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- Title
Recombinant ADAMTS-13 Improves Survival of Mice Subjected to Endotoxemia.
- Authors
Gao, Daniel; Zhou, Zhou; Ma, Ruidong; Wu, Huaizhu; Nguyen, Trung; Liu, Li; Dong, Jingfei
- Abstract
When stimulated by proinflammatory mediators, endothelial cells release ultra-large von Willebrand factor (ULVWF) multimers that are hyperactive in activating and aggregating platelets. These ULVWF multimers can accumulate in the circulation and on the inflamed endothelium because they are insufficiently cleaved by the metalloprotease ADAMTS-13, which becomes moderately deficient under conditions of systemic inflammation. This moderate ADAMTS-13 deficiency may lead to thrombotic complications that contribute to ischemic tissue injury and organ failure that are associated with severe infections. To test this hypothesis, we investigated whether recombinant ADAMTS-13 improves the pathological course of endotoxemia in lipopolysaccharide (LPS)-treated mice. C57BL/J6 mice received a bolus infusion of either 5 µg/mouse of ADAMTS-13 or vehicle control 30 min after LPS challenge and were monitored for seven-day survival. During the monitoring period, platelet counts, VWF antigen, and ADAMTS-13 activity were measured. Thrombosis was also examined by the immunohistochemistry in the liver. We found that ADAMTS-13 reduced mortality from 66% to 34.9%. The improved survival was associated with a greater recovery from thrombocytopenia, higher plasma ADAMTS-13 activity, and less thrombotic vascular occlusion. These results suggest that systemic inflammation could result in deficient ULVWF proteolysis by ADAMTS-13 and that ADAMTS-13 improves the outcomes of endotoxemia-induced inflammation.
- Subjects
ENDOTOXEMIA; VON Willebrand factor; BOLUS drug administration; PLATELET count; MICE; THROMBOPOIETIN receptors
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 14, p11782
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms241411782