Accumulating evidence indicates papain-family cysteine proteases are involved in the pathobiology of emphysema. One of these enzymes, cathepsin S, is a potent extracellular elastase stable at neutral pH and also a key endosomal acidic protease in MHC class II antigen presentation. Cathepsin S expression is higher in lungs of cigarette smokers and is induced in numerous cell types by interferon-v (IFN-y). Findings during the current funding period indicate that cathepsin S is required for smoking-induced murine emphysema and contributes significantly to IFN-y induced emphysema. These studies also implicate a previously unsuspected role for cathepsin S in emphysema: promotion of an interferon-y (IFN-y) driven immune response (possibly autoimmune) leading to the deposition of complement-activating IgG in the mouse lungs. Given the recent strong evidence linking the number of human B cells in airway walls with progressive loss of lung function in COPD patients and evidence IFN-y signaling is prominent in lungs of COPD patients, the following main hypothesis is advanced: Cathepsin S by virtue of its extracellular proteolytic activity not only contributes to extracellular matrix degradation but also generates potential antigens and by virtue of its critical intracellular role in antigen presentation promotes local antibody responses to tissue antigens and progression of lung injury. Both pathways may synergize to promote progressive emphysema, the latter pathway driven in mice by IFN-Y an^ we hypothesize in humans by intermittent infection. The research strategy is to pursue the identification of the biochemical "signature" of excess cathepsin S activity in mouse lung using 2D gel electrophoresis and mass spectroscopy , guided in part by identification of candidate genes in human emphysema through collaborationwith the early-onset Boston COPD Project, and to define the nature and importance of local antibody responses in experimental emphysema. Experiments will then be undertaken to search for characteristic cathepsin S protein cleavages and lung antibodies in stored sera and tissues of patients with COPD. Identification of biomarkers of cathepsin S activity in COPD patients could :erve as a surrogate for disease progression and an in vivo measure of efficacy during drug trials.