lactoferrin and Liver-Failure--Acute

Polyethylene glycol (PEG) is attached to proteins in order to increase their half-life in circulation and reduce their immunogenicity in vivo. The present study was conducted to examine whether two different sizes of PEGylated bovine lactoferrin (40k- and 20k-PEG-bLf) would enhance the protective effect of native bLf on liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in rats. The treatment of PEGylated bLf more remarkably prevented the elevation of serum levels of hepatic enzyme markers and inhibited inflammatory and hemorrhagic changes and hepatic apoptosis induced by GalN/LPS than native bLf. The treatment of PEGylated bLf more significantly inhibited the increased concentration of proinflammatory cytokines (TNF-alpha and IL-6) in serum caused by GaIN/LPS, and enhanced anti-inflammatory cytokine (IL-10) production more than native bLf. PEGylated bLf decreased serum levels of nitric oxide (NO) more than native bLf. These results indicate that PEGylated bLf inhibits more significantly the induction of inflammatory mediators such as cytokines and NO than native bLf, resulting in the enhancement of its prevention of fulminant liver failure induced by GalN/LPS in rats. The present study provided evidence that PEGylated bLf may offer a novel alternative therapy for the prevention of acute hepatic failure through its anti-inflammatory and immunomodulatory properties.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cytokines; Disease Models, Animal; Galactosamine; Histocytochemistry; Lactoferrin; Lipopolysaccharides; Liver Failure, Acute; Male; Nitric Oxide; Pilot Projects; Polyethylene Glycols; Rats; Rats, Wistar

To assess the effect of lactoferrin on oxidative liver damage and its mechanism, we used Long-Evans Cinnamon (LEC) rats that spontaneously develop fulminant-like hepatitis and lethal hepatic failure.. Four-week-old female LEC rats were divided into the untreated and treated groups. The latter was fed bovine lactoferrin at 2% mixed with conventional diet.. The cumulative survival rates were 75.0% vs. 100% at 14 weeks, 37.5% vs. 91.7% at 15 weeks, and 12.5% vs. 91.7% at 16 weeks, respectively, for untreated and treated rats (P=0.0008). The 8-OHdG levels in liver mitochondrial DNA and malondialdehyde in plasma and liver tissues were significantly lower in treated than untreated rats (P<0.001, =0.017 and 0.034, respectively). Mitochondrial DNA mutations were more common in untreated rats. OGG1 mRNA and protein expression levels were significantly lower in untreated than treated rats (P=0.003 and 0.007, respectively). Hypermethylation of the second CpG island located upstream of OGG1 gene was observed in untreated rats.. Our findings indicated that lactoferrin inhibits oxidative liver damage in LEC rats. Lactoferrin could be potentially useful for the treatment of oxidative stress-induced liver diseases.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Caspase 3; Cattle; CpG Islands; Deoxyguanosine; Disease Models, Animal; DNA Damage; DNA Glycosylases; DNA Methylation; DNA Repair; DNA, Mitochondrial; Down-Regulation; Female; Hepatitis; Lactoferrin; Liver; Liver Failure, Acute; Malondialdehyde; Mitochondria, Liver; Rats; Rats, Inbred LEC