title: Inhibition of immune-mediated concanavalin a-induced liver damage by free-radical scavengers.
abstract: OBJECTIVE
  The aims of the present study were to elucidate whether oxidative stress has a role in Con A-induced hepatitis and to examine if antioxidants may protect against liver damage in this model.
  
  
  METHODS
  Hepatitis was induced in Balb/c mice by administration of Con A (18 mg/kg) to the tail vein. Liver enzymes and histology were determined 24 h after Con A injection. Tumor necrosis factor alpha (TNFalpha) and interleukin-10 (IL-10) levels were assayed 2 h after Con A injection. Hepatic malondialdehyde levels were measured at 1, 3, 8, 12, 18, and 24 h after Con A injection in order to examine the timing of free-radicals formation. Nuclear factor kappa B (NF-kappabeta) activation was determined by electrophoresis mobility shift assay (EMSA) 1 and 2 h after Con A injection. In separate experiments, mice were pretreated with either dimethylsulfoxide or dimethylthiourea before Con A inoculation. The antioxidant and NF-kappabeta inhibitor pyrrolidine dithiocarbamate (PDTC) was used as positive control.
  
  
  RESULTS
  Hepatic malondialdehyde levels increased 12, 18, and 24 h after Con A inoculation but not earlier. Serum levels of liver enzymes and TNFalpha, hepatic malondialdehyde, and protein carbonyls and the histologic necroinflammatory score were significantly reduced in the antioxidants-treated mice, while IL-10 levels were increased. Dimethylsulfoxide, dimethylthiourea, and PDTC inhibited oxidative stress, but only PDTC inhibited Con A-induced NF-kappaB activation.
  
  
  CONCLUSIONS
  Reactive oxygen species play a role in immune-mediated Con A-induced hepatitis probably secondary to immune-mediated liver damage. Scavenging of reactive oxygen species by antioxidants prevents hepatitis independently of NF-kappaB inhibition and may be a new therapeutic target in this experimental model.
authors.affiliation: Department of Gastroenterology, The E Wolfson Medical Center, Holon, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Shirin
authors.forename: Hussein
authors.initials: H
authors.lastname: Aeed
authors.forename: Avi
authors.initials: A
authors.lastname: Alin
authors.forename: Zipora
authors.initials: Z
authors.lastname: Matas
authors.forename: Michal
authors.initials: M
authors.lastname: Kirchner
authors.forename: Eli
authors.initials: E
authors.lastname: Brazowski
authors.forename: Ilana
authors.initials: I
authors.lastname: Goldiner
authors.forename: Rafael
authors.initials: R
authors.lastname: Bruck
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003208:Concanavalin A / Q000633:toxicity*; D004121:Dimethyl Sulfoxide / Q000627:therapeutic use; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011392:Proline / Q000031:analogs & derivatives / Q000627:therapeutic use; D013859:Thiocarbamates / Q000627:therapeutic use; D013890:Thiourea / Q000031:analogs & derivatives / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D016328:NF-kappa B; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D016753:Interleukin-10; C066229:prolinedithiocarbamate; D008315:Malondialdehyde; C038983:1,3-dimethylthiourea; D011392:Proline; D013890:Thiourea; D004121:Dimethyl Sulfoxide