Document Detail

Antioxidant defense in hepatic ischemia-reperfusion injury is regulated by damage-associated molecular pattern signal molecules.
MedLine Citation:
PMID:  18675899     Owner:  NLM     Status:  MEDLINE    
Hepatic ischemia-reperfusion (I/R) injury occurs in a variety of clinical settings and generates the release of endogenous noninfectious ligands called damage-associated molecular pattern (DAMP) signal molecules from damaged cells. This study investigates the effect of DAMP molecules released by Kupffer cells (KC) in I/R injury on the expression of liver manganese superoxide dismutase (MnSOD), a key mitochondrial antioxidant enzyme. We show that MnSOD expression levels are increased in rats and remain high for 24 h after 30 min of ischemia. KC were damaged and depleted after I/R, in association with MnSOD upregulation. Causality was established by treatment with gadolinium chloride, known to selectively destroy KC, which also increased MnSOD levels. Recovery from the early damage (6 h) to the liver tissue was evidenced after 24 h. A physiological protective role for MnSOD was also confirmed by the increased susceptibility of MnSOD-knockdown AML-12 hepatocyte cells to I/R-induced cell death. Inhibition of DAMP molecule high-mobility group box-1 activity by injection of neutralizing antibody partially abolished the increase in liver MnSOD after I/R. Direct injection of ATP, to animals or cells, stimulated MnSOD upregulation. Another DAMP molecule, monosodium urate, also induced MnSOD expression in hepatocyte AML-12 and FaO cell cultures. In conclusion, a connection between danger signals and upregulation of the antioxidant defense system is shown here for the first time in the context of I/R liver injury.
Michal Pardo; Noga Budick-Harmelin; Boaz Tirosh; Oren Tirosh
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-07-08
Journal Detail:
Title:  Free radical biology & medicine     Volume:  45     ISSN:  0891-5849     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-20     Completed Date:  2008-12-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1073-83     Citation Subset:  IM    
Institute of Biochemistry, Food Science, and Nutrition, Faculty of Agricultural, Food, and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
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MeSH Terms
Adenosine Triphosphate / metabolism
Antioxidants / metabolism*,  pharmacology
Blotting, Western
HMGB1 Protein / metabolism
Kupffer Cells / metabolism
Liver / injuries,  metabolism*
Rats, Sprague-Dawley
Reactive Oxygen Species / metabolism
Reperfusion Injury / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / physiology*
Superoxide Dismutase / metabolism*
Uric Acid / metabolism
Reg. No./Substance:
0/Antioxidants; 0/HMGB1 Protein; 0/Reactive Oxygen Species; 56-65-5/Adenosine Triphosphate; 69-93-2/Uric Acid; EC Dismutase

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