The participation of leukocytic proteases and oxidants in the production of inflammatory injury of tissues will be examined. The presence of these effectors and the consequences of their activity will be related to injury developing in two experimental models of inflammatory disease. These are (1) the in vitro, perfused rabbit lung, in which known oxidants and proteases, or stimulated human neutrophils will be perfused through the vasculature, and (2) whole animals (rabbits and rhesus monkeys), in which leukocytic stimuli given intrabronchially induce acute and subacute-chronic inflammation. We presume that these models relate basically to the organ failure seen after trauma. Proteases and their inhibitors will be quantitatively measured in situ by assays of activity and protein (ELISA methods). Oxidants will be monitored biochemically as described in the proposal. Alterations of targets of protease and oxidants in the tissues will be assessed, including release or cleavage of tissue (cellular) fibronectin and laminin into the soluble phase, and strand breaks of DNA and depletion of NAD in cells, reflecting exposure to oxidants. In relationship to diminished pulmonary function of the lung associated with inflammation, alterations in surfactant will be analyzed. In particular, the effect of changes in the apoprotein will be defined. Replacement of surfactant will be attempted in experimental models to determine its effect on the atelectasis observed in inflammatory lung disease.
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