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

Abstract

Background: The transcription factor nuclear factor κB 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 κB–mediated transcriptional activation in vitro. Objective: We hypothesized that inhibition of nuclear factor κB with dithiocarbamate treatment in vivo would attenuate interleukin 1 α–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 μg/kg interleukin 1 α. Nuclear factor κB activation was evaluated by electrophoretic gel mobility shift assay of whole-tissue homogenates. Results: Infusion of interleukin 1 α 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 κB–binding activity was increased within heart, lung, and liver tissue 4 hours after interleukin 1 α infusion. Treatment with dithiocarbamate resulted in decreased nuclear factor κB activation in lung and liver tissue with respect to that in control animals. Conclusions: These results demonstrate that nuclear factor κB is systemically activated during whole-body inflammation and that inhibition of nuclear factor κB in vivo attenuates interleukin 1 α–induced hypotension. Nuclear factor κB thus represents a potential therapeutic target in the treatment of hemodynamic instability associated with the whole-body inflammatory response. (J Thorac Cardiovasc Surg 1999;118:154-62)