) The goal of the investigators' proposal is to determine the role that products of genes located on human chromosome 19p13.3-pter play in the pathogenesis of COPD. This locus contains the genes for three coordinately expressed neutrophil-derived serine proteinase homologues, neutrophil elastase (NE), proteinase-3 (PR-3) and azurocidin (AZU). The products of this gene cluster represent multi-functional inflammatory mediators with distinct but overlapping functions that are involved not only in matrix destruction, but that also provide signals for production of proinflammatory cytokines, lymphocyte and monocyte recruitment, and apoptosis. The first specific aim will determine the ability of the 19p13.3-pter serine proteinase homologues to function as proinflammatory mediators in vitro. The second specific aim will create models of loss or gain of function of the 19p13.3-pter serine proteinase homologues by genetic manipulation in vivo. The third specific aim will determine the consequences of altered gene expression of the 19p13.3-pter serine proteinase homologues on inflammation, tissue destruction and airflow limitation in COPD. The investigators' strategy for the first specific aim will be to inclusively determine the ability the 19p13.3-pter homologues to induce synthesis and release of proinflammatory cytokines by lung cells. The second part of this aim will pursue recent observations that activated lymphocytes synthesize the 19p13.3-pter proteinases, thus extending the proteinase pathogenesis hypothesis to include a role for lymphocytes. The second specific aim will develop models of 19p13.3-pter serine proteinase homologue(s) loss of function by creating targeted deletions using homologous recombination in mice. Gain of function models will be developed by targeting expression of these genes to myeloid cells using myeloid specific promoters. The third specific aim will determine the consequences of altered gene expression of the 19p13.3-pter serine proteinase homologues on the development of COPD in cigarette smoke- exposed mice. This work will provide new insights into the role of the 19p13.3-pter serine proteinase homologues in lung health and disease, particularly in the pathogenesis of COPD. The results will help define the relationships of lung inflammation and tissue destruction to airflow limitation and hyperinflation in COPD sufferers.
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