Diethylmaleate attenuates endotoxin-induced lung injury

A. B. Nathens, J. C. Marshall, R. W G Watson, A. P B Dackiw, O. D. Rotstein

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Background. Alterations in the cellular redox state play a critical role in cell signaling and cell activation, suggesting that administration of sulfhydryl-reactive agents may have important modulatory effects on the inflammatocy response. We postulated that intracellular thiol depletion may attenuate the pulmonary inflammatory response after intratracheal administration of endotoxin (LPS) and that this attenuation would supersede the reduction in antioxidant defenses associated with depletion of the endogenous antioxidant, glutathione. Methods. Sprague Dawley rats were administered diethylmaleate (6 mmol/kg intraperitoneally), a rapidly acting glutathione-depleting agent, followed by intratracheal administration of LPS. Lung injury was assessed by measuring the transpulmonary flux of 125-I albumin and expressed as a permeability index. Results. Administration of diethylmaleate reduced lung glutathione levels from 1310 ± 114 to 185 ± 48 nmol/gm. This was associated with a reduction in the permeability index after LPS treatment (LPS, 0.22 ± 0.03 versus LPS + diethylmaleate, 0.03 ± 0.01). Bronchoalveolar lavage fluid polymorphonuclear neutrophil counts were markedly reduced in animals pretreated with diethylmaleate (LPS, 90.5 ± 24 x 106 versus LPS + diethylmaleate, 1.9 ± 0.4 x 106). Peripheral blood polymorphonuclear neutrophils isolated from animals treated with diethylmaleate had equivalent chemotactic responses to n-formyl-methionyl-leucyl-phenylalanine and normal up-regulation of CD11b as determined by flow cytometry. Levels of bronchoalveolar lavage fluid tumor necrosis factor-α were unaffected. Conclusions. Diethylmaleate attenuates LPS-induced lung injury through a reduction in lung polymorphonuclear neutrophil sequestration. Normal peripheral blood neutrophil chemotactic responses and CD11b expression suggest that thiol depletion might mediate this effect through inhibition of endothelial cell adhesion molecule activity.

Original languageEnglish (US)
Pages (from-to)360-366
Number of pages7
JournalSurgery
Volume120
Issue number2
DOIs
StatePublished - Jan 1 1996

ASJC Scopus subject areas

  • Surgery

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    Nathens, A. B., Marshall, J. C., Watson, R. W. G., Dackiw, A. P. B., & Rotstein, O. D. (1996). Diethylmaleate attenuates endotoxin-induced lung injury. Surgery, 120(2), 360-366. https://doi.org/10.1016/S0039-6060(96)80310-2