Control of fibroblast function by prostaglandin E2 and plasminogen activation

Summary

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

Top Publications

  1. pmc Phosphatase and tensin homologue on chromosome 10 (PTEN) directs prostaglandin E2-mediated fibroblast responses via regulation of E prostanoid 2 receptor expression
    Rommel 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
  2. ncbi Critical role of 5-lipoxygenase and heme oxygenase-1 in wound healing
    Ariane R Brogliato
    Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
    J Invest Dermatol 134:1436-45. 2014
  3. pmc Prostaglandin E₂ suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells
    Zbigniew 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
  4. pmc Inhibition of protein translation as a novel mechanism for prostaglandin E2 regulation of cell functions
    Katsuhide Okunishi
    26301 MSRB III, 1150 W Medical Center Drive, Ann Arbor, MI 48109 5642
    FASEB J 28:56-66. 2014
  5. pmc Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts
    S 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
  6. pmc 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
  7. pmc Prostaglandin E₂ increases fibroblast gene-specific and global DNA methylation via increased DNA methyltransferase expression
    Steven K Huang
    Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
    FASEB J 26:3703-14. 2012
  8. pmc Airway remodeling in murine asthma correlates with a defect in PGE2 synthesis by lung fibroblasts
    Camila 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
  9. pmc Plasmin overcomes resistance to prostaglandin E2 in fibrotic lung fibroblasts by reorganizing protein kinase A signaling
    Katsuhide 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
  10. pmc Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts
    Natalie Walker
    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

Research Grants

Detail Information

Publications15

  1. pmc Phosphatase and tensin homologue on chromosome 10 (PTEN) directs prostaglandin E2-mediated fibroblast responses via regulation of E prostanoid 2 receptor expression
    Rommel 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...
  2. ncbi Critical role of 5-lipoxygenase and heme oxygenase-1 in wound healing
    Ariane R Brogliato
    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. ..
  3. pmc Prostaglandin E₂ suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells
    Zbigniew 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...
  4. pmc Inhibition of protein translation as a novel mechanism for prostaglandin E2 regulation of cell functions
    Katsuhide 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...
  5. pmc Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts
    S 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
    ....
  6. pmc 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...
  7. pmc Prostaglandin E₂ increases fibroblast gene-specific and global DNA methylation via increased DNA methyltransferase expression
    Steven K Huang
    Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
    FASEB J 26:3703-14. 2012
    ....
  8. pmc Airway remodeling in murine asthma correlates with a defect in PGE2 synthesis by lung fibroblasts
    Camila 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
    ....
  9. pmc Plasmin overcomes resistance to prostaglandin E2 in fibrotic lung fibroblasts by reorganizing protein kinase A signaling
    Katsuhide 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
    ....
  10. pmc Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts
    Natalie Walker
    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...
  11. pmc Epithelial interactions and local engraftment of lung-resident mesenchymal stem cells
    Linda 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
    ....
  12. pmc Leukotrienes and airway inflammation
    Katsuhide 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...
  13. pmc Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice
    Steven 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
    ....
  14. pmc The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice
    Kristy 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...
  15. pmc Prostaglandin E2 reduces Toll-like receptor 4 expression in alveolar macrophages by inhibition of translation
    Angela 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. ..

Research Grants30

  1. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
    ..g., heart attacks and strokes), as well as other organs and tissues of the body. These mechanistic insights may help identify novel therapeutic targets for the treatment of a broad spectrum of inflammatory diseases. ..
  2. ADAPTATIONS TO HYPOXIA
    Kurt R Stenmark; Fiscal Year: 2013
    ..abstract_text> ..
  3. Mechanisms of Airway Smooth Muscle Hypertrophy
    Marc B Hershenson; Fiscal Year: 2013
    ..Completion of this work will provide insight into the pathogenesis of BPD, lead to the development of more accurate biomarkers, and provide new information on the role of matricellular proteins in lung fibrosis. ..
  4. Novel Molecular Mechanisms Promote GPCR-Induced Bronchodilation in Asthma
    REYNOLD ALEXANDER PANETTIERI; Fiscal Year: 2013
    ..abstract_text> ..
  5. A Protective Role for Fibroblast Activation Protein (FAP) in Pulmonary Fibrosis
    Ming Hui Fan; Fiscal Year: 2013
    ..Dr. Fan's project will determine the mechanism(s) by which FAP protects against the development of pulmonary fibrosis after lung injury. ..
  6. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  7. Mechanisms of Adaptation to Exercise in Health and COPD
    Peter D Wagner; Fiscal Year: 2013
    ....
  8. Mechanisms of proteasomal regulation of fibrosis
    Manu Jain; Fiscal Year: 2013
    ..Targeting this protein would represent a new and novel therapeutic strategy for the treatment of Veterans with lung fibrosis. ..
  9. Nicotine-induced fibronectin expression in lung injury and repair
    Jesse Roman; Fiscal Year: 2013
    ....
  10. Regulation of pulmonary fibrosis by the sonic hedgehog pathway
    William E Lawson; Fiscal Year: 2013
    ....
  11. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  12. Epigenetic Regulation of the E Prostanoid 2 Receptor Gene in Lung Fibroblasts
    Steven K Huang; Fiscal Year: 2013
    ..The research proposed in this plan seeks to better understand the pathogenesis of pulmonary fibrosis which may lead to the development of better therapeutic strategies against this deadly disease. ..
  13. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  14. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  15. Pulmonary Surface Liquid Homeostasis
    RICHARD CHARLES BOUCHER; Fiscal Year: 2013
    ..abstract_text> ..
  16. Integrin-collagen signaling and control of fibroblast proliferation
    Craig A Henke; Fiscal Year: 2013
    ..Aim 3. Validation of in vitro studies implicating abnormal function of the [unreadable]1 integrin PI3K/Akt/S6K1-PTEN signaling axis in IPF fibrogenesis by in vivo methodology. ..
  17. Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
    Augustine M Choi; Fiscal Year: 2013
    ..4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core ..
  18. Signaling Pathways Regulating Serum Response Factor in Pulmonary Fibrosis
    NATHAN K SANDBO; Fiscal Year: 2013
    ..Identification of these signaling pathways may lead to the development of new drug treatments for this progressive, fatal disease. (End of Abstract) ..