Accumulation of neutrophils in the lung and injury to lung vascular endothelial cells appear to be key contributing features in acute edematous lung injury seen in the Adult Respiratory Distress Syndrome (ARDS) and pulmonary O2 toxicity. Recent evidence suggests that neutrophil-derived toxic O2 metabolites (O2 radicals) may cause endothelial cell injury and acute edematous lung injury. It also appears that increasing antioxidant defenses O2 radical scavengers) can prevent lung injury from O2 radicals. However, a fundamental problem has arisen because the important concept that O2 radicals cause acute edematous lung injury remains suspect because it has not been definitively shown using direct measurement of O2 radicals in biological systems (in vivo). In addition, without direct measurements of O2 radicals in vivo, the mechanism of purported O2 radical scavengers or other interventions which could decrease lung injury cannot be determined. Fortunately, our extensive, preliminary studies now indicate that measurement of the disappearance of small, non-toxic, non-protecting doses of the O2 radical scavenger, dimethylthiourea (DMTU) can be used to assess O2 radical concentrations in vivo and to determine the mechanism of action of O2 radical scavengers or other interventions. Accordingly, we have hypothesized that the new technique of measuring DMTU disappearance can be used 1) to clearly document that O2 radicals cause lung endothelial cell injury and acute endematous injury in vivo, and (2) to determine if proposed interventions act by scavenging O2 radicals in vivo. Our immediate goals are to determine: (1) if chemically generated O2 radicals or phorbol myristate acetate (PMA)-stimulated neutrophils cause DMTU disappearance, (2) if DMTU disappearance reflects concentrations of O2 radicals and O2 radical mediated injury and/or edema, and (3) if O2 radical scavengers, such as erythrocytes, polyethylene-glycol conjugated superoxide dismutase and catalase, DMSO or mannitol, act by scavenging O2 radicals as indicated by their ability to similarly decrease injury and DMTU disappearance. We will pursue our goals in parallel in vitro, lung endothelial cell culture, isolated perfused lung and intact animal studies. The significance of our studies is that the contribution of O2 radicals to acute edematous lung injury will be more clearly defined and that our basic understanding of lung, cardiovascular and other disorders involving neutrophils, O2 radicals or vascular endothelium will be improved.
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