Elastases and emphysema. Current assessment of the protease-antiprotease hypothesis

Many studies have been carried out in the past 10 yr dealing with the possible role of elastase in the pathogenesis of pulmonary emphysema. These include newer observations in animal models revealing augmentation of elastase-induced lesions by lathyrogens or by exposure to cigarette smoke. In general, the animal model experiments have focussed attention on repair-processes in the lung and shown that such processes may exert a major influence on the outcome of the initial proteolytic insult. Human studies exploring correlations between elastase levels in neutrophils or serum and development of disease have provided conflicting data; however, measurement of enzymes in pulmonary secretions have yielded more suggestive results. Assessments of lung elastase inhibitors in humans continue to support the importance of alpha-1-proteinase inhibitor in the protection of the lower respiratory tract, but newer information on locally produced, low molecular weight elastase inhibitors indicates that these, too, may play a significant role. Attempts have been made to link cigarette smoking to the development of emphysema at the chemical and cellular levels. These studies have focussed on: (1) the recruitment of elastase-producing leukocytes to smokers' lungs, (2) inactivation of lung elastase-inhibitors by tobacco products or by metabolites released from tobacco-stimulated lung cells, and (3) interference with elastin neosynthesis (repair) in the smoker. Additional information is also available concerning the biochemical properties of neutrophil and macrophage elastases, although it is still unclear which of these enzymes plays the predominant role in chronic lung injury associated with smoking. Perhaps the greatest advance in the emphysema field in recent years involves new discoveries concerning the structure and function of the alpha-1-proteinase (elastase) inhibitor. Applications of recombinant DNA technology and genetic engineering have made it possible to design modified inhibitors with striking new properties. These agents may enjoy significant clinical application in the not too distant future.