Interleukin-1 (IL-1) receptor antagonist prevents Staphylococcus epidermidis-induced hypotension and reduces circulating levels of tumor necrosis factor and IL-1 beta in rabbits.
Similar to shock in gram-negative sepsis, shock from gram-positive organisms is mediated, in part, by tumor necrosis factor (TNF) and interleukin-1 (IL-1). In the present study, rabbits were infused with IL-1 receptor antagonist (IL-1ra) prior to and during Staphylococcus epidermidis-induced hypotension. After injection of bacteria, a maximal fall in mean arterial pressure to -42% below baseline occurred at 200 min in vehicle-treated animals compared with a nonsignificant decrease of only 7% in the IL-1ra-treated group (P < 0.01, vehicle versus IL-1ra). A similar attenuation was observed in the fall in systemic vascular resistance (P < 0.05). After the injection of S. epidermidis, TNF levels rose to a peak elevation of 475 +/- 160 U/ml in vehicle-treated rabbits, but in rabbits receiving IL-1ra, maximal TNF levels rose only to 85 +/- 23 U/ml (P < 0.01). Plasma IL-1 beta reached maximal concentrations at 180 min of 364 +/- 71 pg/ml in vehicle-treated animals but only 145 +/- 12 pg/ml in rabbits given IL-1ra (P < 0.05). The reductions in TNF and IL-1 were not due to interference by IL-1ra in the respective assays. In vitro, IL-1ra inhibited S. epidermidis-induced TNF from mononuclear cells by 31% +/- 11%, from spleen cells by 17% +/- 4% (P < 0.05), and from whole blood by 42% +/- 17%. Despite the near reversal of the fall in mean arterial pressure and systemic vascular resistance in IL-1ra-treated rabbits, leukopenia and thrombocytopenia were unaffected. These results demonstrate that IL-1ra blocks shock-like hemodynamic parameters and reduces circulating IL-1 and TNF levels in a model of gram-positive sepsis.
Aiura
K
K
Department of Medicine, Tufts University and New England Medical Center Hospital, Boston, Massachusetts 02111.
Gelfand
J A
JA
Burke
J F
JF
Thompson
R C
RC
Dinarello
C A
CA
D000818:Animals; D016470:Bacteremia / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000209:etiology / Q000517:prevention & control*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000097:blood*; D011817:Rabbits; D011863:Radioimmunoassay; D012795:Sialoglycoproteins / Q000097:blood / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000150:complications / Q000473:pathology; D013212:Staphylococcus epidermidis / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis* / Q000096:biosynthesis
D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha