Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disorder of the lung, and patients suffering from this condition experience significant morbidity and mortality. Unfortunately, treatment options for these individuals are limited, and no intervention has significantly impacted the severe disease course. As such, we are in desperate need of new candidate therapies. Plasminogen activator inhibitor-1 (PAI-1) provides a promising target for the treatment of IPF based on observations that intrapulmonary levels of PAI-1 are consistently elevated in patients with fibrotic lung disease and that the level of PAI-1 tightly correlates with the severity of fibrosis in several different animal models of lung scarring. Although the mechanism by which PAI-1 promotes lung fibrosis remains unclear, we made significant advances in our understanding of its function during our previous funding period. First, we demonstrated that PAI-1 drives fibrogenesis through its somatomedin B binding domain rather than its more well-recognized antiprotease function. Second, we have identified a role for PAI-1, through its SMB-binding activity, in the intra- pulmonary accumulation of profibrotic Ly6Chigh monocytes and their derivative exudate macrophages following lung injury. Despite these advances in our understanding of PAI-1's role in pulmonary fibrosis, there remain many unanswered questions. First, the target protein for PAI-1's somatomedin B binding domain has not been identified. The most well defined binding partner for PAI-1 is vitronectin, making this matrix molecule a potential candidate. However, our preliminary data indicate that PAI-1 interacts with a yet-to-be described binding partner to exert its pro-fibrotic effect. Second, the mechanism by which PAI-1 regulates monocyte/macrophage lung accrual following injury has yet to be determined. And third, the requirement for PAI-1 in monocyte/macrophage accumulation following lung injury raises the question as to whether a third PAI-1 function, its interaction with the low density lipoprotein-like receptor (LRP), contributes to fibrogenesis as this activity has been shown to facilitate macrophage motility. The aforementioned knowledge gaps serve as the motivation for the specific aims of this proposal. Specifically, we plan: 1) To demonstrate the molecular interactions by which the SMB-binding function of PAI-1 exerts its pro-fibrotic activity, 2) To determine the mechanistic link between PAI-1, monocyte/macrophage accrual, and lung fibrosis., and 3) To define the contribution of the LRP-interactive activity of PAI-1 in pulmonary fibrosis. Because PAI-1 has such a potent effect on the severity of fibrosis in multiple different animal models, it is certain to play a central role in disease pathogenesis. As such, completion of these aims will provide core insights into the pathobiology of lung fibrosis and refine therapeutic strategies for patients with IPF.

Public Health Relevance

Idiopathic Pulmonary Fibrosis is a devastating disorder for which there is currently no approved therapy. As such, there is a desperate need to better understand the basic pathobiology of lung fibrosis in order to define new therapeutic strategies. Because PAI-1 is a consistent and potent mediator of IPF, elucidating the mechanisms by which it exerts its effect will provide insight into the fundamental pathobiology of fibrosis and thereby define novel treatment targets. Also, by further delineating its mechanism of action, we will be able to develop an optimal inhibitory strategy of PAI-1's actions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL078871-06A1
Application #
8693370
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Eu, Jerry Pc
Project Start
2004-12-01
Project End
2019-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Dodi, Amos E; Ajayi, Iyabode O; Chang, Christine et al. (2018) Regulation of fibroblast Fas expression by soluble and mechanical pro-fibrotic stimuli. Respir Res 19:91
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
Sheth, Jamie S; Belperio, John A; Fishbein, Michael C et al. (2017) Utility of Transbronchial vs Surgical Lung Biopsy in the Diagnosis of Suspected Fibrotic Interstitial Lung Disease. Chest 151:389-399
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:

Showing the most recent 10 out of 23 publications