TNF-alpha Signaling in Silica-Induced Lung Fibrosis

Summary

Principal Investigator: Luis A Ortiz
Affiliation: University of Pittsburgh
Country: USA
Abstract: The pneumoconioses are a group of fibrotic lung diseases caused by the environmental exposure to a variety of inorganic dusts. Several of these dusts, including silica, are associated with lung inflammation and the subsequent development of lung fibrosis. The inflammatory response to silica is characterized by an increased expression of tumor necrosis factor-alpha (TNF). Inhaled silica triggers TNF receptor-mediated signal transduction pathways promoting NF-kappaB and AP-1 activation which in turn induce the expression of genes mediating the proinflammatory (TNF) and profibrotic (collagen, matrix metalloproteinases, TIMP- 1) effects of silica. These TNF-mediated signal transduction pathways, in response to silica, includes activation of the ERK1/2 family of mitogen-activated protein kinases (MAPK) that induces TNF receptor phosphorylation. The importance of TNF receptor phosphorylation in silicosis is not known. Here we propose that TNF receptor phosphorylation promotes cell survival signals that protect the lungs from silica-induced apoptosis. Our in vitro preliminary data show that differences in the silica-induced-TNF-mediated signal transduction correlate with macrophage cell survival. The macrophage cell line RAW 264.7 reacts to silica exposure with enhanced TNF expression. This enhanced TNF expression promotes NF-kappaB and ERK1/2 activation. Activated ERK1/2 kinases induce phosphorylation of the TNF receptors and protect RAW 264.7 cells from silica-induced apoptosis. In contrast, the IC-21 macrophage cell line does not upregulate TNF expression in response to silica. IC-21 cells do not activate NF-kappaB or ERK kinases in response to silica. IC- 21 cells do not phosphorylate TNF receptors and exhibit enhanced silica-induced apoptosis. Our in vivo data demonstrate that individual TNF receptor deficient mice are protected from the fibrogenic effects of silica. This protection correlates with a decreased AP-1 activation and decreased expression of the Tissue Inhibitor of Metalloproteinase 1 (TIMP-1) observed in the lungs of silica-sensitive (C57BL/6) mice in response to silica. Our working hypothesis to further understand the mechanisms of silica-induced lung fibrosis is that disruption of the silica- induced and TNF receptor-mediated activation of NFkappaB and ERK in the lung will enhance apoptosis in alveolar epithelial type II cells thus aggravating silica-induced lung injury and fibrosis. Specific Aims are: 1). To determine whether inhibition of NF- kappaB activation in alveolar epithelial type II cells will exacerbate silica-induced lung injury in mice. 2). To determine whether inhibition of ERK-mediated phosphorylation of TNF receptors will exacerbate silica-induced lung injury. 3). To determine whether overexpression of Tissue Inhibitor of Metalloproteinase 1 (TIMP-1) in mouse lung exacerbates silica- induced lung injury.
Funding Period: 2002-02-04 - 2008-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Apoptotic cells quench reactive oxygen and nitrogen species and modulate TNF-alpha/TGF-beta1 balance in activated macrophages: involvement of phosphatidylserine-dependent and -independent pathways
    B F Serinkan
    Cell Death Differ 12:1141-4. 2005
  2. ncbi Loss of fibroblast Thy-1 expression correlates with lung fibrogenesis
    James S Hagood
    Department of Pediatrics, University of Alabama, Birmingham, USA
    Am J Pathol 167:365-79. 2005
  3. ncbi Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury
    Luis A Ortiz
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Proc Natl Acad Sci U S A 104:11002-7. 2007
  4. ncbi Epithelial expression of TIMP-1 does not alter sensitivity to bleomycin-induced lung injury in C57BL/6 mice
    Cheryl L Fattman
    University of Pittsburgh, Graduate School of Public Health, Department of Environmental and Occupational Health, Bridgeside Point, 100 Technology Dr, Suite 328, Pittsburgh, PA 15219 3130, USA
    Am J Physiol Lung Cell Mol Physiol 294:L572-81. 2008
  5. ncbi Systemic inhibition of NF-kappaB activation protects from silicosis
    Michelangelo Di Giuseppe
    Division of Occupational and Environmental Medicine, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 4:e5689. 2009

Scientific Experts

  • J S Hagood
  • Luis A Ortiz
  • Michelangelo Di Giuseppe
  • Federica Gambelli
  • Cheryl L Fattman
  • B F Serinkan
  • Thomas Richards
  • Ken McCurry
  • GEORGE LEIKAUF
  • Giuseppe Lungarella
  • Sean M Studer
  • James Dauber
  • Gary W Hoyle
  • Naftali Kaminski
  • Sam Yousem
  • Gary Hoyle
  • Bruce R Pitt
  • Maria DuTreil
  • Donald G Phinney
  • Cheryl Fattman
  • German Torres
  • Kristina Go
  • Amitabh C Pandey
  • H Babu
  • M Di Giuseppe
  • J P Fabisiak
  • V E Kagan
  • A I Potapovich
  • L A Ortiz
  • F Gambelli

Detail Information

Publications5

  1. ncbi Apoptotic cells quench reactive oxygen and nitrogen species and modulate TNF-alpha/TGF-beta1 balance in activated macrophages: involvement of phosphatidylserine-dependent and -independent pathways
    B F Serinkan
    Cell Death Differ 12:1141-4. 2005
  2. ncbi Loss of fibroblast Thy-1 expression correlates with lung fibrogenesis
    James S Hagood
    Department of Pediatrics, University of Alabama, Birmingham, USA
    Am J Pathol 167:365-79. 2005
    ..These results suggest that fibrogenic injury promotes loss of lung fibroblast Thy-1 expression, resulting in enhanced fibrogenesis...
  3. ncbi Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury
    Luis A Ortiz
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Proc Natl Acad Sci U S A 104:11002-7. 2007
    ..Identification of IL1RN-expressing human MSC subpopulations may provide a novel cellular vector for treating chronic inflammatory diseases in humans...
  4. ncbi Epithelial expression of TIMP-1 does not alter sensitivity to bleomycin-induced lung injury in C57BL/6 mice
    Cheryl L Fattman
    University of Pittsburgh, Graduate School of Public Health, Department of Environmental and Occupational Health, Bridgeside Point, 100 Technology Dr, Suite 328, Pittsburgh, PA 15219 3130, USA
    Am J Physiol Lung Cell Mol Physiol 294:L572-81. 2008
    ..We conclude that although TIMP-1 expression is differentially regulated in fibrosis-sensitive and fibrosis-resistant strains, epithelial overexpression of TIMP-1 does not appear to substantially alter fibrotic lung disease in mice...
  5. ncbi Systemic inhibition of NF-kappaB activation protects from silicosis
    Michelangelo Di Giuseppe
    Division of Occupational and Environmental Medicine, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 4:e5689. 2009
    ..Therefore, inhibition of NF-kappaB activation represents a potential therapeutic strategy for silicosis...