Inhibition of nuclear factor-κB activation by IRFI 042, protects against endotoxin-induced shock (Publication with Expression of Concern. See MAR, 2023)

Background: The aim of our study was to investigate the effect of IRFI 042, a novel duat vitamin F-like antioxidant, on nuclear factor-kappaB (NF-kappaB) activation, TNF-alpha 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) if Salmonella enteritidis lipopolysaccharide (LPS). Survival rate. mean arterial blood pressure, serum TNF-alpha and plasma malondialdehyde (MAL) levels were investigated. We then evaluated in the liver TNF-alpha mRNA levels. NF-kappaB binding activity and the inhibitor protein IkappaB-alpha. Moreover we studied in LPS stimulated (50 mug ml(-1)) peritoneal macrophages (Mphi). NF-kappaB activation, cytoplasmic IkappaB-alpha degradation, the rnessage for TNF-alpha. and TNF-alpha and MAL levels. Results: LPS administration reduced survival rate (0%, 72 h after LPS administration). decreased mean arterial blood pressure. augmented serum TNF-alpha (60+/-11 ng ml (1)) and enhanced plasma malondialdehyde (MAL) levels (55+/-7.1 nmol l (1)) LPS shocked rats also had increased TNF-alpha mRNA levels. augmented liver NF-kappaB binding activity in the nucleus and decreased levels of the inhibitory protein IkappaBalpha. lit addition, in vitro LPS stimulation (50 mug, ml (1)) significantly induced NF-kappaB activation and cytoplasmic IkappaBalpha degradation in Mphi. enhanced TNF-alpha mRNA levels and increased M(1) TNF-alpha 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 MAI, (0.9+/-0.9 nmol l (1)) and decreased serum TNF-alpha (15+/-3 ng ml(-1)). The antioxidant also inhibited the loss of IkappaBalpha protein front the hepatic C ItoplaSrn. blunted the increased NF-KB binding activity in the liver and decreased hepatic liver mRNA for TNF-alpha. Furthermore 'in vitro' IRFI 042 (50 muM) significantly inhibited activation of NF-KB through inhibition of IkappaBalpha degradation. reduced the amount of TNF-alpha mRNA. decreased LPS-induced TNF-alpha release and blunted lipid peroxidation (MAL) in LPS stimulated Mphi. Conclusions: These data suggest that IRFI 042 blocks the activation of NF-kappaB. reduces TNF-alpha mRNA levels, and finally reverses endotoxic shock. (C) 2002 Elsevier Science B.V All rights reserved.