title: Inhibition of the transcriptional activator protein nuclear factor kappaB prevents hemodynamic instability associated with the whole-body inflammatory response syndrome.
abstract: BACKGROUND
  The transcription factor nuclear factor kappaB mediates the expression of a number of inflammatory genes involved in the whole-body inflammatory response to injury. We and others have found that dithiocarbamates specifically inhibit nuclear factor kappaB-mediated transcriptional activation in vitro.
  
  
  OBJECTIVE
  We hypothesized that inhibition of nuclear factor kappaB with dithiocarbamate treatment in vivo would attenuate interleukin 1 alpha-mediated hypotension in a rabbit model of systemic inflammation.
  
  
  METHODS
  New Zealand White rabbits were anesthetized and cannulated for continuous hemodynamic monitoring during 240 minutes. Rabbits were treated intravenously with either phosphate-buffered saline solution or 15 mg/kg of a dithiocarbamate, either pyrrolidine dithiocarbamate or proline dithiocarbamate, 60 minutes before the intravenous infusion of 5 micrograms/kg interleukin 1 alpha. Nuclear factor kappaB activation was evaluated by electrophoretic gel mobility shift assay of whole-tissue homogenates.
  
  
  RESULTS
  Infusion of interleukin 1 alpha resulted in significant decreases in mean arterial pressure and systemic vascular resistance, both of which were prevented by treatment with dithiocarbamate. Pyrrolidine dithiocarbamate induced a significant metabolic acidosis, whereas proline dithiocarbamate did not. Nuclear factor kappaB-binding activity was increased within heart, lung, and liver tissue 4 hours after interleukin 1 alpha infusion. Treatment with dithiocarbamate resulted in decreased nuclear factor kappaB activation in lung and liver tissue with respect to that in control animals.
  
  
  CONCLUSIONS
  These results demonstrate that nuclear factor kappaB is systemically activated during whole-body inflammation and that inhibition of nuclear factor kappaB in vivo attenuates interleukin 1 alpha-induced hypotension. Nuclear factor kappaB thus represents a potential therapeutic target in the treatment of hemodynamic instability associated with the whole-body inflammatory response.
authors.affiliation: Department of Surgery, University of Washington, Seattle, Wash, and the Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: J C
authors.initials: JC
authors.lastname: Kovacich
authors.forename: E M
authors.initials: EM
authors.lastname: Boyle
authors.forename: E N
authors.initials: EN
authors.lastname: Morgan
authors.forename: T G
authors.initials: TG
authors.lastname: Canty
authors.forename: A L
authors.initials: AL
authors.lastname: Farr
authors.forename: M T
authors.initials: MT
authors.lastname: Caps
authors.forename: N
authors.initials: N
authors.lastname: Frank
authors.forename: T H
authors.initials: TH
authors.lastname: Pohlman
authors.forename: E D
authors.initials: ED
authors.lastname: Verrier
mesh_terms: D000138:Acidosis / Q000139:chemically induced; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006439:Hemodynamics / Q000187:drug effects*; D007022:Hypotension / Q000209:etiology* / Q000503:physiopathology*; D007262:Infusions, Intravenous; D007375:Interleukin-1 / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D016328:NF-kappa B / Q000032:analysis / Q000187:drug effects* / Q000276:immunology*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D011897:Random Allocation; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology; D013859:Thiocarbamates / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D007375:Interleukin-1; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; C020972:pyrrolidine dithiocarbamic acid; D011392:Proline