Control of fibroblast function by prostaglandin E2 and plasminogen activation

Summary

Principal Investigator: Marc Peters-Golden
Affiliation: University of Michigan
Country: USA
Abstract: Fibroblasts are the principal effector cells that mediate tissue remodeling in idiopathic pulmonary fibrosis (IPF) via their capacities for enhanced survival, proliferation, collagen deposition, and myofibroblast differentiation. Although research in the pathogenesis of pulmonary fibrosis has been dominated by studies investigating fibroblast activation signals, evidence indicates that this disorder is also characterized by a relative deficiency in counter-regulatory anti-fibrotic signals. Two such anti-fibrotic signals are the prostanoid prostaglandin E2 (PGE2) and plasminogen activator (PA) activity. Each of these has been shown to be deficient in patients with IPF, and deficiency of each has been established to be pathogenically important in animal models of pulmonary fibrosis. PGE2 is a lipid mediator derived from cyclooxygenase metabolism of the fatty acid arachidonic acid that acts via cell surface G protein-coupled E prostanoid receptors. The PA system is a proteolytic cascade that includes the protease urokinase-type PA (uPA) and its associated inhibitor (plasminogen activator inhibitor-1). Although PGE2 inhibits the activation of all relevant pro-fibrotic cellular phenotypes in lung fibroblasts via intracellular cyclic AMP (cAMP) signaling, the downstream mechanisms by which it does so are incompletely understood. The PA system is recognized to orchestrate fibrinolysis and to modulate cellular adhesion and cellular signaling, but little is known about its direct effects on fibroblasts or their relevant phenotypes. Finally, there is no information about cross-talk between PGE2 and the PA system in lung cells of any kind, including fibroblasts. This project seeks to understand the mechanisms by which both mediators modulate fibroblast function, to characterize the cross-talk between them, and to determine how fibrotic lung injury influences the responses of fibroblasts to each of them. The general hypothesis is that the PGE2 and PA systems up-regulate each other and interact to influence pulmonary fibroblast phenotypes in a manner which favors lung repair over fibrosis. This hypothesis will be tested in fibroblast cell lines and in primary cells isolated from normal and fibrotic murine and human lungs. Aim 1 will examine the roles of cAMP effectors protein kinase A and guanylate exchange protein activated by cAMP as well as the phosphatase PTEN in mediating PGE2 effects on fibroblast phenotypes. Aim 2 will determine the mechanisms by which PGE2 and PA activity influence the expression of each other, while the role of each in mediating the actions of the other will be explored in Aim 3. Aim 4 will compare the effects of PGE2 and PA activity on phenotypes of fibroblasts derived from normal vs. injured mouse lungs and from histologically normal vs. IPF human lungs. The proposed studies will provide novel insights into the regulation of fibroblast activation by these two mediators, and will inform future efforts to target these molecules therapeutically. PUBLIC HEALTH RELEVANCE: The development of a serious condition known as lung scarring (pulmonary fibrosis) is opposed by two substances produced by the body, prostaglandin E2 and urokinase plasminogen activator. This proposal will examine how these two substances act and interact to suppress scarring responses of the key lung cell type known as the fibroblast. These studies will enhance our understanding of how scarring responses are regulated, and may provide insight as to whether these substances could be administered to patients to treat this devastating condition.
Funding Period: ----------------2009 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. ncbi 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
  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 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
  9. 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
  10. 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

Scientific Experts

  • Steven K Huang
  • Marc Peters-Golden
  • Katsuhide Okunishi
  • Zbigniew Zasłona
  • Linda Badri
  • Bethany B Moore
  • Ariane R Brogliato
  • Emilie Bourdonnay
  • Angela Juliette Degraaf
  • Garth Garrison
  • David M Aronoff
  • Natalie Walker
  • Andrew Flint
  • Camila Leindecker Stumm
  • Paul H Krebsbach
  • Vibha N Lama
  • Thomas H Sisson
  • Cory M Hogaboam
  • Richard H Simon
  • Galen B Toews
  • Scott H Wettlaufer
  • Kristy A Bauman
  • Eric S White
  • Rommel L Sagana
  • Lisa J Gould
  • Angela J Degraaf
  • Janaína L Georgii
  • Racquel Domingo-Gonzalez
  • Shannon L Kesl
  • Claudia F Benjamim
  • Rafael F Guilherme
  • Claudio Canetti
  • Nicholas W Lukacs
  • Andrea N Moor
  • Zbigniew Zaslona
  • Anne M Scruggs
  • Jacob P Scott
  • Loka Raghu Kumar Penke
  • Uma Sajjan
  • Venkateshwar G Keshamouni
  • Takashi Ohtsuka
  • Sonia Jancar
  • Scott Wettlaufer
  • Zhuo Wang
  • Natalie M Walker
  • David J Pinsky
  • Mario Delmar
  • Anthony J Courey
  • Joshua S Stoolman
  • Kevin M Vannella
  • Megan N Ballinger
  • David A Stephenson
  • Mei Yan
  • Christopher D Kontos
  • Ashley M Cornett
  • Jessica L Tsui
  • Janet Melonakos

Detail Information

Publications15

  1. ncbi 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. ..
  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
    ..Okunishi K., DeGraaf, A. J., Zasłona, Z., Peters-Golden, M. Inhibition of protein translation as a novel mechanism for prostaglandin E2 regulation of cell functions. ..
  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 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
    ....
  9. 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
    ....
  10. 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
    ....
  11. 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...
  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 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...