Our objectives are to investigate mechanisms by which proteinase inhibitor deficiencies can occur in tissues. Examination of the alpha-1-proteinase inhibitor-neutrophil elastase balance will be made as perturbance of this equilibrium can result in abnormal connective tissue turnover and the development of pulmonary emphysema. The study involves investigations of the mechanism of alpha-1-proteinase inhibitor function, using recombinant DNA produced variants of this inhibitor. Studies of the methods of inhibitor inactivation, including oxidation and enzymatic turnover will also be made to determine the role each plays in changing active inhibitor levels in tissues. Enzymes which are clearly involved in connective tissue proteolysis (neutrophil elastase and cathepsin G) will also be investigated in terms of a) their primary structure, using both protein sequencing and cDNA sequencing techniques, and b) their ability to degrade other macromolecular substrates. Finally, using monoclonal antibodies measurements of the levels of oxidized alpha-1-proteinase inhibitor, as well as enzymes which might affect formation of this modified, inactive protein, will be made in lung lavage fluids. It is believed that all of these studies should lead to a better understanding of the mechanisms involved in the onset of abnormal connective tissue turnover, associated with the development of emphysema, and other disease states.
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