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

Background: The transcription factor nuclear factor kappa B 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 kappa B-mediated transcriptional activation 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.,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 mu g/kg interleukin 1 alpha. Nuclear factor kappa B 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 kappa B-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 MB activation in lung and liver tissue with respect to that in control animals. Conclusions: These results demonstrate that nuclear factor kappa B is systemically activated during whole-body inflammation and that inhibition of nuclear factor kappa B in vivo attenuates interleukin 1 alpha-induced hypotension. Nuclear factor kappa B thus represents a potential therapeutic target in the treatment of hemodynamic instability associated with the whole-body inflammatory response.