title: Hypoxic suppression of E. coli-induced NF-kappa B and AP-1 transactivation by oxyradical signaling.
abstract: 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.
authors.affiliation: Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Internal Medicine, St. Louis University School of Medicine, and Department of Critical Care Medicine, St. John's Mercy Medical Center, St. Louis, Missouri, USA. Matuscgm@slu.edu
authors.forename: George M
authors.initials: GM
authors.lastname: Matuschak
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lechner
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.forename: Subhash
authors.initials: S
authors.lastname: Todi
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Doyle
authors.forename: Laura L
authors.initials: LL
authors.lastname: Loftis
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000503:physiopathology; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D020672:I-kappa B Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D000072000:NF-KappaB Inhibitor alpha; D014969:Xanthine Oxidase; D005978:Glutathione; D019803:Glutathione Disulfide