Alterations in the cellular redox state play a critical role in cell signaling a nd cell activation, suggesting that administration of sulflhydryl-reactive agents h ave important modulatory effects on the inflammatory response. Intracellular thiol depletion attenuates the pulmonary inflammatory response following intratracheal administration of endotoxin (LPS), and this attenuation supersedes the reduction in antioxidant defenses associated with depletion of the endogenous antioxidant, glutathione (GSH). Sprague Dawley rats were administered diethylmaleate (DEM, 6 mmole/kg), a rapidly acting GSH-depleting agent, followed by intratracheal administration of LPS. Lung injury was assessed by measuring the transpulmonary flux of 125l albumin and expressed as a permeability index (Pl). Administration of DEM reduced lung GSH levels from 1310~114 to 185~48 nmoles/g. This was associated with a reduction in the Pl following LPS treatment (LPS: 0.22~0.03 vs LPS+DEM: 0.03~0.01). Bronchoalveolar lavage fluid PMN counts were markedly reduced in animals pretreated with DEM (LPS: 90.5~24x106 vs LPS+DEM: 1 .9~0.4x106). The reduction in lung neutrophil sequestration was not due to an effect on the neutrophil, as peripheral blood PMN isolated from DEM-treated anim als had equivalent chemotactic responses to fMLP, and normal upregulation of CD11b. DEM pretreatment mitigated LPS induced upregulation of lung lCAM-1 protein and mRNA expression as demonstrated by immunohistochemistry and Northern analysis, respectively. DEM attenuates LPS-induced lung injury by preventing lun g PMN sequestration. This effect appears to be mediated through abrogation of endothelial lCAM-1 upregulation in response to LPS. These data suggest that intracellular thiols modulate lCAM-1 expression.
ANTI-INFLAMMATORY AGENT