Abstract 242: Toll-like Receptor 3 Activation Is Involved in Venous Thrombosis Development
Venous thromboembolism (VTE) afflicts 117 people per 100,000 each year and is an important cause of morbidity and mortality. Inflammation may have a role in both the genesis and resolution of venous thrombi. Although septic thrombophlebitis occurs, most deep venous thrombosis are sterile. Recently, the role of toll-like receptor (TLR) signaling in modulating sterile inflammation has become better defined in experimental injury models. TLR3, for example, is activated by viral long double stranded RNA and endogenous RNA released by cellular apoptosis and necrosis, and induce a proinflammatory cellular response. Short single-stranded RNA, such as those used in RNA inhibition, stimulate TLR3 in endothelial cells and inhibit neoangiogenesis. Thus, we hypothesize that TLR3 might be involved in the inflammatory development of venous thrombosis. Intravenous injection of polyinosine polycytidylic acid (polyI:C), a synthetic double-stranded RNA analog, increase the size of thrombi after FeCl3-induced inferior vena cava injury (IVC) compared to mice treated with vehicle (p<0.05). TLR3 stimulation with polyI:C is also associated with an increased fibrin, neutrophil and macrophage content (p<0.05). Using a specific fluorescent probe for RNA, we found that FeCl3 induces RNA release and thus increases RNA content in the thrombus. We next investigated the effect of RNase on thrombus development. Intravenous injection of RNase decreased thrombus size, as well as fibrin, neutrophil and macrophage content in the thrombus compared to vehicle (p<0.05). To verify the direct implication of TLR3, thrombosis was induced on TLR3 deficient mice using the FeCl3 model. Results showed that fibrin content after FeCl3-induced thrombosis is comparable between the groups. However, the occlusion of the IVC was only partial (80%) in the TLR3 deficient mice, whereas it was complete in the wild type animals. Taken together, these results strongly suggest that RNA release and TLR3 stimulation after endothelial cell injury participate in thrombus formation by inducing a pro-inflammatory response leading to the recruitment of neutrophils and macrophages.
- © 2012 by American Heart Association, Inc.