MODULATION OF EXTRACELLULAR NEUTROPHIL ELASTASE ACTIVITY

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Elastase released from neutrophils during inflammation has been implicated in the pathogenesis of tissue injury in a number of disease processes, including pulmonary emphysema. Control of extracellular neutrophil elastase activity depends upon: 1) proteinase inhibitors (primarily alpha1-proteinase inhibitor and alpha2-macroglobulin); and 2) interaction with the mononuclear phagocyte system. Because alpha2-macroglobulin is absent or present in low concentrations in the lower respiratory tract and interstitial space, control of released elastase in these locations would be expected to depend upon inhibition by alpha1-proteinase inhibitor and binding of active enzyme to alveolar (and interstitial) macrophages. We hypothesize that inactivation of alpha1-proteinase inhibitor by oxidants (including oxidants from cigarette smoke and activated neutrophilis) increases the risk of tissue injury during inflammation, and also causes the mononuclear phagocyte system to assume greater importance in antielastase defenses. We therefore propose to: 1) Further study the in vitro binding and internalization of neutrophil elastase by alveolar macrophages with regard to the nature of the macrophage receptor for elastase, the enzymatic activity of internalized enzyme, the intracellular localization of internalized enzyme relative to the macrophage inhibitor of elastase, and conditions which promote release of elastase previously internalized by macrophages; and 2) quantify the fraction of oxidized alpha1-proteinase inhibitor in a pilot study in plasma and bronchoalveolar lavage fluid from human nonsmokers and cigarette smokers, and relate the results to smoking history, respiratory symptoms; and degree of ventilatory impairment. We anticipate that the improved insight into control of released neutrophil elastase activity in health and disease which results from these studies will be helpful in developing strategies for limitation of proteolytic tissue injury in diseases such as pulmonary emphysema.