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Departments of Surgery and Medicine, University of Toronto, and the Toronto Hospital, Toronto, Canada
The intracellular redox state regulates several aspects of cell
function, suggesting that strategies directed toward altering the
cellular redox state may modulate cell activation in inflammatory
states. As the most abundant intracellular thiol, glutathione plays a
critical role as an intracellular redox buffer. Using diethylmaleate
(DEM) as a glutathione-depleting agent, we evaluated the effects of GSH
depletion in a rodent model of polymorphonuclear neutrophil
(PMN)-dependent acute lung injury. Rats received 500 µg of LPS by
intratracheal challenge, inducing a 5.5-fold increase in lung
permeability and sixfold increase in lung PMN content. Pretreatment
with DEM prevented the LPS-induced increase in lung PMN influx and lung
permeability. Northern analysis and immunohistochemical studies suggest
that this effect may be mediated by preventing up-regulation of lung
ICAM-1 mRNA and protein expression. This effect is specific to ICAM-1,
because lung cytokine-induced neutrophil chemoattractant and TNF-
mRNA levels are unaffected. This finding is not unique to the lung,
because a similar effect on PMN influx was recapitulated in a rodent
model of chemical peritonitis. Further, in vitro studies demonstrated
that pretreatment of HUVEC monolayers with DEM prevented both ICAM-1
up-regulation and PMN transendothelial migration. These data indicate
the presence of a thiol-sensitive mechanism for modulating ICAM-1 gene
expression and suggest a potential novel therapeutic strategy for
diseases characterized by PMN-mediated tissue injury.
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