Glutathione depletion prevents lipopolysaccharide-induced local skin inflammation
J. J. Jones, I. D. McGilvray, A. B. Nathens, R. Bitar and O. D. Rotstein
Department of Surgery, Toronto Hospital, Ontario.
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. DESIGN: Swiss Webster mice were injected with
intradermal LPS (30 micrograms) 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 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.
