title: Differential Relevance of NF-κB and JNK in the Pathophysiology of Hemorrhage/Resususcitation-Induced Liver Injury after Chronic Ethanol Feeding.
abstract: BACKGROUND
  Chronic ethanol (EtOH) abuse worsens pathophysiological derangements after hemorrhagic shock and resuscitation (H/R) that induce hepatic injury and strong inflammatory changes via JNK and NF-κB activation. Inhibiting JNK with a cell-penetrating, protease-resistant peptide D-JNKI-1 after H/R in mice with healthy livers ameliorated these effects. Here, we studied if JNK inhibition by D-JNKI-1 in chronically EtOH-fed mice after hemorrhagic shock prior to the onset of resuscitation also confers protection.
  
  
  METHODS
  Male mice were fed a Lieber-DeCarli diet containing EtOH or an isocaloric control (ctrl) diet for 4 weeks. Animals were hemorrhaged for 90 min (32 ± 2 mm Hg) and randomly received either D-JNKI-1 (11 mg/kg, intraperitoneally, i. p.) or sterile saline as vehicle (veh) immediately before the onset of resuscitation. Sham animals underwent surgical procedures without H/R and were either D-JNKI-1 or veh treated. Two hours after resuscitation, blood samples and liver tissue were harvested.
  
  
  RESULTS
  H/R induced hepatic injury with increased systemic interleukin (IL)-6 levels, and enhanced local gene expression of NF-κB-controlled genes such as intercellular adhesion molecule (ICAM)-1 and matrix metallopeptidase (MMP)9. c-Jun and NF-κB phosphorylation were increased after H/R. These effects were further increased in EtOH-fed mice after H/R. D-JNKI-1 application inhibited the proinflammatory changes and reduced significantly hepatic injury after H/R in ctrl-fed mice. Moreover, D-JNKI-1 reduces in ctrl-fed mice the H/R-induced c-Jun and NF-κB phosphorylation. However, in chronically EtOH-fed mice, JNK inhibition did not prevent the H/R-induced hepatic damage and proinflammatory changes nor c-Jun and NF-κB phosphorylation after H/R.
  
  
  CONCLUSIONS
  These results indicate, that JNK inhibition is protective only in not pre-harmed liver after H/R. In contrast, the pronounced H/R-induced liver damage in mice being chronically fed with ethanol cannot be prevented by JNK inhibition after H/R and seems to be under the control of NF-κB.
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
authors.forename: Borna
authors.initials: B
authors.lastname: Relja
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
authors.forename: Roxane
authors.initials: R
authors.lastname: Weber
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Maraslioglu
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Wagner
authors.affiliation: Neuronal Death and Neuroprotection Unit, Instituto Di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Borsello
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Marzi
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Lehnert
mesh_terms: D000437:Alcoholism / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000097:blood; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D012151:Resuscitation / Q000009:adverse effects* / Q000379:methods; D012771:Shock, Hemorrhagic / Q000378:metabolism / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D000431:Ethanol; D048670:MAP Kinase Kinase 4; C478085:D-JNKI-1