Sf. Liu et al., Inhibition of NF-kappa B activation by pyrrolidine dithiocarbamate prevents in vivo expression of proinflammatory genes, CIRCULATION, 100(12), 1999, pp. 1330-1337
Citations number
27
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Background-The inability to inhibit multiple mediators of septic shock repr
esents a major hurdle in the treatment of septic shock. In vivo inhibition
of nuclear factor (NF)-kappa B activation, a transcription factor regulatin
g 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/k
g IV, we determined the time course of NF-kappa B activation and expression
of multiple inflammatory signals: tumor necrosis factor-alpha (TNF-alpha),
cyclooxygenase-2 (COX-2), cytokine-inducible neutrophil chemoattractant (C
INC), and intercellular adhesion molecule-1 (ICAM)-1. We studied the effect
s of in vivo inhibition of NF- kappa B activation using pyrrolidine dithioc
arbamate (PDTC) on the expression of these mediators. NF-kappa B activation
preceded the induction of TNF-alpha, COX-2, CINC, and ICAM-1 mRNAs, PDTC p
revented the LPS-induced NF-kappa B activation but did not inhibit activati
on of the transcription factors AP-1, Sp-1, and CREB, PDTC inhibited the LP
S-induced expression of TNF-alpha, COX-2, CINC, and ICAM-1 mRNA and protein
s and reduced the LPS-induced increases in plasma TNF-alpha, 6-keto-prostag
landin F-1 alpha, and CINC concentrations. Inhibition of expression of thes
e mediators prevented the increases in myeloperoxidase activity (a measure
of neutrophil sequestration) in the heart, lungs, and liver.
Conclusions-NF-kappa B activation correlates with LPS-induced expression of
TNF-alpha, COX-2, CINC, and ICAM-I genes in vivo. PDTC inhibits NF-kappa B
activation and expression of these proinflammatory genes and their product
s. Thus, blocking NF-kappa B activation may be an effective strategy in the
treatment of septic shock.