P-selectin and TNF inhibition reduce venous thrombosis inflammation

Venous thrombosis induces a detrimental inflammatory response in the vein wall. The cytokine tumor necrosis factor-alpha (TNF) and the adhesion molecules, selectins, have been found to be important in mediating inflammatory cell stimulation and leukocyte-endothelial cell adhesion, respectively. This study assesses the role of TNF and P-selectin in the inflammatory events associated with venous thrombosis. Rats were passively immunized with neutralizing anti-TNF serum alone, anti-TNF plus anti-P-selectin antibody, anti-P-selectin antibody alone, control serum, or control anti-P-selectin antibody. Antibodies or control sera were given prior to occlusion and at Days 2 and 4 postocclusion. Rats were sacrificed at Days 1-6 and Day 13 after occlusion for inferior vena caval (IVC) wall histopathology and TNF analysis. Differences in the extent of inflammatory cell infiltrate into the vein wall were found on Days 2, 6, and 13. TNF levels were elevated in the vein wall of the three groups not given anti-TNF antibody. The levels of TNF at Day 6 positively correlated with both total inflammatory cell (r = 0.53, P < 0.05) and neutrophil presence (r = 0.72, P < 0.01). The lowest IVC wall neutrophil and total inflammatory cell count at Days 2 and 6 and the lowest neutrophil count at Day 13 were found in the anti-TNF plus anti-P-selectin antibody group. Monocyte influx was also inhibited at Day 13 in this group. These results suggest a role for combined neutralization of TNF and P-selectin in the attenuation of inflammation induced by venous thrombosis.