Proteolysis of lung elastin and other connective tissue proteins released from leukocytes is generally thought to cause the destruction of the lung which is observed in pulmonary emphysema. The two major serine proteases of leukocytes (human leukocyte elastase and cathepsin G) will both hydrolyze lung elastin, although elastase is more effective. In addition to emphysema, elastase is involved in adult respiratory distress syndrome, amyloidosis, and chronic inflammation, while pancreatic elastase is involved in pancreatitis. Cathepsin G and other chymotrypsin-like enzymes from mast cells are speculated to play a role in inflammation and arthritis. The goal of this research is the development of an elastase inhibitor which would be useful for the treatment of human emphysema. A variety of structures will be investigated including heterocyclic structures which are mechanism-based or suicide inhibitors and peptide transition state analogs. All the inhibitors will be tested with cathepsin G, mast cell chymotrypsin-like enzymes, and other serine proteases to determine specificity. Any promising inhibitors will be provided to other investigators for studies in animal models of emphysema. This research should lead to a better understanding of the active site structures of the enzymes involved in connective tissue turnover and should lead to new therapeutic methods for the treatment of pulmonary emphysema.
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