Role of NFκB in the mortality of sepsis

Abstract

Binding activity for nuclear factor kappa B (NFκB) consensus probes was studied in nuclear extracts from peripheral blood mononuclear cells of 15 septic patients (10 surviving and 5 not surviving). Nonsurvivors could be distinguished from survivors by an increase in NFκB binding activity during the observation period (P < 0.001). The increase in NFκB binding activity was comparable to the APACHE-II score as a predictor of outcome. Intravenous somatic gene transfer with an expression plasmid coding for IκBα was used to investigate the role of members of the NFκB family in a mouse model of endotoxemia. In this model, increased NFκB binding activity was present after injection of LPS. Intravenous somatic gene transfer with IκBα given before LPS attenuated renal NFκB binding activity and increased survival. Endothelial cells and monocytes/macrophages were the major target cells for somatic gene transfer, transfected with an average transfection efficiency of 20-35%. Tissue factor, a gene under regulatory control of NFκB, was induced by LPS. Somatic gene transfer with a reporter plasmid containing the functional tissue factor promoter demonstrated NFκB-dependent stimulation by LPS. Intravenous somatic gene transfer with IκBα reduced LPS-induced renal tissue factor expression, activation of the plasmatic coagulation system (decrease of thrombin-antithrombin III complexes) and renal fibrin/fibrinogen deposition. Somatic gene transfer with an expression plasmid with tissue factor cDNA in the antisense direction (in contrast to sense or vector alone) also increased survival. Furthermore, antisense tissue factor decreased renal tissue factor expression and the activation of the plasmatic coagulation system.