Inhibition of the transcriptional activator protein nuclear factor kappa Bprevents hemodynamic instability associated with the whole-body inflammatory response syndrome

Background: The transcription factor nuclear factor kappa B mediates the ex pression of a number of inflammatory genes involved in the whole-body infla mmatory response to injury. We and others have found that dithiocarbamates specifically inhibit nuclear factor kappa B-mediated transcriptional activa tion in vitro. Objective: We hypothesized that inhibition of nuclear factor kappa B nifh dithiocarbamate treatment in vivo would attenuate interleukin 1 alpha-mediated hypotension in a rabbit model of systemic inflammation.,M ethods: New Zealand White rabbits were anesthetized and cannulated for cont inuous hemodynamic monitoring during 240 minutes. Rabbits were treated intr avenously with either phosphate-buffered saline solution or 15 mg/kg of a d ithiocarbamate, either pyrrolidine dithiocarbamate or proline dithiocarbama te, 60 minutes before the intravenous infusion of 5 mu g/kg interleukin 1 a lpha. Nuclear factor kappa B activation was evaluated by electrophoretic ge l mobility shift assay of whole-tissue homogenates. Results: Infusion of in terleukin 1 alpha resulted in significant decreases in mean arterial pressu re and systemic vascular resistance, both of which were prevented by treatm ent with dithiocarbamate. Pyrrolidine dithiocarbamate induced a significant metabolic acidosis, whereas proline dithiocarbamate did not. Nuclear facto r kappa B-binding activity was increased within heart, lung, and liver tiss ue 4 hours after interleukin 1 alpha infusion. Treatment with dithiocarbama te resulted in decreased nuclear factor MB activation in lung and liver tis sue with respect to that in control animals. Conclusions: These results dem onstrate that nuclear factor kappa B is systemically activated during whole -body inflammation and that inhibition of nuclear factor kappa B in vivo at tenuates interleukin 1 alpha-induced hypotension. Nuclear factor kappa B th us represents a potential therapeutic target in the treatment of hemodynami c instability associated with the whole-body inflammatory response.