Pyrrolidine dithiocarbamate prevents I-kappa B degradation and reduces microvascular injury induced by lipopolysaccharide in multiple organs

Lipopolysaccharide (LPS) is a key mediator of multiple organ injury observe d in septic shock. The mechanisms responsible for LPS-induced multiple orga n injury remain obscure. In the present study, we tested the hypothesis tha t the LPS-induced injury occurs through activation of the transcription fac tor, nuclear factor-kappa B (NF-kappa B). We examined the effects of inhibi ting NF-kappa B activation in vivo in the rat on LPS-induced: 1) gene and p rotein expression of the cytokine-inducible neutrophil chemoattractant (CIN C) and intercellular adhesion molecule-1 (ICAM-1); b) neutrophil influx int o lungs, heart, and liver; and c) increase in microvascular permeability in duced by LPS in these organs. LPS (8 mg/kg, i.v.) challenge of rats activat ed NF-kappa B and induced CINC and ICAM-1 mRNA and protein expression. Pret reatment of rats with pyrrolidine dithiocarbamate (50, 100, and 200 mg/kg, i.p.), an inhibitor of NF-kappa B activation, prevented LPS-induced I-kappa B alpha degradation and the resultant NF-kappa B activation and inhibited, in a dose-related manner, the LPS-induced CINC and ICAM-1 mRNA and protein expression. Pyrrolidine dithiocarbamate also markedly reduced the LPS-indu ced tissue myeloperoxidase activity (an indicator of tissue neutrophil rete ntion) and the LPS-induced increase in microvascular permeability in these organs. These results demonstrate that NF-kappa B activation is an importan t in vivo mechanism mediating LPS-induced CINC and ICAM-1 expression, as we ll as neutrophil recruitment, and the subsequent organ injury. Thus, inhibi tion of NF-kappa B activation may be an important strategy for the treatmen t of sepsis-induced multiple organ injury.