The aim of this project will be to utilized chemical modification and molecular biological techniques to create new variants of superoxide dismutase (SOD) which have much more attractive pharmacological properties than native human SODs. While SOD is dramatically protective in number of laboratory models involving inflammation and/or reperfusion injury, its unfavorable clearance time, slow interstitial equilibration, and inability to approach or bind to cell surfaces have rendered most clinical trials marginally successful, at best. There is much evidence to support the use of a better behaved SOD to treat inflammatory injury the lung, specifically, the adult respiratory distress syndrome (ARDS). Structural variants of SOD with optimized properties of size, charge, and heparin-binding affinities will be tested in models of neutrophil- mediated lung injury, as well as in other models of inflammation, reperfusion injury, and oxidant injury to cultured or isolated cells. It is not known whether a single SOD variant will display optimal properties against different oxidative insults (e.g., inflammation vs. reperfusion v. hyperoxia) to different tissues or cell types (e.g., lung vs. myocardium, vs. neutrophils vs. HeLa cells), or whether SODs must be """"""""tailored"""""""" to a specific application. As a clinical correlate, we will also attempt to determine whether natural levels of extracellular SODs A, B, and C (which have increasing tendencies to bind to endothelial surfaces) are perturbed in ARDS patients, either as a sequela (due to increased plasma protease activity) or as a predisposing genetic factor.
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