Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo.
Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo.
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DOI：
10.1016/j.cell.2009.11.001
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发表时间：
2009-12-11
期刊：
影响因子：
64.5
通讯作者：
Renné T
中科院分区：
文献类型：
--
作者：
Müller F;Mutch NJ;Schenk WA;Smith SA;Esterl L;Spronk HM;Schmidbauer S;Gahl WA;Morrissey JH;Renné T
血小板在血栓形成、止血和炎症中起核心作用。我们发现，活化的血小板释放无机聚磷酸盐（聚P），60-100磷酸残基的聚合物，直接绑定到并激活血浆蛋白酶因子XII。PolyP驱动的因子XII激活通过血浆激肽释放酶介导的激肽原加工触发炎症介质缓激肽的释放PolyP增加小鼠皮肤微血管的血管通透性并诱导液体外渗。缺乏因子XII或缓激肽受体的小鼠对聚P诱导的渗漏具有抗性。PolyP通过接触途径引发血浆凝血。内源性凝血途径蛋白酶因子XII和因子XI的消融保护小鼠免受polyP触发的致死性肺栓塞。用磷酸酶靶向聚P干扰活化血小板的促凝活性并阻断小鼠血小板诱导的血栓形成。输注polyP恢复了缺乏血小板polyP的Hermansky-Pudlak综合征患者的有缺陷的血浆凝血。这些数据将聚P鉴定为一类新的介质，其在血小板驱动的促炎性和促凝血性疾病中具有基本作用。
Platelets play a central role in thrombosis, hemostasis, and inflammation. We show that activated platelets release inorganic polyphosphate (polyP), a polymer of 60-100 phosphate residues that directly bound to and activated the plasma protease factor XII. PolyP-driven factor XII-activation triggered release of the inflammatory mediator bradykinin by plasma kallikrein-mediated kininogen processing. PolyP increased vascular permeability and induced fluid extravasation in skin microvessels of mice. Mice deficient in factor XII or bradykinin receptors were resistant to polyP-induced leakage. PolyP initiated clotting of plasma via the contact pathway. Ablation of intrinsic coagulation pathway proteases factor XII and factor XI protected mice from polyP-triggered lethal pulmonary embolism. Targeting polyP with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Infusion of polyP restored defective plasma clotting of Hermansky-Pudlak Syndrome patients, which lack platelet polyP. The data identify polyP as a new class of mediator having fundamental roles in platelet-driven proinflammatory and procoagulant disorders.
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DOI：
10.1084/jem.20052458
发表时间：
2006-03-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kleinschnitz C;Stoll G;Bendszus M;Schuh K;Pauer HU;Burfeind P;Renné C;Gailani D;Nieswandt B;Renné T
通讯作者：
Renné T
影响因子：
82.9
作者：
Herwald, H;Mörgelin, M;Björck, L
通讯作者：
Björck, L
影响因子：
4.8
作者：
KUMBLE, KD;KORNBERG, A
通讯作者：
KORNBERG, A
影响因子：
20.3
作者：
Salomon, Ophira;Steinberg, David M.;Seligsohn, Uri
通讯作者：
Seligsohn, Uri
影响因子：
64.8
作者：
Mackman, Nigel
通讯作者：
Mackman, Nigel