Inhibition of the transcriptional activator protein nuclear factor kappaB prevents hemodynamic instability associated with the whole-body inflammatory response syndrome.

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Other Article

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.

Full Text

Duke Authors

Cited Authors

  • Kovacich, JC; Boyle, EM; Morgan, EN; Canty, TG; Farr, AL; Caps, MT; Frank, N; Pohlman, TH; Verrier, ED

Published Date

  • July 1999

Published In

Volume / Issue

  • 118 / 1

Start / End Page

  • 154 - 162

PubMed ID

  • 10384198

Pubmed Central ID

  • 10384198

International Standard Serial Number (ISSN)

  • 0022-5223

Digital Object Identifier (DOI)

  • 10.1016/s0022-5223(99)70154-6

Language

  • eng

Conference Location

  • United States