EXTRACELLULAR MATRIX REPAIR IN PULMONARY EMPHYSEMA

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Chronic inhalation of cigarette smoke leads to intrapulmonary recruitment and activation of inflammatory cells with release of elastases, in excess of inhibitors. Elastic fiber degradation coupled with abnormal repair leads to disordered and non-functional elastic fibers resulting in permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of their walls which defines emphysema. Elastic fiber assembly is complex requiring tropoelastin monomers to be aligned on a scaffold of potentially several microfibril proteins where they are then cross-linked by lysyl oxidase(s) to form insoluble elastin. We believe that inability to spatially and temporally coordinate expression of tropoelastin, microfibril proteins, and lysyl oxidase in adult cigarette smokers plays a key role in the development of emphysema. Interestingly, Massaro et.al. recently has shown that airspace enlargement following elastase- induced emphysema can be reversed by treatment with retinoic acid (RA). Although not directly investigated, they believe that correction of the structural abnormality also restored normal lung elasticity. It is known that RA induces synthesis of tropoelastin by fibroblast, but whether this occurs in vivo and the fate of other elastic fiber components is unknown. In addition to the importance of elastin in lung repair, elastin may be involved in perpetuation lung injury in emphysema. Extracellular matrix (ECM) provides important signals by which cells sense their external environment and disruption of ECM often leads to a variety of cellular responses. Along this theme, we have found that proteolytic fragments to elastin both attract macrophage to the lung and induce macrophage biosynthesis of specific matrix metalloproteinases (MMPs); macrophage elastase and collagenase . The long-term goals of this proposal are to test the hypothesis that RA reverses airspace enlargement in our murine model of cigarette smoke- induced emphysema and to define the role of elastic fibers in both perpetuating alveolar injury and in initiating alveolar repair in emphysema. To achieve these goals we propose to 1. Assess the capacity of RA to reverse cigarette smoke-induced emphysema in adult mice. 2. Determine the mechanism by which elastin fragments induce MMP expression thus perpetuating destruction and inhibiting alveolarization. 3. Investigate elastic fiber repair by a) defining the spatial and temporal expression of elastin, microfibril proteins, and lysyl oxidases during lung development, in response to cigarette smoke exposure, and upon treatment with RA, and b) defining the capacity of mice deficient in individual elastic fiber components, to develop pulmonary emphysema in response to cigarette smoke.