P-selectin inhibition decreases post-thrombotic vein wall fibrosis in a rat model.
BACKGROUND
Post-deep vein thrombosis (DVT) venous insufficiency is a vexing problem despite effective anticoagulation, and is characterized by vein wall fibrosis. This study tested the hypothesis that P-selectin inhibition would decrease post-thrombotic vein wall fibrosis and associated profibrotic mediators.


METHODS
A rat stasis model of DVT was used to produce a 2-day-old DVT. Rats then received either intravenous saline (control), rPSGL-Ig (4 mg/kg) once, or daily subcutaneous low molecular weight heparin (LMWH) (0.5 mg/kg). Inferior vena cava wall was harvested 7 days after treatment and processed for thrombus size; leukocyte content; profibrotic mediators by enzyme-linked immunosorbent assay; collagen I and III mRNA expression by semiquantitative real-time polymerase chain reaction; and for collagen protein.


RESULTS
Thrombus mass and leukocyte counts were similar between the groups. Treatment with rPSGL-Ig and LMWH resulted in less vein wall collagen (P <.05). rPSGL-Ig treatment (and a similar trend for LMWH) was associated with decreased profibrotic mediators, including less IL-13, MCP-1, bFGH, and transforming growth factor-beta (P <.05). Collagen III gene expression, but not collagen I gene expression, was increased with LMWH treatment (P <.05).


CONCLUSIONS
P-selectin inhibition with rPSGL-Ig or LMWH decreases post-DVT vein wall fibrosis, and is associated with decreased vein wall profibrotic mediators. This effect is independent of thrombus mass and vein wall leukocytes.
Thanaporn
Porama
P
Section of Vascular Surgery, Department of Surgery, Jobst Vascular Laboratory and Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Myers
Daniel D
DD
Wrobleski
Shirley K
SK
Hawley
Angela E
AE
Farris
Diana M
DM
Wakefield
Thomas W
TW
Henke
Peter K
PK
D000818:Animals; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D003094:Collagen / Q000037:antagonists & inhibitors; D024061:Collagen Type III / Q000235:genetics; D004334:Drug Administration Schedule; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D018793:Interleukin-13 / Q000037:antagonists & inhibitors; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage*; D019007:P-Selectin / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014682:Vena Cava, Inferior / Q000378:metabolism / Q000473:pathology; D020246:Venous Thrombosis / Q000378:metabolism* / Q000473:pathology*
D018932:Chemokine CCL2; D024061:Collagen Type III; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D018793:Interleukin-13; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D016212:Transforming Growth Factor beta; D003094:Collagen