Thiol-mediated regulation of ICAM-1 expression in endotoxin-induced acute lung injury

Avery B. Nathens, Richard Bitar, Ronald W G Watson, Thomas B. Issekutz, John C. Marshall, Alan P B Dackiw, Ori D. Rotstein

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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 six-fold 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-α 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.

Original languageEnglish (US)
Pages (from-to)2959-2966
Number of pages8
JournalJournal of Immunology
Volume160
Issue number6
StatePublished - Mar 15 1998

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Nathens, A. B., Bitar, R., Watson, R. W. G., Issekutz, T. B., Marshall, J. C., Dackiw, A. P. B., & Rotstein, O. D. (1998). Thiol-mediated regulation of ICAM-1 expression in endotoxin-induced acute lung injury. Journal of Immunology, 160(6), 2959-2966.