title: Antioxidant defense in hepatic ischemia-reperfusion injury is regulated by damage-associated molecular pattern signal molecules.
abstract: 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.
authors.affiliation: Institute of Biochemistry, Food Science, and Nutrition, Faculty of Agricultural, Food, and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Pardo
authors.forename: Noga
authors.initials: N
authors.lastname: Budick-Harmelin
authors.forename: Boaz
authors.initials: B
authors.lastname: Tirosh
authors.forename: Oren
authors.initials: O
authors.lastname: Tirosh
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western; D024243:HMGB1 Protein / Q000378:metabolism; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000293:injuries / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism*; D014527:Uric Acid / Q000378:metabolism
chemical_list: D000975:Antioxidants; D024243:HMGB1 Protein; D017382:Reactive Oxygen Species; D014527:Uric Acid; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase