Mannose-binding lectin-associated serine protease-1 is a significant contributor to coagulation in a murine model of occlusive thrombosis.
Mannose-binding lectin-associated serine protease-1 is a significant contributor to coagulation in a murine model of occlusive thrombosis.
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DOI：
10.4049/jimmunol.1102916
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发表时间：
2012-01-15
期刊：
影响因子：
--
通讯作者：
Stahl GL
中科院分区：
文献类型：
--
作者：
La Bonte LR;Pavlov VI;Tan YS;Takahashi K;Takahashi M;Banda NK;Zou C;Fujita T;Stahl GL
出血性疾病和血栓并发症是全世界死亡和残疾的主要原因。虽然已知补体和凝血系统相互作用，但没有研究调查凝集素介导的体内凝血的具体作用或机制。氯化铁 (FeCl3) 治疗导致野生型 (WT) 和 C2/fB 缺失小鼠在 10 分钟内出现动脉内闭塞性血栓形成。相比之下，MBL null 和 MASP-1/-3 KO 小鼠显着减少 FeCl3 诱导的血栓形成。用rhMBL重建将MBL缺失小鼠中FeCl3诱导的血栓形成恢复至与WT小鼠相当的水平，这表明MBL-MASP复合物对于体内凝血具有重要作用。此外，全血聚集显示 MBL-MASP 复合物依赖性血小板聚集增加。在体外，MBL-MASP 复合物被捕获在甘露聚糖包被的板上，并测量显色凝血酶底物 (S2238) 的裂解。我们观察到 WT、C2/fB null、MBL-A−/− 或 MBL-C−/− 血清之间的 S2238 裂解没有显着差异，但 MBL null 或 MASP-1/-3 KO 小鼠血清显示 S2238 裂解显着降低。单独的重组人 (rh)MBL 无法裂解 S2238，但是当将 rMASP-1 添加到 MASP-1/-3 KO 血清或 rhMBL 中时，裂解恢复。总而言之，这些发现表明 MBL-MASP 复合物，特别是 MASP-1，在体外和体内血栓形成中发挥关键作用。
Bleeding disorders and thrombotic complications constitute a major cause of death and disability worldwide. While it’s known that the complement and coagulation systems interact, no studies have investigated the specific role or mechanisms of lectin-mediated coagulation in vivo. Ferric chloride (FeCl3) treatment resulted in intra-arterial occlusive thrombogenesis within 10min in wild-type (WT) and C2/fB null mice. In contrast, MBL null and MASP-1/-3 KO mice had significantly decreased FeCl3-induced thrombogenesis. Reconstitution with rhMBL restored FeCl3-induced thrombogenesis in MBL null mice to levels comparable to WT mice, suggesting a significant role of the MBL-MASP complex for in vivo coagulation. Additionally, whole blood aggregation demonstrated increased MBL-MASP complex-dependent platelet aggregation. In vitro, MBL-MASP complexes were captured on mannan-coated plates and cleavage of a chromogenic thrombin substrate (S2238) was measured. We observed no significant differences in S2238 cleavage between WT, C2/fB null, MBL-A−/− or MBL-C−/− sera, however MBL null or MASP-1/-3 KO mouse sera demonstrated significantly decreased S2238 cleavage. Recombinant human (rh)MBL alone failed to cleave S2238, however cleavage was restored when rMASP-1 was added to either MASP-1/-3 KO sera or rhMBL. Taken together, these findings indicate that MBL-MASP complexes, and specifically MASP-1, play a key role in thrombus formation in vitro and in vivo.
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