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This Article Full Text Full Text (PDF) All Versions of this Article: 287/2/R437    most recent 00404.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Matuschak, G. M. Articles by Loftis, L. L. Search for Related Content PubMed PubMed Citation Articles by Matuschak, G. M. Articles by Loftis, L. L.

INFLAMMATION AND CYTOKINES

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

¹Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Internal Medicine, ²Department of Pharmacological and Physiological Science, and ³Division of Critical Care Medicine, Department of Pediatrics, St. Louis University School of Medicine, St. Louis 63104; and ⁴Department of Critical Care Medicine, St. John's Mercy Medical Center, St. Louis, Missouri 63141

Submitted 18 July 2003 ; accepted in final form 1 April 2004

Transactivation of the DNA-binding proteins nuclear factor-B (NF-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-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 PO₂, 40 ± 5 mmHg) followed by reoxygenation and infection with 10⁹ EC or 0.9% NaCl infusion. In H/R + EC livers, nuclear translocation of NF-B and AP-1 was unexpectedly reduced in gel shift assays vs. normoxic EC controls, as were perfusate TNF- and IL-1 levels. Preceding hypoxic stress paradoxically increased postbacteremic reduced-to-oxidized glutathione ratios plus nuclear localization of IB and phospho-IB, 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.

liver-lung interactions; complex systems; transcription networks; transcription factors; JunB; FosB; gram-negative bacteremia; posttraumatic sepsis; TNF-; IL-1; transcription protein/DNA array; gene regulation; reactive oxygen species; oxidation-reduction; antioxidants; multiple organ failure