Bloodworks Research Institute, Seattle, WA 98102, USA.
Department of Chemistry, Pomona College, Claremont, CA 91711, USA.
Int J Mol Sci. 2023 Jul 22;24(14):11782. doi: 10.3390/ijms241411782.
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.
当受到促炎介质的刺激时，内皮细胞释放超大 von Willebrand 因子（ULVWF）多聚体，这些多聚体在激活和聚集血小板方面非常活跃。这些 ULVWF 多聚体可能会在循环中积聚，并在内皮细胞上积聚，因为它们不能被金属蛋白酶 ADAMTS-13 充分切割，而 ADAMTS-13 在全身炎症条件下会适度缺乏。这种适度的 ADAMTS-13 缺乏可能导致血栓形成并发症，从而导致与严重感染相关的缺血性组织损伤和器官衰竭。为了验证这一假设，我们研究了重组 ADAMTS-13 是否可以改善脂多糖 (LPS) 处理的小鼠内毒素血症的病理过程。C57BL/J6 小鼠在 LPS 挑战后 30 分钟接受 5 µg/小鼠的 ADAMTS-13 或载体对照的推注，并监测 7 天的存活情况。在监测期间，测量血小板计数、VWF 抗原和 ADAMTS-13 活性。还通过肝脏的免疫组织化学检查血栓形成情况。我们发现 ADAMTS-13 将死亡率从 66%降低到 34.9%。改善的生存与血小板减少症的更大恢复、更高的血浆 ADAMTS-13 活性和更少的血栓性血管闭塞有关。这些结果表明，全身炎症可能导致 ADAMTS-13 缺乏对 ULVWF 的蛋白水解作用，并且 ADAMTS-13 改善了内毒素血症引起的炎症的结果。
