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Lipopolysaccharide augments venous and arterial thrombosis in the mouse
1Discovery Translational Medicine, Wyeth Research, Collegeville, PA 19426, USA. wangx8@wyeth.com
Background:
Animal models of diseases are essential for therapeutic target validation, drug discovery and development. Increasing evidence has demonstrated the importance of inflammation in thrombosis. Here, murine models of vena cava thrombosis and carotid arterial thrombosis augmented by lipopolysaccharide (LPS) were established and characterized to study the association between inflammation and thrombosis.
Materials And Methods:
Murine (C57BL/6 mice) models of ferric chloride (FeCl(3))-induced carotid arterial and vena cava thrombosis were established. Thrombus formation was measured indirectly by Doppler blood flow (i.e., clot functional interference with blood flow) in the arterial thrombosis model and directly by protein content of the clot in the venous thrombosis model. An optimal concentration of FeCl(3) was defined to induce thrombus formation and used to study the effects of LPS (i.e., a well-known inflammatory stimulus under these conditions). Real-time polymerase chain reaction (PCR) was used to examine the effect of LPS on TNFalpha and IL-1beta mRNA expression in thrombus formation.
Results:
Dose-dependent analysis demonstrated that 2 mg/kg, i.p., LPS provided a maximal prothrombotic effect in 2.5% ferric chloride-induced vena cava thrombosis, with a 60% increase in thrombus size (n=8, p<0.05) compared to vehicle treatment. In contrast, 2 mg/kg LPS had no significant effect on thrombus formation in a more severe, 3.5% FeCl(3)-induced vena cava thrombosis. A similar prothrombotic effect was observed for LPS in 2.5% FeCl(3)-induced carotid arterial thrombosis model. Treatment of 2 mg/kg LPS significantly augmented arterial thrombosis immediately (between 5-30 minutes) following FeCl(3) injury as assessed by change of Doppler blood flow (n=8, p<0.05). Real-time PCR demonstrated significant induction of TNFalpha and IL-1beta mRNA expression in the thrombus formation in the vessels in response to LPS challenge.
Conclusion:
These data demonstrate that LPS augments thrombus formation in acute vascular injury and that LPS-augmented thrombosis might be a useful tool to study the relationship between inflammation and thrombosis.
