Diethylmaleate attenuates endotoxin-induced lung injury.
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 inflammatory 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 10(6) versus LPS + diethylmaleate, 1.9 +/- 0.4 x 10(6)). 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-alpha 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.
Nathens
A B
AB
Department of Surgery, Toronto Hospital Ontario, Canada.
Marshall
J C
JC
Watson
R W
RW
Dackiw
A P
AP
Rotstein
O D
OD
D000418:Albumins / Q000378:metabolism; D000818:Animals; D002196:Capillaries / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D004731:Endotoxins; D004926:Escherichia coli / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000098:blood supply / Q000166:cytology* / Q000276:immunology; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000276:immunology
D000418:Albumins; D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D008298:Maleates; C014476:diethyl maleate; D005978:Glutathione