© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Inhibition of nuclear factor-
B activation by IRFI 042, protects against endotoxin-induced shock
aDepartment of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology School of Medicine, University of Messina, Torre Biologica, Azienda Ospedaliera Universitaria ‘G Martino’, Via C. Valeria, Gazzi, 98125 Messina, Italy
bDepartment of Internal Medicine, University of Messina, Messina, Italy
cDepartment of Physiology and Pharmacology, University of Messina, Messina, Italy
dDepartment of Neurosciences, Psychiatry and Anesthesiology, University of Messina, Messina, Italy
francesco.squadrito{at}unime.it
* Corresponding author. Tel.: +39-90-221-3648; fax: +39-90-221-3300
Background: The aim of our study was to investigate the effect of IRFI 042, a novel dual vitamin E-like antioxidant, on nuclear factor-
B (NF-B) activation, TNF-
gene priming and on the release of the mature protein during endotoxin shock. Methods: Endotoxin shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg kg–1 of Salmonella enteritidis lipopolysaccharide (LPS). Survival rate, mean arterial blood pressure, serum TNF- and plasma malondialdehyde (MAL) levels were investigated. We then evaluated in the liver TNF- mRNA levels, NF-B binding activity and the inhibitory protein IB. Moreover we studied in LPS stimulated (50 µg ml–1) peritoneal macrophages (M
), NF-B activation, cytoplasmic IB- degradation, the message for TNF-, and TNF- and MAL levels. Results: LPS administration reduced survival rate (0%, 72 h after LPS administration), decreased mean arterial blood pressure, augmented serum TNF- (60±11 ng ml–1) and enhanced plasma malondialdehyde (MAL) levels (55±7.1 nmol l–1). LPS shocked rats also had increased TNF- mRNA levels, augmented liver NF-B binding activity in the nucleus and decreased levels of the inhibitory protein IB. In addition, in vitro LPS stimulation (50 µg ml–1) significantly induced NF-B activation and cytoplasmic IB degradation in M, enhanced TNF- mRNA levels and increased M TNF- and MAL. Treatment with IRFI 042 (20 mg kg–1, i.v., 5 min after endotoxin challenge) protected against LPS-induced lethality (90% survival rate 24 h and 80% survival rate 72 h after LPS injection, respectively), reduced hypotension, blunted plasma MAL (9.0±0.9 nmol l–1) and decreased serum TNF- (15±3 ng ml–1). The antioxidant also inhibited the loss of IB protein from the hepatic cytoplasm, blunted the increased NF-B binding activity in the liver and decreased hepatic liver mRNA for TNF-. Furthermore ‘in vitro’ IRFI 042 (50 µM) significantly inhibited activation of NF-B through inhibition of IB degradation, reduced the amount of TNF- mRNA, decreased LPS-induced TNF- release and blunted lipid peroxidation (MAL) in LPS stimulated M. Conclusions: These data suggest that IRFI 042 blocks the activation of NF-B, reduces TNF- mRNA levels, and finally reverses endotoxic shock.
KEYWORDS Cytokines; Endotoxins; Free radicals; Gene expression; Macrophages; Septic shock; Signal transduction
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