期刊
INFLAMMATORY BOWEL DISEASES
卷 17, 期 11, 页码 2217-2223出版社
OXFORD UNIV PRESS INC
DOI: 10.1002/ibd.21593
关键词
thrombus formation; interleukin-1 beta; microcirculation; inflammation
资金
- National Institutes of Diabetes, Digestive and Kidney Diseases [P01 DK43785]
Background: Inflammatory bowel diseases (IBDs) are associated with a hypercoagulable state and an increased risk of thromboembolism, with accelerated thrombus formation occurring both within the inflamed bowel and in distant tissues. While the IBD-associated prothrombogenic state has been linked to the inflammatory response, the mediators that link inflammation and thrombosis remain poorly defined. The objective of this study was to assess the role of tumor necrosis factor alpha (TNF-alpha) in the enhanced extraintestinal microvascular thrombosis that accompanies colonic inflammation. Methods: TNF-alpha concentration was measured in plasma, colon, and skeletal muscle of control mice and in mice with dextran sodium sulfate (DSS)-induced colitis. A light/dye injury method was used to induce microvascular thrombosis in cremaster microvessels. The effects of exogenous TNF-alpha on thrombus formation were determined in control mice. DSS-enhanced thrombus formation was evaluated in wildtype (WT) mice treated with an anti-TNF-alpha antibody (+/- an anti-IL-1 beta antibody) and in TNF-a receptor-deficient (TNFr-/-) mice. Results: DSS colitis enhanced thrombus formation in cremaster arterioles. A similar response was produced by TNF-alpha administration in control mice. TNF-alpha concentration was elevated in plasma, colon, and skeletal muscle. Immunoblockade of TNF-alpha or genetic deficiency of the TNF-alpha receptor blunted the thrombotic response of arterioles to DSS colitis. Additional protection was noted in mice receiving antibodies to both TNF-alpha and IL-1 beta. Conclusions: Our findings implicate TNF-alpha in the enhanced microvascular thrombosis that occurs in extraintestinal tissue during colonic inflammation, and suggests that the combined actions of TNF-alpha and IL-1 beta accounts for most of the colitis-enhanced thrombotic response. (Inflamm Bowel Dis 2011;17:2217-2223)
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