Inhibition of the transcriptional activator protein nuclear factor [kappa]b prevents hemodynamic instability associated with the whole-body inflammatory response syndrome

Byline: J.Craig Kovacich, Edward M. Boyle, Elizabeth N. Morgan, Timothy G. Canty, Angela L. Farr, Michael T. Caps, Norbert Frank, Timothy H. Pohlman, Edward D. Verrier Abstract: 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 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 [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 [kappa]B 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. (J Thorac Cardiovasc Surg 1999;118:154-62) Author Affiliation: Department of Surgery, University of Washington, Seattle, Wash, and the Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany Article History: Received 16 April 1998; Revised 5 November 1998; Revised 5 February 1999; Accepted 2 March 1999 Article Note: (footnote) [star] Supported in part by the 3M/Surgical Infection Society Resident Research Fellowship (E.M.B.), the Thoracic Surgery Foundation for Research and Education Fellowship (E.M.B. and E.N.M.), an unrestricted grant from the Bayer Corporation for the study of blood conservation in thoracic surgery (E.M.B.), the American Heart Association Student Scholarship in Cardiovascular Disease and Stroke (J.C.K.), the Alpha Omega Alpha Student Research Award (J.C.K.), and the National Institutes of Health grants GM 46662 and T32 GM 07037 (T.H.P.)., [star][star] Address for reprints: Edward D. Verrier, MD, Professor and Chief, Division of Cardiothoracic Surgery, University of Washington, 1959 Pacific Ave NE, Box 356310, Seattle, WA 98195., a 12/6/98430