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)
Type
Research Project (R01)
Project #
5R01HL115618-02
Application #
8704825
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
2
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
Kleaveland, Kathryn R; Moore, Bethany B; Kim, Kevin K (2014) Paracrine functions of fibrocytes to promote lung fibrosis. Expert Rev Respir Med 8:163-72
Ashley, Shanna L; Jegal, Yangjin; Moore, Thomas A et al. (2014) ?-Herpes virus-68, but not Pseudomonas aeruginosa or influenza A (H1N1), exacerbates established murine lung fibrosis. Am J Physiol Lung Cell Mol Physiol 307:L219-30
Blackwell, Timothy S; Tager, Andrew M; Borok, Zea et al. (2014) Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med 189:214-22
Moore, Bethany B (2014) Following the path of CCL2 from prostaglandins to periostin in lung fibrosis. Am J Respir Cell Mol Biol 50:848-52
Kleaveland, Kathryn R; Velikoff, Miranda; Yang, Jibing et al. (2014) Fibrocytes are not an essential source of type I collagen during lung fibrosis. J Immunol 193:5229-39