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 toshock ingram-negative sepsis, shock fromgram-positive organisms ismediated, inpart, bytumor necrosis factor (TNF) andinterleukin-1 (IL-1). Inthepresent study, rabbits wereinfused withIL-1receptor antagonist (IL-ira) prior toandduring Staphylococcus epidermidis-induced hypotension. Afterinjection of bacteria, a maximalfall inmeanarterial pressure to-42% belowbaseline occurred at200minin vehicle-treated animals compared withanonsignificant decrease ofonly7% intheIL-lra-treated group(P< 0.01, vehicle versus IL-Ira). A similar attenuation wasobserved inthefall insystemic vascular resistance (P < 0.05). After theinjection ofS.epidermidis, TNFlevels rosetoapeakelevation of475± 160U/mlin vehicle-treated rabbits, butinrabbits receiving IL-lra, maximal TNFlevels roseonlyto85+ 23U/ml(P< 0.01). Plasma IL-1p reached maximal concentrations at180minof364± 71pg/ml invehicle-treated animals butonly 1454 12pg/ml inrabbits given IL-Ira (P< 0.05). Thereductions inTNFandIL-1werenotdueto interference byIL-lra intherespective assays. Invitro, IL-lra inhibited S.epidermidis-induced TNFfrom mononuclear cells by31%_ 11%,fromspleen cells by17%± 4% (P< 0.05), andfromwhole blood by42% _ 17%.Despite thenearreversal ofthefall inmeanarterial pressure andsystemic vascular resistance in IL-ira-treated rabbits, leukopenia andthrombocytopenia wereunaffected. Theseresults demonstrate that IL-Ira blocks shock-like hemodynamic parameters andreduces circulating IL-1andTNFlevels inamodelof gram-positive sepsis. Animal models ofsepsis haveusually employed lipopolysaccharide (LPS) orgram-negative bacteria astheinducer of ashock-like state. However, inhumans, septic shockalso occurs during gram-positive bacteremia (6,9,36), andthe mortality forpatients withgram-negative orgram-positive bacteremia doesnotdiffer greatly (5). Byusing a wellcharacterized canine modelofseptic shock, Natanson etal. (33) demonstrated thatStaphylococcus aureus, intheabsenceofendotoxemia, induced thesamecardiovascular abnormalities ofseptic shockasEscherichia coli did, suggesting thatstructurally andfunctionally distinct microorganisms couldactivate a commonpathway resulting in similar cardiovascular injury andmortality. We recently demonstrated that heat-killed Staphylococcus epidernidis is alsocapable ofinducing ashock-like state andtissue injury inrabbits (42). Inthatmodel, we observed asimilar degree ofcomplementactivation andgeneration ofcirculating levels ofinterleukin-1 (IL-1) andtumornecrosis factor (TNF)butinthe absence ofdetectable endotoxemia. Inaddition, circulating IL-11 levels hadagreater correlation coefficient (r= 0.81; P < 0001) withthedegree ofhypotension thanTNFlevels did (r= 0.48; P < 0.02). Thesefindings areconsistent withthe observation that TNF andIL-1canindependently induce a shock-like state; moreover, these twocytokines actsynergistically ininducing hypotension andtissue injury (35).