Our goal is to elucidate the biochemical and functional properties of proteinase 3 and the basis for its emphysema producing potential. Emphysema is an important medical problem. The mechanisms responsible for the development of emphysema are not known. However, it is known that 1) polymorphonuclear leukocytes (PMNL) are strategically located in smokers at sites of lung destruction; 2) PMNL neutral porteases are leading candidates for mediating extracellular proteolysis associated with cigarette smoking; and 3) preliminary studies have demonstrated that purified proteinase 3,a PMNL serine proteinase distinct from leukocyte elastase, causes striking emphysema in hamsters. The first specific aim will be to characterize physical and functional properties of proteinase 3 in vitro. A combined biochemical and immunologic approach will be used to comprehensively characterize proteinase 3 and to determine the relationship between proteinase 3 and other PMNL serine proteinases. The second specific aim will be to determine the ability of proteinase 3 to facilitate chemotaxis and to degrade lung matrix in situ. These studies will use human amnion, hamster lung explants and an isolated perfused lung preparation to invesigate the role of proteinase 3 in physiologic and pathophysiologic processes. The third specific aim will be to further investigate the emphysema producing potential of proteinase 3 and to determine the mechanism for this effect. A model of proteinase 3 induced emphysema in hamsters will be used to investigate the importance of lung inflammation, the synergistic effects effects of proteinase 3 and other PMNL serine proteinases, and the molecular targets of proteinase 3 in vivo. The research will provide a better understanding of mechanisms of lung inflammation and lung injury which could have important implications in the pathogenesis of emphysema in cigarette smokers.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pathology A Study Section (PTHA)
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University of Utah
Schools of Medicine
Salt Lake City
United States
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