Recombinant ADAMTS-13 Improves Survival of Mice Subjected to Endotoxemia.
Recombinant ADAMTS-13 Improves Survival of Mice Subjected to Endotoxemia.
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DOI：
10.3390/ijms241411782
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发表时间：
2023-07-22
影响因子：
5.6
通讯作者：
Dong, Jingfei
中科院分区：
文献类型：
--
作者：
Gao, Daniel;Zhou, Zhou;Ma, Ruidong;Wu, Huaizhu;Nguyen, Trung;Liu, Li;Dong, Jingfei
当受促炎介质刺激时，内皮细胞释放在活化和聚集血小板方面过度活跃的超大型血管性血友病因子（ULVWF）多聚体。这些ULVWF多聚体可以在循环中和发炎的内皮上积累，因为它们不能被金属蛋白酶ADAMTS-13充分切割，而金属蛋白酶ADAMTS-13在全身炎症条件下变得中度缺乏。这种中度ADAMTS-13缺乏可能导致血栓性并发症，导致缺血性组织损伤和器官衰竭，与严重感染相关。为了验证这一假设，我们研究了重组ADAMTS-13是否改善了脂多糖（LPS）处理的小鼠内毒素血症的病理过程。C57 BL/J6小鼠在LPS攻击后30分钟接受5 μg/小鼠ADAMTS-13或溶媒对照的推注，并监测7天存活率。在监测期间，测量血小板计数、VWF抗原和ADAMTS-13活性。还通过免疫组织化学检查了肝脏中的血栓形成。我们发现ADAMTS-13将死亡率从66%降低到34.9%。生存率的提高与血小板减少症的恢复程度更高、血浆ADAMTS-13活性更高和血栓性血管闭塞更少相关。这些结果表明，全身性炎症可能导致ADAMTS-13对ULVWF蛋白水解的缺陷，ADAMTS-13改善了内毒素血症诱导的炎症的结果。
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.
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DOI：
10.1111/jth.15873
发表时间：
2022-12
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
通讯作者：
--
DOI：
10.3324/haematol.10262
发表时间：
2007-01-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Nguyen, Trung C.;Liu, Anne;Dong, Jing-fei
通讯作者：
Dong, Jing-fei
影响因子：
15.9
作者：
Netea, MG;Demacker, PNM;vanderMeer, JWM
通讯作者：
vanderMeer, JWM
影响因子：
7.5
作者：
Edvardsen, Magnus S.;Hindberg, Kristian;Hansen, John-Bjarne
通讯作者：
Hansen, John-Bjarne
影响因子：
20.3
作者：
Arya, M;Anvari, B;López, JA
通讯作者：
López, JA