This represents an extension of our prior four year study into mechanisms of lung injury caused by generation in phagocytic cells of oxygen radicals. Based on our published (observatrions) and recent preliminary data, we plan to investigate five separate but related areas: 1. Defining the role of complement activation products not only on effector cells (neutrophils) but also on target (endothelial) cells; 2. Studying further the source and the role iron required in oxygen radical-mediated injury of endothelial cells and the lung microvasculature; 3. Exploring the biochemical events related to endothelial injury by activated neutrophils or H- 2-0-2; 4. Determining the source(s) of eicosanoids appearing during the cause of complement dependent and oxygen radical mediated lung injury; and 5. Pursuing preliminary evidence that the peptides IL-1 and tumor necrosis factor facilitate oxygen radical mediated lung injury by enhancement of oxygen radical generation from phagocytes and generation of relevant of mRNA's. For those experiments, we will use a variety of in vivo, ex vivo and in vitro techniques. We anticipate these studies will significantly extend our understanding of mediator events involved in the induction of acute lung injury caused by toxic oxygen products from phagocytic cells.
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