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CD40/CD40L signalling in microvascular thrombosis It is now accepted that there is a crosstalk between inflammation and thrombosis, in which both processes activate and propagate each other. Despite this knowledge the signalling molecules that link these two processes remain poorly understood. The aim of this study was to assess the contribution of the CD40/CD40L dyad to the enhanced microvascular thrombosis that accompanies two distinct experimental models of inflammation: endotoxemia (LPS) and dextran sulphate sodium (DSS)-induced colitis. Thrombosis was induced in cerebral (LPS model: Mice were treated for 2h with 5.0 x 106 EU/kg body weight, in 0.5 ml of sterile saline (1)) and cremaster muscle (DSS model:2) arterioles and venules of wild type (WT) mice and mice deficient in either CD40 (CD40-/-) or CD40L (CD40L-/-) using the light/dye (photoactivation) method (3). A comparison of thrombus formation between WT and mutant mice revealed a role for CD40 and/or CD40L in the inflammation-enhanced thrombosis responses in both the cerebral and muscle vasculatures. Unless otherwise indicated, data are presented as means ± SEM of 6mice/group. ANOVA with the Bonferroni post hoc test, with statistical significance at P < 0.05. LPS administration significantly accelerated thrombus formation in both cerebral venules and arterioles, with the former vessels exhibiting a more dramatic reduction in cessation time (52%) than the latter (33%). Cerebral venules in saline-treated CD40-/- mice exhibited a significantly delayed thrombosis response versus their WT counterparts (29.0 ± 3.7 min vs. 12 ± 0.7 min*. * = P<0.05). LPS treatment greatly accelerated thrombus formation in venules of CD40-/- mice, when compared to their saline-treated counterparts(8.0 ± 1.7 min vs. 29.0 ± 3.7 min *. * = P<0.05). In CD40L-/- mice, the time to flow cessation in cerebral venules was only marginally increased following saline treatment, when compared to their WT counterparts (16.3 ± 1.2 min vs. 12 ± 0.7 min) and LPS did not enhance thrombus formation in these vessels. Neither the time of onset of thrombosis nor the time to flow cessation in both arterioles and venules were affected by genetic deficiency of either CD40 or CD40L in the cremaster. An exception was arterioles in CD40L-/- mice, which exhibited a prolonged time to flow cessation compared to WT mice. An accelerated thrombosis response was observed in DSS, which was largely prevented by CD40L deficiency. A protective response was not observed in colitic CD40-/- mice. However, CD40 deficiency appeared to further accelerate the onset (p<0.05) of thrombus development without significantly (p = 0.34) altering the time to flow cessation. These findings implicate CD40 and its ligand in the enhanced thrombus formation that is associated with acute and chronic inflammation.
1. Anthoni C et al. (2007) J Exp Med. 204:1595-601.
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