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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.080857

Accepted for publication January 22, 2009.

Article

Reactive Oxygen Species Mediate Liver Injury Through Parenchymal Nuclear Factor-{kappa}B Inactivation in Prolonged Ischemia/Reperfusion

Laura Llacuna, Montserrat Marí, Josep M. Lluis, Carmen García-Ruiz, José C. Fernández-Checa@, and Albert Morales@

From the Liver Unit, Hospital Clinic, Instituto de Investigaciones Biomédicas August Pi i Sunyer - Centro Investigaciones Biomédicas Esther Koplowitz, Centro de Investigacion Biomédicas en Red en enfermedades hepáticas y digestivas, and the Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona Consejo Superior de Investigaciones Cientificas, Barcelona, Spain

@ To whom correspondence should be addressed. E-mail: checa229{at}yahoo.com.


  Abstract

Nuclear factor (NF)-{kappa}B participates in ischemia/reperfusion (I/R) hepatic signaling, stimulating both protective mechanisms and the generation of inflammatory cytokines. After analyzing NF-{kappa}B activation during increasing times of ischemia in murine I/R, we observed that the nuclear translocation of p65 paralleled Src and I{kappa}B tyrosine phosphorylation, which peaked after 60 minutes of ischemia. After extended ischemic periods (90 to 120 minutes) however, nuclear p65 levels were inversely correlated with the progressive induction of oxidative stress. Despite this profile of NF-{kappa}B activation, inflammatory genes, such as tumor necrosis factor (TNF) and interleukin (IL)-1{beta}, predominantly induced by Kupffer cells, increased throughout time during ischemia (30 to 120 minutes), whereas protective NF-{kappa}B-dependent genes, such as manganese superoxide dismutase (Mn-SOD), expressed in parenchymal cells, decreased. Consistent with this behavior, gadolinium chloride pretreatment abolished TNF/IL-1{beta} up-regulation during ischemia without affecting Mn-SOD levels. Interestingly, specific glutathione (GSH) up-regulation in hepatocytes by S-adenosylmethionine increased Mn-SOD expression and protected against I/R-mediated liver injury despite TNF/IL-1{beta} induction. Similar protection was achieved by administration of the SOD mimetic MnTBAP. In contrast, indiscriminate hepatic GSH depletion by buthionine-sulfoximine before I/R potentiated oxidative stress and decreased both nuclear p65 and Mn-SOD expression levels, increasing TNF/IL-1{beta} up-regulation and I/R-induced liver damage. Thus, the divergent role of NF-{kappa}B activation in selective liver cell populations underlies the dichotomy of NF-{kappa}B in hepatic I/R injury, illustrating the relevance of specifically maintaining NF-{kappa}B activation in parenchymal cells.






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Copyright © 2009 by the American Society for Investigative Pathology.