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 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 microg/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.
Jones
J J
JJ
Department of Surgery, The Toronto General Hospital, and the University of Toronto, Toronto, Ontario, Canada.
Fan
J
J
Nathens
A B
AB
Kapus
A
A
Shekhman
M
M
Marshall
J C
JC
Parodo
J
J
Rotstein
O D
OD
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
D008298:Maleates; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000410:Alanine Transaminase; C014476:diethyl maleate; D005978:Glutathione