title: Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia.
abstract: The present study was undertaken to evaluate the extent to which an endogenous interleukin-1 (IL-1) response contributes to the hemodynamic and metabolic consequences of sublethal endotoxemia or lethal Gram-negative septic shock. Young, healthy baboons received either a sublethal dose of lipopolysaccharide (LPS) or an LD100 of live Escherichia coli bacteria, and one half of the animals in each group were continuously infused with IL-1 receptor antagonist (IL-1ra). Plasma IL-1 beta was not detected in this model of endotoxemia. Administration of IL-1ra had only minimal effects on the modest hemodynamic and metabolic responses to sublethal endotoxemia, and did not attenuate the plasma cytokine response. In contrast, high circulating levels of IL-1 beta (range 300-800 pg/ml) were seen during lethal E. coli septic shock. IL-1ra treatment significantly attenuated the decrease in mean arterial blood pressure (MAP) (from -72 +/- 8 to -43 +/- 6 mm Hg; P less than 0.05) and cardiac output (from -0.81 +/- 0.17 to -0.48 +/- 0.15 liter/min; P less than 0.05), and significantly improved survival from 43 to 100% at 24 h (P less than 0.05). The plasma IL-1 beta and IL-6 responses to lethal E. coli septic shock were also significantly diminished by IL-1ra treatment (P less than 0.05), whereas tumor necrosis factor-alpha (TNF alpha) concentrations were unaffected. We conclude that an exaggerated systemic IL-1 beta response is characteristic of lethal E. coli septic shock, and contributes significantly to the hemodynamic and metabolic consequences of E. coli septic shock. IL-1ra can significantly attenuate the cytokine cascade and improve survival.
authors.affiliation: Department of Surgery, Cornell University Medical College, New York 10021.
authors.forename: E
authors.initials: E
authors.lastname: Fischer
authors.forename: M A
authors.initials: MA
authors.lastname: Marano
authors.forename: K J
authors.initials: KJ
authors.lastname: Van Zee
authors.forename: C S
authors.initials: CS
authors.lastname: Rock
authors.forename: A S
authors.initials: AS
authors.lastname: Hawes
authors.forename: W A
authors.initials: WA
authors.lastname: Thompson
authors.forename: L
authors.initials: L
authors.lastname: DeForge
authors.forename: J S
authors.initials: JS
authors.lastname: Kenney
authors.forename: D G
authors.initials: DG
authors.lastname: Remick
authors.forename: D C
authors.initials: DC
authors.lastname: Bloedow
mesh_terms: D000818:Animals; D004731:Endotoxins / Q000097:blood; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D010215:Papio; D011506:Proteins / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D017472:Receptors, Interleukin-1; D012772:Shock, Septic / Q000503:physiopathology*; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004731:Endotoxins; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D011506:Proteins; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha