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Background —The inability to inhibit multiple mediators of septic shock represents a major hurdle in the treatment of septic shock. In vivo inhibition of nuclear factor (NF)-κB activation, a transcription factor regulating expression of many proinflammatory genes, could provide a useful strategy for the treatment of septic shock.Methods and Results —In rats challenged with lipopolysaccharide (LPS) 8 mg/kg IV, we determined the time course of NF-κB activation and expression of multiple inflammatory signals: tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), cytokine-inducible neutrophil chemoattractant (CINC), and intercellular adhesion molecule-1 (ICAM)-1. We studied the effects of in vivo inhibition of NF-κB activation using pyrrolidine dithiocarbamate (PDTC) on the expression of these mediators. NF-κB activation preceded the induction of TNF-α, COX-2, CINC, and ICAM-1 mRNAs. PDTC prevented the LPS-induced NF-κB activation but did not inhibit activation of the transcription factors AP-1, Sp-1, and CREB. PDTC inhibited the LPS-induced expression of TNF-α, COX-2, CINC, and ICAM-1 mRNA and proteins and reduced the LPS-induced increases in plasma TNF-α, 6-keto-prostaglandin F1α , and CINC concentrations. Inhibition of expression of these mediators prevented the increases in myeloperoxidase activity (a measure of neutrophil sequestration) in the heart, lungs, and liver.Conclusions —NF-κB activation correlates with LPS-induced expression of TNF-α, COX-2, CINC, and ICAM-1 genes in vivo. PDTC inhibits NF-κB activation and expression of these proinflammatory genes and their products. Thus, blocking NF-κB activation may be an effective strategy in the treatment of septic shock.

Inhibition of NF-κB Activation by Pyrrolidine Dithiocarbamate Prevents In Vivo Expression of Proinflammatory Genes