15059791

pubmed:Citation

2

Transactivation of the DNA-binding proteins nuclear factor-kappa B (NF-kappa B) and activator protein (AP)-1 by de novo oxyradical generation is a stereotypic redox-sensitive process during hypoxic stress of the liver. Systemic trauma is associated with splanchnic hypoxia-reoxygenation (H/R) followed by intraportal gram-negative bacteremia, which collectively have been implicated in posttraumatic liver dysfunction and multiple organ damage. We hypothesized that hypoxic stress of the liver before stimulation by Escherichia coli serotype O55:B5 (EC) amplifies oxyradical-mediated transactivation of NF-kappa B and AP-1 as well as cytokine production compared with noninfectious H/R or gram-negative sepsis without prior hypoxia. Livers from Sprague-Dawley rats underwent perfusion for 180 min with or without 0.5 h of hypoxia (perfusate PO(2), 40 +/- 5 mmHg) followed by reoxygenation and infection with 10(9) EC or 0.9% NaCl infusion. In H/R + EC livers, nuclear translocation of NF-kappa B and AP-1 was unexpectedly reduced in gel shift assays vs. normoxic EC controls, as were perfusate TNF-alpha and IL-1 beta levels. Preceding hypoxic stress paradoxically increased postbacteremic reduced-to-oxidized glutathione ratios plus nuclear localization of I kappa B alpha and phospho-I kappa B alpha, but not JunB/FosB profiles. Notably, xanthine oxidase inhibition increased transactivation as well as cytokine production in H/R + EC livers. Thus brief hypoxic stress of the liver before intraportal gram-negative bacteremia potently suppresses activation of canonical redox-sensitive transcription factors and production of inflammatory cytokines by mechanisms including xanthine oxidase-induced oxyradicals functioning in an anti-inflammatory signaling role. These results suggest a novel multifunctionality of oxyradicals in decoupling hepatic transcriptional activity and cytokine biosynthesis early in the posttraumatic milieu.

eng

IM

MEDLINE

0363-6119

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NLM

R437-45

pubmed-meshheading:15059791-Animals, pubmed-meshheading:15059791-Anoxia, pubmed-meshheading:15059791-Cell Nucleus, pubmed-meshheading:15059791-Cytokines, pubmed-meshheading:15059791-Cytoplasm, pubmed-meshheading:15059791-Escherichia coli Infections, pubmed-meshheading:15059791-Glutathione, pubmed-meshheading:15059791-Glutathione Disulfide, pubmed-meshheading:15059791-I-kappa B Proteins, pubmed-meshheading:15059791-Liver, pubmed-meshheading:15059791-Male, pubmed-meshheading:15059791-NF-kappa B, pubmed-meshheading:15059791-Oxidation-Reduction, pubmed-meshheading:15059791-Oxidative Stress, pubmed-meshheading:15059791-Rats, pubmed-meshheading:15059791-Rats, Sprague-Dawley, pubmed-meshheading:15059791-Reactive Oxygen Species, pubmed-meshheading:15059791-Signal Transduction, pubmed-meshheading:15059791-Transcription, Genetic, pubmed-meshheading:15059791-Transcription Factor AP-1, pubmed-meshheading:15059791-Xanthine Oxidase

Hypoxic suppression of E. coli-induced NF-kappa B and AP-1 transactivation by oxyradical signaling.

Journal Article, Research Support, U.S. Gov't, P.H.S.