Redox manipulation using the thiol-oxidizing agent diethyl maleate prevents hepatocellular necrosis and apoptosis in a rodent endotoxemia model

Manipulation of the intracellular redox state has been shown to alter cell activation pathways with resultant changes in cellular function. Previous s tudies have suggested that thiol oxidation, using the glutathione-depleting agent diethyl maleate (DEM), was able to inhibit endothelial cell activati on. We hypothesized that this agent might exert beneficial effects followin g endotoxemia in the rat, a model in which transendothelial migration of ne utrophils is central to the development of hepatocellular injury. Sprague-D awley rats treated intraperitoneally with lipopolysaccharide (LPS) (200 mu g/kg) plus D-galactosamine (GalN) (600 mg/kg) developed hepatocellular necr osis, as evidenced by liver enzyme release and morphological changes. Pretr eatment with DEM abrogated this injury in a dose-dependent fashion. Histolo gy revealed reduced neutrophil accumulation in both the parenchyma and sinu soids, consistent with reduced neutrophil sequestration and transendothelia l migration. This effect appeared to be related to the ability of DEM to pr event LPS-induced up-regulation of both vascular cell adhesion molecule-1 ( VCAM-1) mRNA and intercellular adhesion molecule-1 (ICAM-1) mRNA in the liv er, as well as reducing tumor necrosis factor (TNF) mRNA expression. In add ition, DEM prevented hepatocyte apoptosis following LPS treatment. The effe ct was reproduced when TNF was used as an inflammatory stimulus, suggesting a direct protective effect on the hepatocyte. Taken together, these studie s show that redox manipulation through thiol oxidation may represent a nove l approach to preventing liver necrosis and apoptosis in inflammatory condi tions.