The goals of the current proposal are to continue investigations into the role of proteinase inhibitors and their target enzymes in the development of lung disease. Focus will be made on determining the contribution of lung epithelial cells in synthesizing and secreting functional acute phase proteinase inhibitors for defense against tissue proteolysis in this by organ by neutrophil-derived proteinases. In this context, the specific aims of the grant involve a) an investigation of the properties of the epithelial cell-derived inhibitors and b) assessment of the effect on epithelial cells of various cytokines which are known to stimulate acute phase protein synthesis. Because the lung can easily be infected by a variety of bacterial and fungal organisms, many of which can release their own, uncontrolled proteolytic activities, experiments are also planned c) to examine the stability of cytokines involved in either acute phase protein synthesis or in neutrophil chemotaxis, after- treatment with non- host proteinases and d) to determine whether such enzymes can also degrade receptors for cytokines and chemotaxins on specific target cells. All of these results should give significant information as to whether locally synthesized proteinase inhibitors do contribute to lung defense against uncontrolled proteolysis by host-derived enzymes. In addition, important data will be obtained regarding the ability of host and non-host proteinases to dysregulate cell to cell communication through either cytokine or receptor degradation.
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