Vein Wall Fibrotic Injury After DVT is SLC-CCR7 Dependent

Summary

Principal Investigator: P K Henke
Affiliation: University of Michigan
Country: USA
Abstract: DESCRIPTION (provided by applicant): The most common sequela of deep vein thrombosis (DVT) is post thrombotic syndrome (PTS). This is a significantly morbid disease that results from vein wall injury secondary to the inflammatory response of the lysing thrombus. Post DVT vein wall remodeling resembles many diseases that are characterized by chronic irreversible fibrotic changes. The chemokine SLC (CCL21) and its primary receptor, CCR7, have been shown to be integral in both human and experimental fibrotic organ injury. In conjunction with our preliminary data, we believe the SLC-CCR7 axis is critical to DVT resolution and pathological vein wall injury response. In this proposal we test the overall hypothesis that SLC, via CCR7 signaling, mediates vein wall fibrotic injury after DVT. This will be addressed by three Specific Aims. I: To define the role of thrombogenic injury on vein wall SLC-CCR7 expression;II: To determine the effect and mechanism of SLC on post-DVT vein wall cellular matrix protein production, proliferation, and proteinase activity, and the contribution of SLC to endothelial to mesenchymal transformation after DVT;III: To demonstrate that bone marrow derived CCR7 positive cells directly mediate vein wall fibrotic injury after DVT, and that currently available therapies and anti- CCR7 strategies can reverse early fibrotic injury. The current proposal will elucidate the role of SLC, and its effector cell, the CCR7 positive leukocyte, on vein wall remodeling by several mechanisms of thrombotic injury in the mouse, and by in vitro vein wall cellular analysis. The long-term goal of this study is to define the basic mechanisms of post DVT vein wall fibrotic injury with the translation to human medical therapies to: 1) accelerate DVT resolution without anticoagulation risks: 2) to reduce vein wall fibrotic injury and thus reduce the incidence of PTS. PUBLIC HEALTH RELEVANCE: This proposal will establish the role of a chemokine that mediates a circulating wound healing cell in vein wall remodeling after deep vein thrombosis. The long term goal is to define a therapy to decrease post thrombotic syndrome, a common and morbid complication of deep vein thrombosis.
Funding Period: 2009-04-01 - 2013-02-28
more information: NIH RePORT

Top Publications

  1. pmc The role of urokinase plasminogen activator and plasmin activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis
    Joe F Baldwin
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
    J Vasc Surg 56:1089-97. 2012
  2. pmc The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling
    Kristopher B Deatrick
    Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Mich
    J Vasc Surg 58:1375-1384.e2. 2013
  3. pmc Matrix metalloproteinase-9 deletion is associated with decreased mid-term vein wall fibrosis in experimental stasis DVT
    Kristopher B Deatrick
    Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Boston MA, United States
    Thromb Res 132:360-6. 2013
  4. pmc Deletion of cysteine-cysteine receptor 7 promotes fibrotic injury in experimental post-thrombotic vein wall remodeling
    Adriana Laser
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, Department of Surgery A L, M E, C L, D S, A s, V S, B D, B M, S K, C H, P K H and Department of Pathology A L, M E, C L, D S, A s, V S, B D, B M, S K, C H, P K H, University of Michigan Medical School, Ann Arbor and Jobst Vascular Center, Toledo, OH C O, A C
    Arterioscler Thromb Vasc Biol 34:377-85. 2014
  5. pmc Postthrombotic vein wall remodeling: preliminary observations
    Kristopher B Deatrick
    Section of Vascular Surgery, Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
    J Vasc Surg 53:139-46. 2011
  6. pmc Toll-like receptor 9 signaling is critical for early experimental deep vein thrombosis resolution
    Peter K Henke
    CVC 5463, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 31:43-9. 2011
  7. pmc Critical review of mouse models of venous thrombosis
    Jose A Diaz
    Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, A570 MSRB II, Dock 6, 1150 W Medical Center Drive, Ann Arbor, MI 48109 0654, USA
    Arterioscler Thromb Vasc Biol 32:556-62. 2012

Scientific Experts

  • P K Henke
  • J A Diaz
  • Kristopher B Deatrick
  • Vikram Sood
  • Megan A Elfline
  • Catherine E Luke
  • Thomas W Wakefield
  • Adriana Laser
  • Gilbert R Upchurch
  • Megan Elfline
  • Joe F Baldwin
  • Barry Deatrick
  • Anuj Shah
  • Cory Hogaboam
  • Steven Kunkel
  • Carson Ostra
  • Dallas Slack
  • Brendan McEvoy
  • Cathy Luke
  • Anthony Comerota
  • Andrea Obi
  • Joseph Baldwin
  • Farouc A Jaffer
  • Farouc Jaffer
  • Thomas Wakefield
  • Nicholas A Dewyer
  • Cathy E Luke
  • Dan D Myers
  • Nichole Baker
  • Catherine Stabler
  • Susan Blackburn

Detail Information

Publications7

  1. pmc The role of urokinase plasminogen activator and plasmin activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis
    Joe F Baldwin
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
    J Vasc Surg 56:1089-97. 2012
    ..This study determined the vein wall response when exposed to increased and decreased plasmin activity...
  2. pmc The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling
    Kristopher B Deatrick
    Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Mich
    J Vasc Surg 58:1375-1384.e2. 2013
    ..Vein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP2 contributes to vein wall remodeling after VT is unknown...
  3. pmc Matrix metalloproteinase-9 deletion is associated with decreased mid-term vein wall fibrosis in experimental stasis DVT
    Kristopher B Deatrick
    Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Boston MA, United States
    Thromb Res 132:360-6. 2013
    ..Vein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP9 directly contributes to vein wall remodeling after VT is unknown...
  4. pmc Deletion of cysteine-cysteine receptor 7 promotes fibrotic injury in experimental post-thrombotic vein wall remodeling
    Adriana Laser
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, Department of Surgery A L, M E, C L, D S, A s, V S, B D, B M, S K, C H, P K H and Department of Pathology A L, M E, C L, D S, A s, V S, B D, B M, S K, C H, P K H, University of Michigan Medical School, Ann Arbor and Jobst Vascular Center, Toledo, OH C O, A C
    Arterioscler Thromb Vasc Biol 34:377-85. 2014
    ..Postinjury fibrosis may be modulated in part through cellular cysteine-cysteine receptor 7 (CCR7)-mediated events. We tested the hypothesis that late vein wall fibrotic remodeling is dependent on CCR7...
  5. pmc Postthrombotic vein wall remodeling: preliminary observations
    Kristopher B Deatrick
    Section of Vascular Surgery, Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
    J Vasc Surg 53:139-46. 2011
    ..We sought to quantify the change in vein wall thickness in patients who fail to resolve DVT by 6 months and whether there were differences in blood or plasma levels of inflammatory proteins associated with venous remodeling...
  6. pmc Toll-like receptor 9 signaling is critical for early experimental deep vein thrombosis resolution
    Peter K Henke
    CVC 5463, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 31:43-9. 2011
    ..Toll-like receptors (TLR) bridge innate immunity and host responses, including inflammation. Sterile inflammation such as a venous thrombus (Vt) may involve TLR signaling, including TLR9...
  7. pmc Critical review of mouse models of venous thrombosis
    Jose A Diaz
    Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, A570 MSRB II, Dock 6, 1150 W Medical Center Drive, Ann Arbor, MI 48109 0654, USA
    Arterioscler Thromb Vasc Biol 32:556-62. 2012
    ..In this work we review the ferric chloride model, the inferior vena cava ligation model, the inferior vena cava stenosis models, and the electrolytic inferior vena cava model and compare their advantages and disadvantages...