Aims: 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.
Main 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.
Key findings: 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.
Significance: Despite its moderate hepatocellular toxicity, the ameliorated stress-induced hepatic reactions provided by GdCl₃ may contribute to its protective effects.
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