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Glutathione Depletion Prevents Lipopolysaccharide-Induced Local Skin Inflammation

Julia J. Jones, MD; Ian D. McGilvray, MD; Avery B. Nathens, MD; Richard Bitar, MSc; Ori D. Rotstein, MD
Arch Surg. 1997;132(11):1165-1170. doi:10.1001/archsurg.1997.01430350015002.
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Background:  We have previously shown that the thioloxidizing 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.

Design:  Swiss Webster mice were injected with intradermal LPS (30 μg) or isotonic saline solution.

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

Main Outcome Measures:  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 LPSinduced 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.Arch Surg. 1997;132:1165-1170


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