Idiopathic Pulmonary Fibrosis is a scarring disorder of the lung for which there is no established therapy. Animal models for this disease have implicated plasminogen activator inhibitor-1 (PAI-1) in the pathogenesis. A deficiency of PAI-1, for example, dramatically protects mice from lung collagen accumulation and mortality following a fibrotic insult while the constitutive over-expression of PAI-1 significantly worsens scarring. The tight correlation between the level of PAI-1 and the severity of scarring suggests that PAI-1 inhibition may be a viable therapeutic strategy. To optimally target this molecule, however, it is important to define its mechanism of action in fibrogenesis. PAI-1 is known to have two important functional properties which could influence pulmonary fibrosis. First, it acts as a protease inhibitor with specificity for the plasminogen activators. Through this mechanism, PAI-1 limits plasmin-mediated proteolysis. Second, PAI-1 is capable of binding to vitronectin, a provisional matrix protein. This interaction significantly stabilizes PAI-1's antiprotease activity. In addition, when bound to vitronectin, PAI-1 disrupts cell attachment to and migration across this matrix molecule by sterically inhibiting both integrin and urokinase plasminogen activator receptor binding sites. Our preliminary data, in conjunction with several published reports, suggest that both PAI-1 functions contribute to its influence on fibrogenesis, and these observations have led us to formulate the following hypothesis: The pro-fibrotic effect of PAI-1 following lung injury requires both its anti-protease and vitronectin-binding activity. To test this hypothesis, we propose a series of studies using the bleomycin model of pulmonary fibrosis and primary cultures of mouse alveolar epithelial cells and fibroblasts.
Our specific aims are to: 1) determine the requirements of PAI-1's anti-protease and vitronectin-binding functions in the development of bleomycin-induced pulmonary fibrosis, 2) determine the contribution of vitronectin to PAI-1 localization, PAI-1 activity, and pulmonary fibrosis following bleomycin-induced lung injury, and 3) determine the influence of PAI-1 and vitronectin on the in vitro phenotypes of fibroblasts and alveolar epithelial cells. Completion of these specific aims will provide important mechanistic information that will help clarify how PAI-1 facilitates the development of pulmonary fibrosis and whether vitronectin is required for PAI-1 to fully manifest its influence. Ultimately, it is our goal with these studies to help guide the development of new inhibitory agents and/or novel therapeutic strategies for this difficult to treat disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Reynolds, Herbert Y
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Kim, Kevin K; Sisson, Thomas H; Horowitz, Jeffrey C (2017) Fibroblast growth factors and pulmonary fibrosis: it's more complex than it sounds. J Pathol 241:6-9
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