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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/G572    most recent 90435.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hong, J.-Y. Articles by Jaeschke, H. Search for Related Content PubMed PubMed Citation Articles by Hong, J.-Y. Articles by Jaeschke, H.

LIVER AND BILIARY TRACT

Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH₂-terminal kinase activation

¹Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; and ²Department of Pathology, Brackenridge Hospital, Austin, Texas

Submitted 15 July 2008 ; accepted in final form 5 January 2009

Oxidant stress is critically involved in various liver diseases. Superoxide formation causes c-Jun NH₂-terminal kinase (JNK)- and caspase-dependent apoptosis in cultured hepatocytes. To verify these findings in vivo, male Fisher rats were treated with diquat and menadione. The oxidant stress induced by both compounds was confirmed by increased formation of glutathione disulfide and 4-hydroxynonenal protein adducts. Plasma alanine aminotransferase activities increased from 46 ± 4 U/l in controls to 955 ± 90 U/l at 6 h after diquat treatment. Hematoxylin and eosin staining of liver sections revealed large areas of necrotic cells at 3 and 6 h. DNA strandbreaks, evaluated with the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, showed clusters of TUNEL-positive cells, where the staining was predominantly cytosolic and the cells were swollen, indicating oncotic necrosis. There was no significant increase in caspase-3 activities or relevant release of DNA fragments into the cytosol at any time between 0 and 6 h after diquat treatment. Despite the activation of JNK after high doses of diquat, the JNK inhibitor SP-600125 did not protect against diquat-induced necrosis. Menadione alone did not cause liver injury, but, in combination with phorone and FeSO₄, induced moderate oncotic necrosis. On the other hand, if animals were treated with galactosamine/endotoxin as positive control for apoptosis, caspase-3 activities were increased by 259%, the number of TUNEL-positive cells with apoptotic morphology was increased 103-fold, and DNA fragmentation was enhanced 6-fold. The data indicate that liver cell death initiated by diquat-induced superoxide formation in vivo is mediated predominantly by oncotic necrosis and is independent of JNK activation.

diquat; galactosamine; endotoxin; menadione; superoxide; mechanisms of cell death; caspases