Recent observations by the principal investigator show that live human alveolar macrophages can degrade purified insoluble elastin (bovine ligamentum). This occurs by a cell-contact dependent process involving one or more cysteine proteases. These studies provide a biological potential that, coupled with the known histopathology, directly implicate alveolar (and perhaps interstitial) macrophages as a major factor in the pathogenesis of emphysema. This proposal tests the proposition that macrophages are intimately involved in the genesis of disabling emphysema by better defining the elastolytic potential of live human macrophages and by directly examining this potential in subjects at high and low risk for the disease. First, studies are planned to quantitate the elastolytic activity of live human alveolar macrophages in co-culture with nascent, extracellular matrix elastin (smooth muscle cell-derived) metabolically labeled with 3H-lysine. Elastin degradation will be assessed by quantitating recovery of matrix elastin following the co-cultures and by direct measurements of solubilized 3H-isodesmosine/desmosine assayed by an amino acid analyzer. Studies are also planned to elucidate the role of cysteine proteases in the degradative process. Correlates will be made between the development of the elastolytic potential of cultured human monocytes (initially very low) and their cysteine protease activity. In addition, the elastolytic activity of cysteine proteases purified from macrophage lysates will be measured. Lastly, the elastolytic potential of alveolar macrophages from young smokers at high and low risk for disabling disease, as judged by FEV1 corrected for age and height, will be assessed. Specifically, it will be determined whether macrophage elastolytic potential per se, the intensity of the bronchoalveolitis, or the macrophage elastolytic inhibitor capacity of the alveolar fluid correlate with risk for progressive emphysema. These studies should provide a clearer understanding of the biology and pathophysiological role of macrophages in emphysema, a disease characterized by connective tissue breakdown. It is hoped that such an understanding will provide insight into the catabolism of connective tissue components by human macrophages in other degenerative processes as well.
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