Control of fibroblast function by prostaglandin E2 and plasminogen activation
Principal Investigator: MARC L PETERS-GOLDEN
Abstract: DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a devastating and usually fatal scarring disease. A pivotal effector cell in this disorder is the myofibroblast, with an exuberant capacity for elaboration of extracellular matrix proteins such as collagen that comprise tissue scars. Emerging research suggests that overactive adhesion/stiffness signaling and protein translation contribute to myofibroblast differentiation and activation. Less attention has been paid to endogenous anti- fibrotic pathways. Two such anti-fibrotic pathways that have been shown to be deficient in IPF are 1) the lipid mediator prostaglandin E2 (PGE2) and its associated G protein-coupled receptors and cyclic AMP (cAMP) effectors, and 2) the proteolytic cascade by which urokinase converts plasminogen to plasmin. We have previously shown that cross-talk between these two pathways is critical for their anti-fibrotic functions. Our new preliminary data suggest that PGE2, via cAMP and distinct isoforms of the classical cAMP effector protein kinase A, can inhibit both adhesion signaling and protein translation by targeting a variety of critical checkpoints. Moreover, our data suggest that, in addition to preventing myofibroblast differentiation, PGE2 can reverse the differentiated state of myofibroblasts back to fibroblasts;this has important therapeutic implications in view of the fact that most patients hav already advanced fibrosis on clinical presentation. The overall objectives of this proposal are to 1) understand the mechanisms by which PGE2 regulates adhesion signaling and protein translation;2) determine whether plasmin has similar effects or if it instead potentiates the effects of PGE2;3) determine the importance of disrupting adhesion signaling and protein translation in the ability of PGE2 to reverse myofibroblast differentiation;and 4) evaluate the potential of inhaled PGE2 and/or urokinase to ameliorate fibrosis and to reverse myofibroblast differentiation in vivo in two mouse models of pulmonary fibrosis. The proposed studies will provide new fundamental insights into fibroblast biology as well as translational control, and a potential new paradigm for therapeutics in IPF and other fibrotic lung diseases.
Funding Period: 2008-12-01 - 2018-05-31
more information: NIH RePORT
- Phosphatase and tensin homologue on chromosome 10 (PTEN) directs prostaglandin E2-mediated fibroblast responses via regulation of E prostanoid 2 receptor expressionRommel L Sagana
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
J Biol Chem 284:32264-71. 2009..This is the first description, to our knowledge, of PI3K/PTEN balance directing GPCR expression, and provides a novel mechanism for cellular effects of PTEN...
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Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
J Invest Dermatol 134:1436-45. 2014..Taken together, our results show that 5-LO disruption improves wound healing and alters fibroblast function by an antioxidant mechanism based on HO-1 induction. Overexpression of HO-1 in wounds may facilitate early wound resolution. ..
- Prostaglandin E₂ suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cellsZbigniew Zasłona
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich
J Allergy Clin Immunol 133:379-87. 2014..Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin (PG) E₂ or of specific E prostanoid (EP) receptors is not known...
- Inhibition of protein translation as a novel mechanism for prostaglandin E2 regulation of cell functionsKatsuhide Okunishi
26301 MSRB III, 1150 W Medical Center Drive, Ann Arbor, MI 48109 5642
FASEB J 28:56-66. 2014..Translational inhibition would be expected to contribute to dynamic alterations in cell function that accompany the changing PGE2 levels observed in disease states and with various pharmacotherapies...
- Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblastsS K Huang
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Cell Death Dis 4:e621. 2013....
- Reversal of myofibroblast differentiation by prostaglandin E(2)Garth Garrison
Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA
Am J Respir Cell Mol Biol 48:550-8. 2013..Because many patients have established or even advanced fibrosis by the time they seek medical attention, this capacity of PGE2 has the potential to be harnessed for therapy of late-stage fibrotic disorders...
- Prostaglandin E₂ increases fibroblast gene-specific and global DNA methylation via increased DNA methyltransferase expressionSteven K Huang
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
FASEB J 26:3703-14. 2012....
- Airway remodeling in murine asthma correlates with a defect in PGE2 synthesis by lung fibroblastsCamila Leindecker Stumm
Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
Am J Physiol Lung Cell Mol Physiol 301:L636-44. 2011....
- Plasmin overcomes resistance to prostaglandin E2 in fibrotic lung fibroblasts by reorganizing protein kinase A signalingKatsuhide Okunishi
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
J Biol Chem 286:32231-43. 2011....
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Division of Pulmonary and Critical Care, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
Am J Pathol 178:2461-9. 2011..These data suggest a key role for local tissue-specific, organ-resident, mesenchymal precursors in the fibrogenic processes in human adult lungs...
- Epithelial interactions and local engraftment of lung-resident mesenchymal stem cellsLinda Badri
Department of Internal Medicine, University of Michigan Health System, 1500 E Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI 48109 0360, USA
Am J Respir Cell Mol Biol 45:809-16. 2011....
- Leukotrienes and airway inflammationKatsuhide Okunishi
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 4810 5642, USA
Biochim Biophys Acta 1810:1096-102. 2011..Cysteinyl LT (cysLT) receptor 1 antagonists (LTRAs) have been utilized worldwide for more than 10years, and while their efficacy in asthma is well accepted, their limitations are also evident...
- Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and miceSteven K Huang
Department of Internal Medicine, University of Michigan Medical School, 6301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA
Am J Pathol 177:2245-55. 2010....
- The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and miceKristy A Bauman
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
J Clin Invest 120:1950-60. 2010..These studies demonstrate crosstalk between plasminogen activation and PGE2 generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway...
- Prostaglandin E2 reduces Toll-like receptor 4 expression in alveolar macrophages by inhibition of translationAngela Juliette Degraaf
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan
Am J Respir Cell Mol Biol 51:242-50. 2014..Because PGE2 is produced in abundance at sites of infection, its inhibitory effects on AM TLR4 expression have important implications for host defense in the lung. ..
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