Pulmonary emphysema results when chronic exposure to cigarette smoke leads to 1) inflammatory cell recruitment within the terminal airspaces of the lung, followed by 2) release of elastolytic proteinases from the inflammatory cells, coupled with 3) inappropriate repair of elastic fibers and perhaps other extracellular matrix components. In the original proposal, we investigated the role of macrophage elastase (ME), a matrix metalloproteinase cloned and characterized in our laboratory, in the development of pulmonary emphysema. We found that human ME is capable of degrading many extracellular matrix proteins including elastin and that its expression is induced in macrophages of cigarette smokers and in patients with emphysema. To determine directly the contribution of macrophage elastase-deficient (MME-/-) mice by gene-targeting, and 3) subjected MME-/- mice and wild-type (MM+/+) litter-mates to chronic cigarette smoke exposure. We found that in contrast to MME+/+ mice, mice lacking MME (MME-/-) did not develop emphysema. Surprisingly, MME-/- mice also failed to recruit macrophages into their lungs in response to cigarette smoke. These finding suggest a causative role for MME in the pathogenesis of cigarette smoking related emphysema in mice and led to hypothesis addressing the three main facets of emphysema. 1) [inflammatory cells] Define the role of proteinases in monocyte recruitment in response to cigarette smoke. We will test the hypothesis that MME generated elastin fragments mediate monocyte chemotaxis, and that monocyte proteinases are required for transvascular migration. 2) [ proteinase regulation] Determine the molecular basis for macrophage-specific expression of ME. Our hypothesis is that macrophage-specific expression of ME is mediated by silencing elements in the immediate 5' flanking sequences of the ME gene. 3) [elastin fiber turnover] Test the hypothesis that turnover of elastin fibers (elastin and microfibril proteins) is critical to the development of emphysema because of the complex and potentially ineffective nature of elastic fiber repair.
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