Inhibition of nuclear factor-κB activation by IRFI 042, protects against endotoxin-induced shock

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• 作者：Altavilla ; Domenica ; Squadrito ; Giovanni ; Minutoli ; Letteria ; Deodato ; Barbara ; Bova ; Antonino ; et. al.
• 关键词：Cytokines ; Endotoxins ; Free radicals ; Gene expression ; Macrophages ; Septic shock ; Signal transduction
• 刊名：Cardiovascular Research
• 出版年：2002
• 出版时间：June, 2002
• 年：2002
• 卷：54
• 期：3
• 页码：684-693
• 全文大小：875 K

文摘

Background: The aim of our study was to investigate the effect of IRFI 042, a novel dual vitamin E-like antioxidant, on nuclear factor-κB (NF-κB) activation, TNF-α 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-α and plasma malondialdehyde (MAL) levels were investigated. We then evaluated in the liver TNF-α mRNA levels, NF-κB binding activity and the inhibitory protein IκBα. Moreover we studied in LPS stimulated (50 μg ml⁻¹) peritoneal macrophages (Mφ), NF-κB activation, cytoplasmic IκB-α degradation, the message for TNF-α, and TNF-α and MAL levels. Results: LPS administration reduced survival rate (0 % , 72 h after LPS administration), decreased mean arterial blood pressure, augmented serum TNF-α (60±11 ng ml⁻¹) and enhanced plasma malondialdehyde (MAL) levels (55±7.1 nmol l⁻¹). LPS shocked rats also had increased TNF-α mRNA levels, augmented liver NF-κB binding activity in the nucleus and decreased levels of the inhibitory protein IκBα. In addition, in vitro LPS stimulation (50 μg ml⁻¹) significantly induced NF-κB activation and cytoplasmic IκBα degradation in Mφ, enhanced TNF-α mRNA levels and increased Mφ TNF-α 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-α (15±3 ng ml⁻¹). The antioxidant also inhibited the loss of IκBα protein from the hepatic cytoplasm, blunted the increased NF-κB binding activity in the liver and decreased hepatic liver mRNA for TNF-α. Furthermore ‘in vitro’ IRFI 042 (50 μM) significantly inhibited activation of NF-κB through inhibition of IκBα degradation, reduced the amount of TNF-α mRNA, decreased LPS-induced TNF-α release and blunted lipid peroxidation (MAL) in LPS stimulated Mφ. Conclusions: These data suggest that IRFI 042 blocks the activation of NF-κB, reduces TNF-α mRNA levels, and finally reverses endotoxic shock.