title: Effects of Kupffer cell blockade on the hepatic expression of metallothionein and heme oxygenase genes in endotoxemic rats with obstructive jaundice.
abstract: OBJECTIVE
  Heme oxygenase (HO) and metallothionein (MT) genes are rapidly upregulated in the liver by pro-inflammatory cytokines and/or endotoxin as protection against cellular stress and inflammation. Gadolinium chloride (GdCl₃)-induced Kupffer cell blockade has beneficial consequences in endotoxemia following bile duct ligation. Herein we further characterized the effects of Kupffer cell inhibition on the activation of the antioxidant defense system (HO and MT gene expressions, and antioxidant enzyme activities) in response to endotoxemia and obstructive jaundice.
  
  
  METHODS
  The isoform-specific expression of MT and HO genes was assessed (RT-PCR) in rat livers following 3-day bile duct ligation, 2-h lipopolysaccharide treatment (1mg/kg) or their combination, with or without GdCl₃ pretreatment (10 mg/kg, 24h before endotoxin). Lipid peroxidation, DNA damage and hepatic antioxidant enzyme activities were also assessed.
  
  
  RESULTS
  All these challenges induced similar extents of DNA damage, whereas the lipid peroxidation increased only when endotoxemia was combined with biliary obstruction. The MT and HO mRNA levels displayed isoform-specific changes: those of MT-1 and HO-2 did not change appreciably, whereas those of MT-2 and HO-1 increased significantly in 2-h endotoxemia, with or without obstructive jaundice. Among the enzymes reflecting the endogenous protective mechanisms, the catalase and copper/zinc-superoxide dismutase levels decreased, while that of Mn-SOD slightly increased. Interestingly, GdCl₃ alone induced lipid peroxidation, DNA damage and MT-2 expression. In response to GdCl₃, HO-1 induction was significantly lower in each model.
  
  
  CONCLUSIONS
  Despite its moderate hepatocellular toxicity, the ameliorated stress-induced hepatic reactions provided by GdCl₃ may contribute to its protective effects.
authors.affiliation: Department of Surgery, University of Szeged, Szeged, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Abrahám
authors.forename: Edit
authors.initials: E
authors.lastname: Hermesz
authors.forename: Andrea
authors.initials: A
authors.lastname: Szabó
authors.forename: Agnes
authors.initials: A
authors.lastname: Ferencz
authors.forename: Zsanett
authors.initials: Z
authors.lastname: Jancsó
authors.forename: Erno
authors.initials: E
authors.lastname: Duda
authors.forename: Magdolna
authors.initials: M
authors.lastname: Abrahám
authors.forename: György
authors.initials: G
authors.lastname: Lázár
authors.forename: György
authors.initials: G
authors.lastname: Lázár
mesh_terms: D000818:Animals; D004249:DNA Damage; D019446:Endotoxemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis; D041781:Jaundice, Obstructive / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D007728:Kupffer Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis* / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000502:physiology
chemical_list: D007527:Isoenzymes; C491055:Mt2A protein, rat; D008668:Metallothionein; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C105245:heme oxygenase-2