Although excessive proteolysis is a key element in the pathogenesis of emphysema, pathways of protease dysregulation in this disorder remain uncertain. New studies implicate lymphocyte-derived cytokines in emphysema. Interferon-y acts on macrophages as well as non-inflammatory cells such as smooth muscle cells to promote expression and secretion of the active cysteine protease cathepsin S, a potent elastase stable at neutral pH. Transgenic mice expressing either IL-13 or interferon-y on airway surfaces develop cysteine protease-dependent emphysematous changes. Further, a significant correlation was recently found between serum levels of cystatin C, the major cysteine protease inhibitor, and severe reductions in FEV1 (<20 percent predicted) in a cohort of 30 patients with early-onset emphysema compared to controls with normal FEV1 and comparable smoking history. These studies invite the hypothesis that pro-inflammatory cytokines and possibly cigarette smoke stimulate mesenchymal lung cells and macrophages to secrete elastolytic cysteine proteases and downregulate their cystatin C release. This imbalance creates an accelerated process of collagen and elastin degradation important to the development of emphysema and COPD. The research plan is centered on the question of whether dysregulation of elastolytic cathepsins is important to the pathogenesis of emphysema. Parallel tracks of animal and human experiments are proposed: Mouse cathepsin S/L and cystatin C """"""""knockouts"""""""" are used in Aims 1 and 2 to answer the question of whether excess elastolytic cathepsin activity exacerbates the development of interferon-y-induced emphysema and whether mesenchymal cells in the lung are a source of these enzymes.
Aim 3 is designed to determine if low levels of cystatin C and/or polymorphic markers in or near the major genes regulating cystatin C (and elastolytic cathepsins) are associated with increased risk of COPD. Together, these studies should determine if some patients with early-onset COPD can be grouped, based on either phenotypic (cystatin C) or genetic markers, into a functional subset defined by a common pathogenic pathway involving dysregulation of elastolytic cathepsins.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL067204-02
Application #
6537980
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Croxton, Thomas
Project Start
2001-06-01
Project End
2006-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$316,675
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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