The severity of pulmonary fibrosis that follows administration of bleomycin to mice can be influenced by manipulations of the plasminogen activation system. Interventions that enhance plasmin formation reduce the extent of collagen that accumulates after injury. This anti-fibrotic effect, which has been seen in other organs as well, suggests that manipulation of the plasminogen activation system may provide a means to limit the fibrosis that occurs during idiopathic pulmonary fibrosis. The long-term objectives of our investigations are to a) understand the relationship between the plasminogen activation system and the processes that lead to pulmonary fibrosis, and b) evaluate the role of the plasminogen activation system in humans with idiopathic pulmonary fibrosis. The Specific Alms of this proposal are to 1) determine whether the beneficial effects from increasing plasminogen activator activity extend beyond the bleomycin model to other types of fibrotic lung injury; 2) determine the spatial distribution of plasn?llinogen activator activity in lung tissue during the processes of lung injury and fibrosis; 3) screen for and evaluate possible mechanisms by which the plasminogen activation system effects the development of pulmonary fibrosis; 4) determine if idiopathic pulmonary fibrosis in humans is influenced by a specific polymorphism found in the promoter region of the human PAM gene; and 5) determine if fibroblasts isolated from lungs of patients with idiopathic pulmonary fibrosis have an altered phenotype regarding the plasminogen activation system. These studies will use a multifaceted approach that employs munine models of pulmonary fibrosis and lung tissue and cells from patients with idiopathic pulmonary fibrosis. The investigations will use molecular biology and molecular genetic techniques, novel histological methods for localizing protease activity, and gene chip microarray technology. Completion of these studies should provide the scientific foundation on which to base a new strategy to treat patients with idiopathic pulmonary fibrosis.
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