiving the PEG-BP-30 survived and these animals exhibited markedly attenuated declines in blood pressure and leukocyte numbers. Septic baboons also manifested monophasic plasma TNFα, IL-1β, IL-6, and IL-8 responses that were significantly attenuated by PEG-BP-30 pretreatment in a dose-dependent manner. We conclude from these data that the administration of PEG-BP-30 improves survival and attenuates the TNFα-mediated pathophysiology in E. coli sepsis.