(Circulation. 1999;100:1330-1337.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Inhibition of NF-
B Activation by Pyrrolidine Dithiocarbamate Prevents In Vivo Expression of Proinflammatory Genes
From the Department of Pharmacology, the University of Illinois College of Medicine, Chicago.
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)-
B 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-B activation and expression of multiple inflammatory
signals: tumor necrosis factor-
(TNF-),
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-B activation using pyrrolidine
dithiocarbamate (PDTC) on the expression of these mediators. NF-B
activation preceded the induction of TNF-, COX-2, CINC, and ICAM-1
mRNAs. PDTC prevented the LPS-induced NF-B activation but did not
inhibit activation of the transcription factors AP-1, Sp-1, and CREB.
PDTC inhibited the LPS-induced expression of TNF-, COX-2, CINC, and
ICAM-1 mRNA and proteins and reduced the LPS-induced increases in
plasma TNF-, 6-keto-prostaglandin F1, 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-B activation correlates with LPS-induced
expression of TNF-, COX-2, CINC, and ICAM-1 genes in vivo. PDTC
inhibits NF-B activation and expression of these proinflammatory
genes and their products. Thus, blocking NF-B activation may be
an effective strategy in the treatment of septic shock.
Key Words: shock • genes • nuclear factor • proteins • cell adhesion molecules
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