• H Rensing, H Jaeschke, I Bauer, C Pätau, V Datene, B H Pannen, and M Bauer.
• Department of Anesthesiology and Critical Care Medicine, University of the Saarland, Homburg, Germany.
• Crit. Care Med. 2001 Oct 1;29(10):1962-71.

ObjectiveTo investigate the role of redox-sensitive transcription factors nuclear factor kappa-B (NF-kappaB) or activator protein-1 (AP-1) for hepatic gene expression of heme oxygenase (HO)-1 and inducible nitric oxide synthase (iNOS) in models of hemorrhagic or endotoxic shock.DesignProspective controlled laboratory study.SettingAnimal research laboratory at a university hospital.SubjectsMale Sprague-Dawley rats (250-350 g).InterventionsAfter anesthesia, animals were assigned to hemorrhagic shock (mean arterial pressure 35-40 mm Hg for 60 mins), sham operation, or endotoxemia (1 mg/kg intraperitoneally). To assess the role of reactive oxygen species for activation of NF-kappaB or AP-1, animals were treated with the antioxidant trolox (6 mg/kg body weight). In additional experiments, animals were pretreated with dexamethasone (10 mg/kg body weight), an inhibitor of the transactivating function of DNA-bound AP-1 or with actinomycin-D (2 mg/kg body weight), an inhibitor of DNA-directed RNA synthesis. Activation of NF-kappaB or AP-1 was assessed by electrophoretic mobility shift assay. HO-1 and iNOS gene expression were assessed by Northern and Western blot.Measurements And Main ResultsHemorrhage and resuscitation induced hepatic HO-1 transcripts 12-fold. Induction was abolished by actinomycin-D and was attenuated by dexamethasone and the antioxidant trolox. Activation of AP-1 was observed after hemorrhagic but not after endotoxic shock. AP-1 activation was inhibitable by trolox and correlated with accumulation of HO-1 transcripts. In contrast, a weak activation of NF-kappaB was observed after hemorrhage that was not affected by trolox. A profound activation of NF-kappaB after endotoxic shock correlated with induction of iNOS but failed to induce HO-1 transcripts.ConclusionsThese data suggest that AP-1 but not NF-kappaB activation is dependent on reactive oxygen intermediates in vivo and contributes to HO-1 gene expression. Thus, AP-1-dependent HO-1 induction under oxidative stress conditions may subserve a similar function as a stress-inducible vasodilator system as does NF-kappaB-dependent iNOS expression in liver inflammation.

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