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Published on: February 19, 2013
Role of the protein C pathway in the extraintestinal thrombosis associated with murine colitis
Hideo Yoshida1, Janice Russell, Karen Y Stokes
1Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-33932, USA.
Insights
Inflammatory bowel diseases (IBD) increase thrombosis risk. This study shows that the protein C pathway protects against extraintestinal thrombosis in dextran sodium sulfate (DSS)-induced colitis, highlighting its therapeutic potential.
Area of Science:
- Vascular Biology
- Inflammation and Immunology
- Thrombosis and Hemostasis
Background:
- Chronic inflammatory bowel diseases (IBD) are linked to a higher risk of thromboembolism, impacting patient morbidity and mortality.
- The precise mechanisms driving hypercoagulability in intestinal inflammation are not fully understood.
- Investigating the role of the protein C pathway in extraintestinal thrombosis associated with IBD is crucial.
Purpose of the Study:
- To investigate the contribution of the protein C pathway to enhanced extraintestinal thrombosis in dextran sodium sulfate (DSS)-induced colitis in mice.
- To determine if modulating the protein C pathway can mitigate thrombosis risk in a model of IBD.
Main Methods:
- Induction of microvascular thrombosis in cremaster muscle microvessels using a light/dye injury model in wild-type and colitic mice.
- Assessment of thrombosis formation in dextran sodium sulfate (DSS)-induced colitis models.
- Evaluation of thrombosis response in transgenic mice overexpressing the endothelial protein C receptor and in wild-type mice treated with activated protein C (APC) or an anti-APC antibody.
Main Results:
- Dextran sodium sulfate (DSS) colitis significantly enhanced thrombus formation in wild-type mice.
- Overexpression of the endothelial protein C receptor greatly attenuated the DSS-induced thrombosis response.
- Administration of activated protein C (APC) protected against thrombosis, while an anti-APC antibody exacerbated it.
Conclusions:
- Elevated levels of activated protein C (APC), whether endogenous or exogenous, provide protection against extraintestinal thrombosis associated with colonic inflammation.
- The protein C pathway plays a significant protective role in mitigating thrombosis risk during experimental colitis.
- Targeting the protein C pathway may offer a therapeutic strategy for managing thromboembolic complications in IBD.
Background & Aims:
Chronic inflammatory bowel diseases (IBD) are associated with an increased risk for thromboembolism. Although thrombosis is known to contribute to the morbidity and mortality of patients with IBD, the underlying mechanisms that contribute to the genesis of a hypercoagulable state during intestinal inflammation remain poorly defined. The objective of this study was to determine whether the protein C pathway contributes to the enhanced extraintestinal thrombosis that is associated with dextran sodium sulfate (DSS)-induced colitis in mice.
Methods:
Microvascular thrombosis was induced in cremaster muscle microvessels of normal and colitic mice using a light/dye injury model. DSS colitis enhanced thrombus formation in cremaster arterioles of wild-type mice.
Results:
The DSS-induced thrombosis response was greatly attenuated in transgenic mice over expressing the endothelial protein C receptor. Activated protein C (APC), administered to colitic WT mice immediately prior to photoactivation, also afforded protection against thrombosis, and an anti-APC antibody enhanced thrombus formation.
Conclusions:
These findings indicate that elevated APC levels, derived from either endogenous or exogenous sources, confer protection against the extraintestinal thrombosis that accompanies colonic inflammation.
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