INFLAMMATORY INJURY OF LUNG ALVEOLAR EPITHELIAL CELLS

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The alveolar injury that occurs in the adult respiratory distress syndrome (ARDS) appears in many cases to be secondary to activation of inflammatory processes, particularly those involving neutrophils and/or oxygen metabolites. Injury of alveolar epithelial cells has been found to be a prominent, early feature of ARDS. Because the integrity of the alveolar epithelium is critical in preventing fluid from accumulating within the alveolar compartment, and because the alveolar epithelium has received relatively little study compared to the vascular endothelium, this proposal contains experiments designed to study the mechanisms by which stimulated neutrophils and/or oxygen metabolites can injure lung epithelial cells. The hypotheses are: that abberations in ATP metabolism are intimately involved in the process of injury; that the susceptibility of target cells to neutrophil-induced injury is dependent upon their ability to detoxify oxidants; and that epithelial cell membrane injury is a prominent, early feature of neutrophil-induced injury. to test these hypotheses, we will expose cultured rat pulmonary alveolar epithelial cells. (and for comparison bovine pulmonary artery endothelial cells) to stimulated human neutrophils and/or exogenous oxygen metabolites. We will concurrently measure cytotoxicity, concentrations of ATP and related compounds, the activities of intracellular antioxidant systems, and specific membrane functions. The information will be used to construct a detailed pathway be which oxygen metabolites and stimulated neutrophils injure pulmonary alveolar epithelial cells. The information gained will provide an improved understanding of inflammatory damage to alveolar epithelium and should assist in developing treatments designed to reduce the lung injury in ARDS.