Idiopathic pulmonary fibrosis (IPF) is a progressive and usually fatal disease of unknown etiology. The median survival after diagnosis is approximately 3 years, with outcomes being largely unaffected by current therapies. Improved understanding of the biologic processes involved in development of lung fibrosis, and more complete identification of the molecular mediators driving these processes, are critically needed to develop effective new therapies. We have recently demonstrated that the potent lipid mediator lysophosphatidic acid (LPA) is critically required for the development of pulmonary fibrosis in mice following bleomycin-induced lung injury. In this model, levels of LPA increase in bronchoalveolar lavage (BAL) fluid following bleomycin challenge, and mice lacking LPA1, one of LPA's receptors, are markedly protected from fibrosis and mortality. We have also demonstrated that LPA levels are increased in the BAL fluid of patients with established IPF, that LPA1 is highly expressed by fibroblasts recovered from IPF BAL, and that pharmacological antagonism of LPA1 markedly reduces fibroblast responses ex vivo to the chemotactic activity of IPF BAL. These results suggest that the LPA pathway may be relevant to the pathogenesis of pulmonary fibrosis in humans as well as mice. The studies proposed in this application are designed to address what we believe are the most important questions raised by our identification of LPA as a mediator of lung fibrosis.
In Aim 1, we will determine whether pharmacological inhibition of the LPA pathway can inhibit the development or progression of pulmonary fibrosis in vivo, by using two novel LPA pathway chemical inhibitors in the bleomycin model.
In Aim 2, we will determine whether the LPA pathway contributes to the development of IPF in humans, first by investigating whether LPA is responsible for fibroblast recruitment in a unique cohort of early stage """"""""preclinical"""""""" pulmonary fibrosis patients. These patients are identified by screening asymptomatic members of familial pulmonary fibrosis kindreds. We will then take a genetic epidemiological approach to investigate whether the LPA pathway contributes to IPF pathogenesis, by determining whether polymorphisms in the genes of this pathway contribute to individuals'risk of developing IPF.
In Aim 3, we will investigate the biological mechanism(s) that are responsible for the dramatic degree to which LPA1-deficient mice are protected from pulmonary fibrosis. In this aim, we will use the Cre-lox system of site-specific recombination to generate and study mice in which LPA1 expression is specifically deleted in fibroblasts, to determine whether fibroblast recruitment directed by the LPA pathway contributes to the development of fibrosis in the bleomycin model. We believe the experiments proposed in this application will both improve our understanding of the role of the LPA pathway in the development of pulmonary fibrosis, and determine whether targeting this pathway has the potential to be an effective new therapeutic strategy for IPF.

Public Health Relevance

Idiopathic pulmonary fibrosis (IPF) is associated with unacceptably high morbidity and mortality. Improved understanding of the molecular mediators driving IPF pathogenesis is desperately needed in order to identify new therapeutic targets for this devastating disease. The proposed studies are designed to provide new insights into the role of the novel mediator lysophosphatidic acid (LPA) in the development of pulmonary fibrosis, and to provide new evidence that targeting the LPA pathway has the potential to be an effective therapeutic strategy for IPF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL095732-01
Application #
7635248
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Reynolds, Herbert Y
Project Start
2009-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$465,876
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Sakai, Norihiko; Chun, Jerold; Duffield, Jeremy S et al. (2017) Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor. Kidney Int 91:628-641
Funke, Manuela; Knudsen, Lars; Lagares, David et al. (2016) Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization. Am J Respir Cell Mol Biol 55:105-16
Ahluwalia, Neil; Grasberger, Paula E; Mugo, Brian M et al. (2016) Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion. Am J Respir Cell Mol Biol 54:831-42
Castelino, Flavia V; Bain, Gretchen; Pace, Veronica A et al. (2016) An Autotaxin/Lysophosphatidic Acid/Interleukin-6 Amplification Loop Drives Scleroderma Fibrosis. Arthritis Rheumatol 68:2964-2974
Knipe, Rachel S; Tager, Andrew M; Liao, James K (2015) The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev 67:103-17
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
Ahluwalia, Neil; Shea, Barry S; Tager, Andrew M (2014) New therapeutic targets in idiopathic pulmonary fibrosis. Aiming to rein in runaway wound-healing responses. Am J Respir Crit Care Med 190:867-78
Ho, Yuen Yee; Lagares, David; Tager, Andrew M et al. (2014) Fibrosis--a lethal component of systemic sclerosis. Nat Rev Rheumatol 10:390-402
Tschumperlin, Daniel J; Liu, Fei; Tager, Andrew M (2013) Biomechanical regulation of mesenchymal cell function. Curr Opin Rheumatol 25:92-100
Sakai, Norihiko; Tager, Andrew M (2013) Fibrosis of two: Epithelial cell-fibroblast interactions in pulmonary fibrosis. Biochim Biophys Acta 1832:911-21

Showing the most recent 10 out of 19 publications