Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Accumulation of neutrophils in the lung and injury to lung microvascular endothelial cells appear to be key contributing features in most forms of acute edematous lung injury, (ARDS and O2 toxicity). Recent evidence suggests that neutrophil-derived O2 radicals may cause endothelial cell injury and acute edematous lung injury and that O2 radical scavengers can prevent injury from O2 radicals. However, the important fundamental concept that O2 radicals can cause endothelial cell damage and acute edematous lung injury as well as the mechanism of purported O2 radical scavengers in vivo remains highly suspect because O2 radicals have not been measured in biological systems. We hypothesized that disappearance of an O2 radical scanvenger would indicate excess, potentially damaging O2 radicals in biological systems. Our preliminary studies supported this premise. We found that the highly permeable O2 radical scavenger, dimethylthiourea (DMTU) disappeared from cultures of endothelial cells or isolated perfused lungs in relation to both the added amount of H2O2 and the corresponding injury produced. Moreover, coaddition of O2 radical scavengers (catalase or RBC) decreased both H2O2 mediated DMTU disappearance and injury. In contrast to H2O2, DMTU disappearance did not occur when leukotrienes, elastase, trypsin, PAF or oleic acid were added to these systems.

Our immediate specific objectives now are to use a recently developed, more sensitive approach for measuring DMTU disappearance:

1. To determine if an how chemically-generated O2 radicals or stimulated neutrophils cause DMTU disappearance in in vitro, cultured lung microvascular endothelial cell monolayer and isolated perfused lung models of edematous lung injury.

2. To determine if and how DMTU disappearance correlates with the added amounts of O2 radical generating systems or stimulated neutrophils and/or corresponding degrees of endothelial and/or acute edematous injury seen in these in vitro models.

3. To determine if and how O2 radical scavengers decrease O2 radical and/or stimulated neutrophil mediated DMTU disappearance and/or injury in these models.

If proven in our models, DMTU disappearance, or this principle, will provide much needed measurement of O2 radicals and improve our basic understanding of mechanisms responsible for lung, cardiovascular, renal and other disorders which may involve interactions between neutrophils, O2 radicals and endothelium.
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