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 largely unaffected by current therapies. Improved understanding of the biological processes involved in development of lung fibrosis, and more complete identification of the molecular mediators that regulate these processes, are critically needed to develop effective therapeutic interventions. We have recently demonstrated that the potent lipid mediator sphingosine 1-phosphate (S1P) protects against the development of pulmonary fibrosis in mice induced by bleomycin lung injury. Loss of S1P signaling through one of its receptors S1P1 markedly worsened vascular leak, fibrosis and mortality in this model. We have found preliminary evidence to suggest that decreased S1P-S1P1 signaling may promote the development of pulmonary fibrosis in humans as well. In a pilot study of a unique cohort of """"""""preclinical"""""""" fibrosis patients, identified by screening asymptomatic members of familial pulmonary fibrosis kindreds, bronchoalveolar lavage (BAL) S1P levels were significantly decreased in these early fibrosis patients compared to controls without lung disease. The studies proposed in this application are designed to address what we believe are the most important questions raised by our data indicating that S1P-S1P1 signaling protects against pulmonary fibrogenesis.
In Aims 1 and 2, we will investigate the biological mechanisms through which S1P-S1P1 signaling limits vascular leak and pulmonary fibrosis induced by bleomycin lung injury in mice.
In Aim 1, we will investigate the hypothesis that S1P signaling through S1P1 expressed by endothelial cells rather than by other cell types is specifically responsible for the ability of this pathway to limit both vascular leak and pulmonary fibrosis. We will test this hypothesis by generating mice in which S1P1 expression is specifically deleted in endothelial cells, using the Cre-lox system of site-specific recombination.
In Aim 2, we will investigate the hypothesis that increased activation of the coagulation cascade, and consequent increased activation of the thrombin receptor PAR-1, represents the mechanistic link between increased vascular leak produced by loss of S1P-S1P1 signaling and increased pulmonary fibrosis. We will test this hypothesis by comparing the effects of S1P-S1P1 pathway inhibition in PAR-1-deficient and wild type mice.
In Aim 3, we will investigate the hypothesis that augmenting lung S1P levels will protect mice from both vascular leak and pulmonary fibrosis induced by bleomycin injury. We will test this hypothesis by overexpressing sphingosine kinase 1, which generates S1P, in the lungs of mice using an adenovirus gene transfer vector.
In Aim 4, we will further investigate the hypothesis that the S1P pathway regulates the development of pulmonary fibrosis in humans. We will test this hypothesis by determining whether polymorphisms in S1P pathway genes contribute to individuals'risk of developing IPF, and by determining whether S1P levels are depressed in the BAL of both early stage """"""""preclinical"""""""" familial pulmonary fibrosis patients and patients with established IPF. Additionally, we will compare S1P plasma levels in IPF patients and healthy controls, to investigate whether plasma S1P levels can serve as a diagnostic or prognostic biomarker in IPF. If successful, we believe that the experiments proposed will improve our understanding of the role of the S1P pathway in the regulation of pulmonary fibrosis, and determine whether augmenting this pathway has the potential to be an effective new therapeutic strategy for IPF.
Idiopathic Pulmonary Fibrosis (IPF) is associated with unacceptably high morbidity and mortality. Improved understanding of the molecular mediators that regulate IPF pathogenesis is desperately needed in order to identify new therapeutic strategies for this devastating disease. The proposed studies are designed to provide new insights into the ability of the sphingosine 1-phosphate (S1P) pathway to protect against the development of pulmonary fibrosis, and to provide evidence that augmenting this pathway has the potential to be an effective therapeutic strategy for IPF.
|Black, Katharine E; Berdyshev, Evgeny; Bain, Gretchen et al. (2016) Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis. FASEB J 30:2435-50|
|Sakai, Norihiko; Chun, Jerold; Duffield, Jeremy S et al. (2016) Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor. Kidney Int :|
|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|
|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|
|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|
|Herzog, Erica L; Mathur, Aditi; Tager, Andrew M et al. (2014) Review: interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: how similar and distinct? Arthritis Rheumatol 66:1967-78|
|Montesi, Sydney B; Mathai, Susan K; Brenner, Laura N et al. (2014) Docosatetraenoyl LPA is elevated in exhaled breath condensate in idiopathic pulmonary fibrosis. BMC Pulm Med 14:5|
|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|
|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|
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