title: Recombinant interleukin-1 receptor antagonist (IL-1ra): effective therapy against gram-negative sepsis in rats.
abstract: BACKGROUND
  Morbidity and mortality from bacterial sepsis remain high despite aggressive diagnostic and therapeutic intervention. Interleukin-1 has been implicated as mediator of the lethal effects of endotoxemia or bacterial sepsis. The current experiments were designed to evaluate the therapeutic efficacy of a human recombinant interleukin-1 receptor antagonist (IL-1ra) against polymicrobial gram-negative septicemia in rats.
  
  
  METHODS
  Male rats underwent placement of indwelling carotid arterial and superior vena caval catheters followed by cecal ligation and puncture (CLP). After 3 hours rats received either IL-1ra (10 mg/kg intravenous bolus followed by 5 mg/kg/hr) or an equal volume of vehicle intravenously for 24 hours. Heart rate, respirations, mean arterial blood pressure, and temperature were recorded at frequent intervals, and survival was assessed for 30 hours after CLP.
  
  
  RESULTS
  There were no differences in vital signs between groups at baseline or before treatment, and all animals appeared ill with huddled posture, piloerection, and hyperventilation. Twenty-four hours after CLP, IL-1ra significantly ameliorated bradycardia (p = 0.01), hypothermia (p = 0.001), and hypotension (p = 0.05), and 30-hour survival was significantly improved (71% vs 20%, p less than 0.05).
  
  
  CONCLUSIONS
  IL-1ra lessens the acute hemodynamic, hypothermic, and mortal effects of gram-negative sepsis induced by CLP in rats. These data suggest that IL-1 receptor blockade may be an important new treatment strategy against overwhelming bacterial sepsis.
authors.affiliation: Surgical Metabolism Section, National Cancer Institute, NIH, Bethesda, MD 20892.
authors.forename: H R
authors.initials: HR
authors.lastname: Alexander
authors.forename: G M
authors.initials: GM
authors.lastname: Doherty
authors.forename: D J
authors.initials: DJ
authors.lastname: Venzon
authors.forename: M J
authors.initials: MJ
authors.lastname: Merino
authors.forename: D L
authors.initials: DL
authors.lastname: Fraker
authors.forename: J A
authors.initials: JA
authors.lastname: Norton
mesh_terms: D000818:Animals; D002432:Cecum; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000473:pathology; D007262:Infusions, Intravenous; D007375:Interleukin-1 / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D010865:Pilot Projects; D011677:Punctures; D051381:Rats; D011916:Rats, Inbred F344; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D013997:Time Factors
chemical_list: D007375:Interleukin-1; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins