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Thromb Haemost 2006; 95(02): 272-281
DOI: 10.1160/TH05-02-0099
Platelets and Blood Cells
Schattauer GmbH

Neutrophils modulate post-thrombotic vein wall remodeling but not thrombus neovascularization

Peter K. Henke
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery
,
Manu R. Varma
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery
,
K. Barry Deatrick
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery
,
Nicholas A. Dewyer
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery
,
Erin M. Lynch
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery
,
Andrea J. Moore
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery
,
Derek A. Dubay
2   Section of General Surgery, Department of Surgery
,
Pasu Sukheepod
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery
,
Charles G. Pearce
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery
,
Gilbert R. Upchurch Jr.
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery
,
Steven L. Kunkel
3   Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Michael G. Franz
2   Section of General Surgery, Department of Surgery
,
Thomas W. Wakefield
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery
› Author AffiliationsFinancial support: Supported by Lifeline Foundation, vonLeibig Foundation, and NIH K-08 HL#69780 (PKH) and HL #70766 (TWW).
Further Information

Publication History

Received 09 February 2005

Accepted after revision 16 January 2005

Publication Date:
28 November 2017 (online)

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Summary

Early deep venous thrombosis (DVT) resolution is associated with neutrophil (PMN) influx. This study examined the role of PMNs in thrombus neovascularization and vein wall injury after DVT. A rat model of DVT by inferior vena cava (IVC) ligation was performed with control serum or rabbit anti-rat PMN serum administered perioperatively with sacrifice at 2 and 7 days. At 2 days, neutropenic rats had 1.6-fold larger thrombi (P = .04) and 1.4-fold higher femoral venous pressures by water manometry (P = .008) but no difference in thrombus neovascularization was observed. By7 days, DVT sizes were similar, but vein wall injury persisted in the neutropenic rats with a 2.0-fold increase in vein wall stiffness by microtensiometry (P< .05), as well asa 1.2-fold increased thickness (P = .04). Collagen and profibrotic growth factors were significantly increased in neutropenic IVC at7 days (all P< .05).Vein wall and intrathrombus uPA by Western immunoblotting, and intrathrombus MMP-9 gelatinase activity were significantly less in neutropenic rats than controls (P < .001). Conversely, MMP-2 was significantly elevated in neutropenic IVC at 2 days after DVT. However, neutropenia induced 24 hours after DVT formation resulted in no significant increase in vein wall stiffness or collagen levels at 7 days, despite 1.4-fold larger thrombi (P < .05). These data suggest a critical early role for PMN in post DVT vein wall remodeling.

Keywords

Animal models - tissue remodelling - leukocyte function / activation - deep vein thrombosis

* Presented in part at the 65th Annual Meeting of the Society of University Surgeons, February 13, 2004, St. Louis, MO, USA.


 

  • References

  • 1 Prandoni P, Lensing AW, Cogo A. et al. The longterm clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
    CrossrefPubMedGoogle Scholar
  • 2 Henke PK, DeBrunye LA, Strieter RM. et al. Viral IL-10 Gene Transfer Decreases Inflammation and Cell Adhesion Molecule Expression in a Rat Model of Venous Thrombosis. J Immunol 2000; 164: 2131-41.
    CrossrefPubMedGoogle Scholar
  • 3 Henke PK, Wakefield TW, Kadell AM. et al. Interleukin-8 administration enhances venous thrombosis resolution ina rat model. J Surg Res 2001; 99: 84-91.
    CrossrefPubMedGoogle Scholar
  • 4 Wakefield TW, Linn MJ, Henke PK. et al. Neovascularization during venous thrombosis organization: A preliminary study. J Vasc Surg 1999; 30: 885-93.
    CrossrefPubMedGoogle Scholar
  • 5 Stewart GJ. Neutrophils and deep venous thrombosis. Haemostasis 1993; 23 (Suppl. 01) 127-40.
    PubMedGoogle Scholar
  • 6 Henke PK, Varga A, De S. et al. Deep vein thrombosis resolution is modulated by monocyte CXCR2-mediated activity ina mouse model. Arterioscler Thromb Vasc Biol 2004; 24: 1130-7.
    CrossrefPubMedGoogle Scholar
  • 7 Varma MR, Moaveni DM, Dewyer NA. et al. Deep vein thrombosis resolution is not accelerated with increased neovascularization. J Vasc Surg 2004; 40: 536-42.
    CrossrefPubMedGoogle Scholar
  • 8 Thanaporn P, Myers DD, Wrobleski SK. et al. P-selectin inhibition decreases post-thrombotic vein wall fibrosis in a rat model. Surgery 2003; 134: 365-71.
    CrossrefPubMedGoogle Scholar
  • 9 Varma MR, Varga AJ, Knipp BS. et al. Neutropenia impairs venous thrombosis resolution in the rat. J Vasc Surg 2003; 38: 1090-8.
    CrossrefPubMedGoogle Scholar
  • 10 Moir E, Booth NA, Bennett B. et al. Polymorphonuclear leucocytes mediate endogenous thrombus lysis via a u-PA-dependent mechanism. Br J Haematol 2001; 113: 72-80.
    CrossrefPubMedGoogle Scholar
  • 11 Singh I, Burnand KG, Collins M. et al. Failure of thrombus to resolve in urokinase-type plasminogen activator gene-knockout mice: rescue by normal bone marrow-derived cells. Circulation 2003; 107: 869-75.
    CrossrefPubMedGoogle Scholar
  • 12 McCourt M, Wang JH, Sookhai S. et al. Proinflammatory mediators stimulate neutrophil-directed angiogenesis. Arch Surg 1999; 134: 1325-31 discussion 1331-2.
    CrossrefPubMedGoogle Scholar
  • 13 Singer AJ, Clark RA. Cutaneous wound healing. N EnglJ Med 1999; 341: 738-46.
    CrossrefPubMedGoogle Scholar
  • 14 Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003; 92: 827-39.
    CrossrefPubMedGoogle Scholar
  • 15 Myers Jr DD, Henke PK, Wrobleski SK. et al. P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a rat model. J Vasc Surg 2002; 36: 928-38.
    CrossrefPubMedGoogle Scholar
  • 16 Couffinhal T, Silver M, Kearney M. et al. Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE−/−mice. Circulation 1999; 99: 3188-98.
    CrossrefPubMedGoogle Scholar
  • 17 Franz MG, Smith PD, Wachtel TL. et al. Fascial incisions heal faster than skin: A new model of abdominal wall repair. Surgery 2001; 129: 203-8.
    CrossrefPubMedGoogle Scholar
  • 18 Upchurch GR, Ford JW, Weiss SJ. et al. Nitric oxide inhibition increases matrix metalloproteinase-9 expression bya rat aortic smooth muscle cells in vitro. J Vasc Surg 2001; 34: 76-83.
    CrossrefPubMedGoogle Scholar
  • 19 Forsberg E, Kjellen L. Heparan sulfate: lessons from knockout mice. J Clin Invest 2001; 108: 175-80.
    CrossrefPubMedGoogle Scholar
  • 20 Schafer K, Konstantinides S, Riedel C. et al. Different mechanisms of increased luminal stenosis after arterial injury in mice deficient for urokinase-or tissuetype plasminogen activator. Circulation 2002; 106: 1847-52.
    CrossrefPubMedGoogle Scholar
  • 21 Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol 2000; 18: 217-42.
    CrossrefPubMedGoogle Scholar
  • 22 See-Tho K, Harris Jr EJ. Thrombosis with outflow obstruction delays thrombolysis and results in chronic wall thickening of rat veins. J Vasc Surg 1998; 28: 115-22 discussion 123.
    CrossrefPubMedGoogle Scholar
  • 23 Zhang G, Kim H, Cai X. et al. Urokinase receptor modulates cellular and angiogenic responses in obstructive nephropathy. J Am Soc Nephrol 2003; 14: 1234-53.
    CrossrefPubMedGoogle Scholar
  • 24 Chou DH-I, Lee W, McCulloch CA. TNFa inactivation of collagen receptors. J Immunol 1996; 156: 4354-62.
    PubMedGoogle Scholar
  • 25 Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol 2001; 69: 513-21.
    PubMedGoogle Scholar
  • 26 Whatling C, McPheat W, Hurt-Camejo E. Matrix management: Assigning different roles for MMP-2 and MMP-9 in vascular remodeling. Arterioscler Thromb Vasc Biol 2004; 24: 10-11.
    CrossrefPubMedGoogle Scholar
  • 27 Tran PK, Tran-Lundmark K, Soininen R. et al. Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfatedeficient perlecan. Circ Res 2004; 94: 550-8.
    CrossrefPubMedGoogle Scholar
  • 28 Kovacs EJ. Fibrogenic cytokines: the role of immune mediators in the development of scar tissue. Immunol Today 1991; 12: 17-23.
    CrossrefPubMedGoogle Scholar
  • 29 Grainger DJ, Wakefield L, Bethell HW. et al. Release and activation of platelet latent TGFb in blood clots during dissolution with plasmin. Nature Med 1995; 01: 932-7.
    CrossrefPubMedGoogle Scholar
  • 30 Dovi JV, He LK, DiPietro LA. Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol 2003; 73: 448-55.
    CrossrefPubMedGoogle Scholar
  • 31 Sunderkotter C, Steinbrink K, Goebeler M. et al. Macrophages and angiogenesis. J Leukoc Biol 1994; 55: 410-22.
    CrossrefPubMedGoogle Scholar
  • 32 Lin J, Proctor MC, Varma M. et al. Factors associated with recurrent venous thromboembolism in patients with malignant disease. J Vasc Surg 2003; 37: 976-83.
    CrossrefPubMedGoogle Scholar
  • 33 Wakefield TW. Treatment options for venous thrombosis. J Vasc Surg 2000; 31: 613-20.
    CrossrefPubMedGoogle Scholar