Selectins influence thrombosis in a mouse model of experimental deep venous thrombosis.
BACKGROUND
This study characterizes venous thrombosis in the mouse and examines the important role that the adhesion molecules P-selectin and E-selectin and the anti-inflammatory cytokine interleukin-10 (IL-10) play in the thrombotic process.


METHODS
C57BL/6 (wild-type) mice in a natural history protocol (Phase I) and gene-targeted (KO) mice for P-selectin, E-selectin, P/E-selectin, and IL-10 in a follow-up protocol (Phase II) were studied. Inferior vena caval thrombosis was produced by ligation just below the renal veins, and mice were sacrificed and evaluated at various time points up to 12 days later.


RESULTS
Phase I: A significant increase in neutrophils on day 2 and in monocytes on day 6 postthrombosis was found in ligated vs sham animals. An associated significant increase in vein wall P-selectin mRNA (6 h, day 2) and an increase in protein (6 h through day 6) were found, while E-selectin mRNA was significantly increased (day 2 through day 6), with a smaller increase in E-selectin protein. IL-10 mRNA increased significantly later (day 2 through day 9), with the values increasing progressively. A positive correlation existed (r = 0.77) between neutrophils and thrombosis at day 2.


METHODS
The E-selectin and P/E-selectin double-KO mice showed the least thrombus at day 2 vs wild-type clotted mice, P < 0.01. Additionally, P/E-KO mice demonstrated the lowest inflammatory cell extravasation into the vein wall at day 2.


CONCLUSIONS
This study demonstrates an acute to chronic inflammatory response in the vein wall associated with venous thrombosis. Inhibition of selectins decreased thrombus formation.
Myers
Daniel
D
Jobst Vascular Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, 48109, USA. ddmyers@umich.edu
Farris
Diana
D
Hawley
Angela
A
Wrobleski
Shirley
S
Chapman
Amy
A
Stoolman
Lloyd
L
Knibbs
Randy
R
Strieter
Robert
R
Wakefield
Thomas
T
D000818:Animals; D002908:Chronic Disease; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000378:metabolism; D007700:Kinetics; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D013194:Staining and Labeling; D014657:Vasculitis / Q000209:etiology / Q000473:pathology; D020246:Venous Thrombosis / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*
D019040:E-Selectin; D019007:P-Selectin; D016753:Interleukin-10