RT Journal Article
SR Electronic
T1 Pyrrolidine Dithiocarbamate Prevents I-κB Degradation and Reduces Microvascular Injury Induced by Lipopolysaccharide in Multiple Organs
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 658
OP 667
VO 55
IS 4
A1 Shu Fang Liu
A1 Xiaobing Ye
A1 Asrar B. Malik
YR 1999
UL http://molpharm.aspetjournals.org/content/55/4/658.abstract
AB Lipopolysaccharide (LPS) is a key mediator of multiple organ injury observed in septic shock. The mechanisms responsible for LPS-induced multiple organ injury remain obscure. In the present study, we tested the hypothesis that the LPS-induced injury occurs through activation of the transcription factor, nuclear factor-κB (NF-κB). We examined the effects of inhibiting NF-κB activation in vivo in the rat on LPS-induced: 1) gene and protein expression of the cytokine-inducible neutrophil chemoattractant (CINC) and intercellular adhesion molecule-1 (ICAM-1); b) neutrophil influx into lungs, heart, and liver; and c) increase in microvascular permeability induced by LPS in these organs. LPS (8 mg/kg, i.v.) challenge of rats activated NF-κB and induced CINC and ICAM-1 mRNA and protein expression. Pretreatment of rats with pyrrolidine dithiocarbamate (50, 100, and 200 mg/kg, i.p.), an inhibitor of NF-κB activation, prevented LPS-induced I-κBα degradation and the resultant NF-κB 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-induced tissue myeloperoxidase activity (an indicator of tissue neutrophil retention) and the LPS-induced increase in microvascular permeability in these organs. These results demonstrate that NF-κB activation is an important in vivo mechanism mediating LPS-induced CINC and ICAM-1 expression, as well as neutrophil recruitment, and the subsequent organ injury. Thus, inhibition of NF-κB activation may be an important strategy for the treatment of sepsis-induced multiple organ injury. The American Society for Pharmacology and Experimental Therapeutics