Toxic O2 metabolites from recruited neutrophils and damaged lung endothelial cells appear to be key contributing features in the development of acute edematous lung injury (ARDS, O2 toxicity). Our recent evidence suggests that erythrocytes (RBC) can decrease O2 metabolite induced acute edematous injury to isolated lungs and damage to lung endothelial cells. Other investigators have found that intratracheal RBC can decrease pulmonary O2 toxicity in vivo. In all experiments, RBC protection appears to involve scavenging of O2 metabolites by intracellular RBC antioxidants, most likely glutathione. These novel and provocative findings have led us to hypothesize that RBC antioxidants can modify and/or predict susceptibility to O2 metabolite induced lung injury. Our goals now are to test this hypothesis using parallel experiments with enzymatically (xanthine oxidase) or stimulated neutrophil generated O2 metabolites to determine the effect of normal or antioxidant modified RBC in in vitro, microvascular lung endothelial cell culture, isolated perfused lung and intact animal models. Our immediate specific aims are: - To determine the effect of RBC antioxidant activities on xanthine oxidase or stimulated neutrophil generated O2 metabolites in vitro (Objective One). - To determine the effect of RBC antioxidant activities on xanthine oxidase or stimulated neutrophil induced injury to cultured lung endothelial cell monolayers (Objective Two) and isolated perfused lungs (Objective Three). - To determine if exposure of RBC to hyperoxia in vitro (Objective Four) or in vivo (Objective Five) alters RBC antioxidant activities and/or the related ability of RBC to modify O2 metabolite concentrations in vitro and O2 metabolite induced injury to cultured endothelial cell monolayers and isolated perfused lungs. These investigations will begin to identify the significance of RBC antioxidants in neutrophil and/or O2 metabolite mediated disorders. This research will also provide new information which will enhance our basic understanding, possibly provide needed markers of susceptibility and perhaps suggest potential therapeutic maneuvers for decreasing lung and other disorders mediated by O2 metabolites.
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