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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078871-04
Application #
7809466
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Reynolds, Herbert Y
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$357,271
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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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Rubin, Jonathan M; Horowitz, Jeffrey C; Sisson, Thomas H et al. (2016) Ultrasound Strain Measurements for Evaluating Local Pulmonary Ventilation. Ultrasound Med Biol 42:2525-2531
Ashley, Shanna L; Sisson, Thomas H; Wheaton, Amanda K et al. (2016) Targeting Inhibitor of Apoptosis Proteins Protects from Bleomycin-Induced Lung Fibrosis. Am J Respir Cell Mol Biol 54:482-92
Sisson, Thomas H; Spagnolo, Paolo (2016) Matriptase, Protease-activated Receptor 2, and Idiopathic Pulmonary Fibrosis. Further Evidence for Signaling Pathway Redundancy in this Difficult-to-Treat Disease? Am J Respir Crit Care Med 193:816-7
Wheaton, Amanda K; Velikoff, Miranda; Agarwal, Manisha et al. (2016) The vitronectin RGD motif regulates TGF-?-induced alveolar epithelial cell apoptosis. Am J Physiol Lung Cell Mol Physiol 310:L1206-17
Liu, Fei; Lagares, David; Choi, Kyoung Moo et al. (2015) Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol 308:L344-57
Sisson, Thomas H; Ajayi, Iyabode O; Subbotina, Natalya et al. (2015) Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis. Am J Pathol 185:969-86
Rubin, Jonathan M; Horowitz, Jeffrey C; Sisson, Thomas H et al. (2015) Ultrasound Strain Measurements for Evaluating Local Pulmonary Ventilation. IEEE Int Ultrason Symp 2015:
Ajayi, Iyabode O; Sisson, Thomas H; Higgins, Peter D R et al. (2013) X-linked inhibitor of apoptosis regulates lung fibroblast resistance to Fas-mediated apoptosis. Am J Respir Cell Mol Biol 49:86-95

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