Periostin Regulation of Lung Fibrosis Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disorder of the lung that is characterized by the accumulation of myofibroblasts and the deposition of extracellular matrix leading to respiratory failure. Unfortunately, the disease is fatal and there are no effective therapies other than lung transplantation. The most potent profibrotic mediator studied to date is transforming growth factor (TGF) b and TGFb is elevated in many models of organ fibrosis. Unfortunately, TGFb is a difficult therapeutic target as total loss of TGFb or TGFb signaling can cause devastating autoimmune inflammation and mortality. As such, there is great interest in identifying downstream mediators of TGFb signaling which may be better targets for therapeutic intervention to treat fibrotic disorders. Recently, the TGFb-regulated matricellular protein, periostin, a molecule which has been studied in asthma, atherosclerosis and cancer, has been implicated in the pathogenesis of interstitial fibrotic lung disease. We and others have shown that periostin is increased in cells and lung tissue of IPF patients and that elevated levels of circulating periostin in IPF patients predict declines in lung function. Additionally, we and other have demonstrated that periostin-/- mice are protected from bleomycin-induced fibrosis. We recently demonstrated that periostin can induce mesenchymal cell proliferation, collagen expression and ability to close a scratch wound. Blockade of periostin interactions with the avb3 and avb5 integrins via the administration of the OC-20 monoclonal Ab could partially reverse periostin-mediated wound closure and partially blocks the development of bleomycin-induced fibrosis when administered during the fibroproliferative phase of the disease. Our published results using bone marrow chimeric mice indicate that both structural and hematopoietic sources of periostin are required for development of bleomycin-induced fibrosis. Preliminary data show that periostin may induce myofibroblast survival via the induction of the anti- apoptotic proteins (survivin, X-linked inhibitor of apoptosis (XIAP) and Bcl-2). Periostin is also elevated in aged mice and may contribute to the enhanced susceptibility of aged mice to gammaherpesvirus-induced fibrosis. Our revised studies are aimed at verifying the ability of periostin to promote fibrosis in two additional animal models. We also have proposed studies to elucidate the role that circulating fibrocytes and fibrocyte-derived periostin may play in regulating fibrotic development in multiple models. TGFb and periostin reciprocally regulate each other; however, the fact that periostin-deficient mice are viable and have relatively few health issues suggests that this molecule may be highly amenable to therapeutic targeting. To further explore this possibility, we will perform mechanistic studies to understand the reciprocal regulation of these mediators and to understand how periostin influences lung mesenchymal cell behavior. Finally, we will measure periostin in the lung and the changes in circulating periostin levels over time in IPF patients and determine the correlations this biomarker may have on disease progression. We hypothesize that the matricellular protein, periostin, promotes the development and progression of pulmonary fibrosis and may serve as a biomarker for disease progression. We will mechanistically explore this hypothesis in the following specific aims.
Aim 1) To determine whether periostin regulates the development of fluorescein isothiocyanate-induced pulmonary fibrosis or gammaherpesvirus-induced fibrosis in aged mice Aim 2) To determine the contribution of fibrocytes and fibrocyte-derived periostin in the development of lung fibrosis in animal models Aim 3) To determine the molecular mechanisms via which periostin and TGFb regulate each other and the function of lung mesenchymal cells Aim 4) To determine whether periostin levels in plasma or bronchoalveolar lavage fluid of IPF patients correlate with disease progression

Public Health Relevance

This project is based on the observation that periostin is produced in high levels in patients with lung fibrosis and elevations of periostin predict declines in lung function. We are now exploring the potential mechanisms whereby this molecule may influence the profibrotic behavior of mesenchymal cells in the lung, and will determine the importance of periostin derived from circulating fibrocytes in disease progression. We will also test the measurement of this protein as a biomarker for disease progression. A better understanding of periostin regulation of lung fibrosis may lead to new therapies for this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
4R01HL115618-04
Application #
9066183
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Harabin, Andrea L
Project Start
2013-08-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
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
O'Dwyer, David N; Gurczynski, Stephen J; Moore, Bethany B (2018) Pulmonary immunity and extracellular matrix interactions. Matrix Biol 73:122-134
Gurczynski, S J; Zhou, X; Flaherty, M et al. (2018) Bone marrow transplant-induced alterations in Notch signaling promote pathologic Th17 responses to ?-herpesvirus infection. Mucosal Immunol 11:881-893
Galli, Jonathan A; Panetta, Nicholas L; Gaeckle, Nathaniel et al. (2017) Pneumothorax After Transbronchial Biopsy in Pulmonary Fibrosis: Lessons from the Multicenter COMET Trial. Lung 195:537-543
O'Dwyer, David N; Moore, Bethany B (2017) The role of periostin in lung fibrosis and airway remodeling. Cell Mol Life Sci 74:4305-4314
Ashley, S L; Wilke, C A; Kim, K K et al. (2017) Periostin regulates fibrocyte function to promote myofibroblast differentiation and lung fibrosis. Mucosal Immunol 10:341-351
Huang, Yong; Ma, Shwu-Fan; Espindola, Milena S et al. (2017) Microbes Are Associated with Host Innate Immune Response in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 196:208-219
Cipolla, Ellyse; Fisher, Amanda J; Gu, Hongmei et al. (2017) IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis. FASEB J 31:5543-5556
Zhou, Xiaofeng; Moore, Bethany B (2017) Adoptive Transfer of Lung Antigen Presenting Cells. Bio Protoc 7:
O'Dwyer, David N; Norman, Katy C; Xia, Meng et al. (2017) The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes. Sci Rep 7:46560
Zhou, Xiaofeng; Moore, Bethany B (2017) Lung Section Staining and Microscopy. Bio Protoc 7:

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