Mechanisms of MMP-3 Action in Acute Lung Injury

Summary

Principal Investigator: JAMES J VARANI
Abstract: Studies conducted with matrix metalloproteinase-3 (MMP-3; stromelysin-1) gene-deleted (MMP-3- /-) animals have indicated an important pro-inflammatory role for this enzyme in acute lung injury, but the mechanism by which stromelysin-1 contributes to the disease process is not well understood. MMP-3 may play a direct role in damage to the alveolar wall. Damage to the alveolar wall, in and of itself, may be sufficient to facilitate lung injury. Alternatively, MMP-3 may promote lung injury by contributing to the generation of factors that stimulate neutrophil recruitment to the lung. Neutrophil chemotactic factors derived from non-collagenous components of the extracellular matrix as well as chemotactic cytokines elaborated by macrophages may be differentially elaborated in MMP-3 -/- animals as compared to normal controls. The overall goal of the proposed research is to evaluate the possible mechanisms in order to understand, specifically, how MMP-3 contributes to acute lung injury. In Specific Aim I, we will delineate the cellular sources of MMP-3 in the lungs of normal mice and determine how MMP-3 levels change during acute lung injury. In normal and MMP-3 -/- mice we will assess the production of several other MMPs that are known to play a role in inflammation and will concomitantly evaluate the production of MMP inhibitors under the same conditions. It is important to determine if there are compensatory changes in other MMPs or MMP inhibitors in animals lacking MMP-3. In specific Aims II and III we will utilize an in vitro model of an alveolar wall to directly assess the role of MMP-3 in damage to the alveolar wall and the role of MMP-3 in neutrophil migration across the alveolar wall. Studies will be conducted under conditions that lead to acute lung injury in intact animals and under conditions that result in neutrophil migration across the alveolar wall occurs but that do not lead to tissue damage, per se. Finally, in Specific Aim IV, we will assess the role of MMP-3 in alveolar wall damage in vivo under conditions that lead to acute lung inflammation or that lead to neutrophil influx into the alveolar space without tissue damage. These studies will provide an overall understanding of the mechanism(s) by which MMP-3 contributes to acute lung injury.
Funding Period: 2003-07-01 - 2006-11-30
more information: NIH RePORT

Top Publications

  1. pmc Hemostatic properties of a venomic protein in rat organ trauma
    Roscoe L Warner
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    Exp Mol Pathol 87:204-11. 2009
  2. ncbi Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury
    Suzanne E G Fligiel
    Department of Pathology, The University of Michigan, Ann Arbor, 48109, USA
    Hum Pathol 37:422-30. 2006
  3. pmc Matrix metalloproteinase-3 (stromelysin-1) in acute inflammatory tissue injury
    Kamalakar C Nerusu
    Department of Pathology, The University of Michigan Medical School, 1301 Catherine Road Box 0602, Ann Arbor, MI 48109, USA
    Exp Mol Pathol 83:169-76. 2007

Scientific Experts

  • Roscoe L Warner
  • Shannon D McClintock
  • Kamalakar C Nerusu
  • James Varani
  • Kent J Johnson
  • Suzanne E G Fligiel
  • Felix A de la Iglesia
  • Adam G Barron
  • Narasimharao Bhagavathula
  • Donald Tashkin
  • Theodore Standiford
  • Helene M Fligiel
  • Robert M Strieter

Detail Information

Publications3

  1. pmc Hemostatic properties of a venomic protein in rat organ trauma
    Roscoe L Warner
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    Exp Mol Pathol 87:204-11. 2009
    ..The protein Q8009 has greater capacity to reduce blood loss and shorten time-to-hemostasis; highly desirable properties where rapid hemostasis is needed in surgical wounds in parenchymatous organs...
  2. ncbi Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury
    Suzanne E G Fligiel
    Department of Pathology, The University of Michigan, Ann Arbor, 48109, USA
    Hum Pathol 37:422-30. 2006
    ..On the other hand, the presence of detectable MMP-1 and/or MMP-3 is an indicator of more ominous disease progression...
  3. pmc Matrix metalloproteinase-3 (stromelysin-1) in acute inflammatory tissue injury
    Kamalakar C Nerusu
    Department of Pathology, The University of Michigan Medical School, 1301 Catherine Road Box 0602, Ann Arbor, MI 48109, USA
    Exp Mol Pathol 83:169-76. 2007
    ..There was also a relationship between tissue injury and influx of neutrophils into the BAL or PL fluid. Taken together, these data demonstrate an important role for MMP-3 in acute inflammatory tissue injury...