The primary goals of the current proposal involve a continuation of investigations designed to determine both the role of host and non-host proteinases in the development of lung-associated diseases as well as the mechanisms utilized to protect this organ against uncontrolled proteolytic events. In this context, the specific aims of the grant will involve a) detailed studies of the proteinases from mast cells, neutrophils, pollen, and bacteria which may be involved in the dysregulation of bronchial homeostasis through either the release of bradykinin and/or the degradation of vasoactive peptides, b) examination of the role of cytokines in the increased expression of proteinase inhibitors from hepatocytes, epithelial cells, and astrocytes during the acute phase proteinase response to inflammation, c) determination of the mechanism of interactions of proteinase inhibitors (serpins) with host serine proteinases, and d) analysis of the structure of the tetramer/heparin complex required to form active, stable mast cell tryptase. All of these results should provide significant information as to the role(s) of host and non-host proteinases in the development of allergies, asthma, bronchitis, and emphysema. In addition, a clearer understanding of the mechanisms for both increased proteinase inhibitor synthesis and regulation of host proteinases should be forthcoming.
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