The discovery of gamma1-antitrypsin deficiency, associated with emphysema in man, coupled with the recent demonstration of elastase elaboration by neutrophils and pulmonary macrophages support the hypothesis that emphysema may be due to an imbalance of proteases and antiproteases. Our work with elastase-induced emphysema in hamsters suggests that gamma2-macroglobulin (gamma-M) plays an important role in complexing the enzymatically active 3H-methylated porcine pancreatic elastase (3H-Me-PE) which is instilled into the lungs of hamsters to produce the disease. Formation of gamma-M-elastase complexes as well as gamma1-antitrypsin (gamma-AT)-elastase appears to retard clearance from the lungs of 3H-Me-PE as compared with chloromethyl ketone inactivated elastase. Complexes of 3H-Me-PE and gamma 2-M from hamsters, humans and other species retain their elastolytic potential which is protected from gamma1-AT inhibition. A sensitive quantitative probe of the """"""""functional"""""""" antiproteases in plasma and serum from hamsters, gamma1-AT deficient and normal humans and rats is provided by 3H-Me-PE. The antiprotease profiles suggest that the preferential formation of gamma2-M-elastase is associated with susceptibility to spontaneous or experimentally-induced emphysema. We plan to investigate the emphysema-inducing potency in hamsters of instilled gamma2-M-elastase complexes. The mechanism of action of gamma2-M-elastase complexes, prepared from purified gamma2-M and one of several radiolabelled elastases, will be elucidated. The use of synthetic elastase inhibitors to control elastase-induced emphysema in hamsters will be investigated. The antiprotease profiles of blood, urine and bronchopulmonary lavage fluid from smokers with and without airway obstruction and normal nonsmokers will be studied in company with improved techniques of measuring levels of elastase activity in polymorphonuclear leukocytes to help develop means of identifying those smokers who are at risk of developing emphysema. These studies may usher in new therapeutic or preventive methods of dealing with human emphysema; at the least they should enhance our understanding of the pathogenesis of this important disease.
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