Effects of hepatocellular iron imbalance on nitric oxide and reactive oxygen intermediates production in a model of sepsis.
OBJECTIVE
In mammals iron homeostasis is most important, as imbalance of iron such as iron overload may lead to severe diseases. Recently, it has been shown that the iron regulatory protein-1 is partially controlled by nitric oxide and reactive oxygen intermediates, molecules frequently seen in inflammatory events. The aim of the present study was to investigate the effects of impaired iron homeostasis on the interaction of nitric oxide, and reactive oxygen intermediate formation in hepatocytes in a model of acute inflammation.


METHODS
Hepatocytes isolated from Corynebacterium parvum (C parvum)-injected rats were used to examine the formation of nitrogen and oxygen intermediates by iron deprivation and iron overload in the presence of lipopolysaccharide. In addition, we investigated the RNA binding and aconitase activity of iron regulatory protein-1.


RESULTS
In the present study we show that iron overload in lipopolysaccharide-treated C. parvum-primed hepatocytes downregulated the RNA binding of iron regulatory protein-1 and aconitase activity. Subsequently, we observed a reduced formation of nitrite/nitrate and S-nitrosothiols but an increased production of reactive oxygen species, and hepatocellular damage. Moreover, the addition of iron to cell cultures caused a further increase in cellular damage, a drop in the cellular glutathione pool, and an increase in peroxynitrite and hydroxyl-like radicals. In contrast, addition of deferoxamine (an iron chelator) to lipopolysaccharide-treated C. parvum-primed hepatocytes protected cells by stabilizing the GSH content, maintaining the nitric oxide formation, and by reducing Fenton oxidants.


CONCLUSIONS
Our results show that the antioxidative effects of iron chelators prevent the formation of toxic Fenton oxidants in severe inflammatory events, which should be considered in the treatment of disorders characterized by an iron imbalance.
Jung
M
M
Department of General Surgery, University of Ulm, Germany.
Drapier
J C
JC
Weidenbach
H
H
Renia
L
L
Oliveira
L
L
Wang
A
A
Beger
H G
HG
Nussler
A K
AK
D000818:Animals; D005978:Glutathione / Q000378:metabolism; D016908:Gram-Positive Bacterial Infections / Q000378:metabolism* / Q000473:pathology; D006524:Hepatitis, Viral, Animal / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D017665:Hydroxyl Radical / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D009574:Nitro Compounds / Q000378:metabolism; D011425:Propionibacterium acnes; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D009566:Nitrates; D009573:Nitrites; D009574:Nitro Compounds; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D013481:Superoxides; C039642:peroxynitric acid; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D007501:Iron; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005978:Glutathione