Glutathione depletion prevents lipopolysaccharide-induced local skin inflammation.
BACKGROUND
We have previously shown that the thiol-oxidizing agent diethyl maleate prevents lipopolysaccharide (LPS)-induced up-regulation of endothelial cell intercellular adhesion molecule-1 (ICAM-1) in vitro.


OBJECTIVE
To determine the effect of glutathione depletion on the development of local skin inflammation in vivo, a model known to be dependent on ICAM-1.


METHODS
Swiss Webster mice were injected with intradermal LPS (30 micrograms) or isotonic saline solution.


METHODS
Mice were pretreated for 1 hour with intraperitoneal diethyl maleate (6 mmol/kg) or corn oil vehicle.


METHODS
Injection sites were harvested after 12 and 24 hours and evaluated for changes in vascular permeability and histological characteristics. To determine the mechanism underlying our findings, we evaluated skin ICAM-1 immunohistochemistry, levels of ICAM-1 protein and messenger RNA (mRNA), and neutrophil CD11b expression at the 24-hour point.


RESULTS
Diethyl maleate significantly decreased the skin permeability index in a dose-dependent fashion at 24 hours but not at 12 hours. Skin histological examination under light microscopy showed a marked LPS-induced neutrophil infiltration at 24 hours, which was inhibited with diethyl maleate pretreatment. Immunohistochemical examination showed that diethyl maleate reduced ICAM-1 expression. In keeping with the hypothesized mechanism, diethyl maleate attenuated the LPS-induced up-regulation of ICAM-1 mRNA by 44%. Diethyl maleate also slightly but insignificantly reduced CD11b expression in vivo.


CONCLUSIONS
Diethyl maleate markedly attenuates LPS-induced dermal inflammation, primarily through a reduction in ICAM-1 protein and mRNA expression. These data suggest that manipulation of the intracellular redox state may have a beneficial role in neutrophil-mediated inflammation.
Jones
J J
JJ
Department of Surgery, Toronto Hospital, Ontario.
McGilvray
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Nathens
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Bitar
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Rotstein
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OD
D000818:Animals; D018845:CD11 Antigens / Q000096:biosynthesis; D003872:Dermatitis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D004926:Escherichia coli; D005978:Glutathione / Q000037:antagonists & inhibitors*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology*; D008298:Maleates / Q000494:pharmacology; D051379:Mice
D018845:CD11 Antigens; D008070:Lipopolysaccharides; D008298:Maleates; D018799:Intercellular Adhesion Molecule-1; C014476:diethyl maleate; D005978:Glutathione