Premium
Redox manipulation using the thiol‐oxidizing agent diethyl maleate prevents hepatocellular necrosis and apoptosis in a rodent endotoxemia model
Author(s) -
Jones Julia J.,
Fan Jie,
Nathens Avery B.,
Kapus Andras,
Shekhman Mark,
Marshall John C.,
Parodo Jean,
Rotstein Ori D.
Publication year - 1999
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510300324
Subject(s) - hepatocyte , tumor necrosis factor alpha , necrosis , apoptosis , vcam 1 , intracellular , cell adhesion , chemistry , liver injury , intercellular adhesion molecule 1 , cell adhesion molecule , pharmacology , oxidative stress , lipopolysaccharide , microbiology and biotechnology , biology , cell , biochemistry , immunology , medicine , in vitro
Manipulation of the intracellular redox state has been shown to alter cell activation pathways with resultant changes in cellular function. Previous studies have suggested that thiol oxidation, using the glutathione‐depleting agent diethyl maleate (DEM), was able to inhibit endothelial cell activation. We hypothesized that this agent might exert beneficial effects following endotoxemia in the rat, a model in which transendothelial migration of neutrophils is central to the development of hepatocellular injury. Sprague‐Dawley rats treated intraperitoneally with lipopolysaccharide (LPS) (200 μg/kg) plus d ‐galactosamine (GalN) (600 mg/kg) developed hepatocellular necrosis, as evidenced by liver enzyme release and morphological changes. Pretreatment with DEM abrogated this injury in a dose‐dependent fashion. Histology revealed reduced neutrophil accumulation in both the parenchyma and sinusoids, consistent with reduced neutrophil sequestration and transendothelial migration. This effect appeared to be related to the ability of DEM to prevent LPS‐induced up‐regulation of both vascular cell adhesion molecule‐1 (VCAM‐1) mRNA and intercellular adhesion molecule‐1 (ICAM‐1) mRNA in the liver, as well as reducing tumor necrosis factor (TNF) mRNA expression. In addition, DEM prevented hepatocyte apoptosis following LPS treatment. The effect was reproduced when TNF was used as an inflammatory stimulus, suggesting a direct protective effect on the hepatocyte. Taken together, these studies show that redox manipulation through thiol oxidation may represent a novel approach to preventing liver necrosis and apoptosis in inflammatory conditions.