SURFACE-MEDIATED DEFENSE REACTIONS - THE PLASMA CONTACT ACTIVATION SYSTEM
SURFACE-MEDIATED DEFENSE REACTIONS - THE PLASMA CONTACT ACTIVATION SYSTEM
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DOI：
10.1172/jci111326
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发表时间：
1984-01-01
影响因子：
15.9
通讯作者：
COLMAN, RW
中科院分区：
文献类型：
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作者：
COLMAN, RW
与液相活化相比，XIIa还以加速的速率在表面上将PK转化为K。K，在流体相中，除了HMWK之外还有多种底物。K直接将纤溶酶原转化为纤溶酶（19），尽管反应速度太慢，不能解释血浆暴露于活化表面后加速凝块溶解的原因。XIIa（20）和XIa（21）也可以催化该反应，但浓度远高于血浆浓度。表面活化纤维蛋白溶解的生理或病理意义仍有待确定。体外血浆K也将PR转化为肾素（R）。然而，这种反应需要事先将血浆暴露于酸，以使PR对K敏感（22），这表明这种途径可能不是生理性的。易感性不仅仅是由于抑制剂的去除，因为在缺乏K抑制剂（Cl抑制剂（Cl INH）和α 2-巨球蛋白）的血浆中，当PK被激活为K或当K直接加入血浆时，没有观察到PR转化为R（23）AK的一种可能与防御反应更相关的功能是其激活中性粒细胞的能力。早期的研究（24）表明K对中性粒细胞具有趋化性，并且需要一个完整的活性位点。最近，K被证明可以聚集中性粒细胞并刺激这些细胞的耗氧量（25）。虽然在兔子中，K将C5裂解为C5 a（26）已被证明是激活机制，但在人类系统中，K使中性粒细胞聚集与C5 a无关（25）。最近的研究表明，血浆中中性粒细胞释放弹性蛋白酶（27）是由于K刺激中性粒细胞嗜天青颗粒分泌弹性蛋白酶的能力（28）。K还刺激人嗜中性粒细胞中的超氧化物和H2 O2形成（29）。这些观察结果扩大了接触系统在涉及中性粒细胞活化的病理状态中的潜在作用。血浆中的XII不仅转化为XIIa，而且转化为XII片段（XIIf），其保留XIIa的活性位点，同时失去表面结合结构域。因此，XIIf扩散回血浆中，在血浆中可能遇到三种潜在底物PK、因子VII和C1。像XIIa一样，XIIf可以将PK切割为K。因子VII凝血活性被XIIf增强40倍，XIIf将其切割成双链分子（30）。然而，与Xa（31）不同，XIIf随后不会通过进一步裂解成三链分子而使VIla失活。与塑料相比，玻璃中凝血酶原时间的缩短（32）是由于激活的XII激活了因子VII。凝血因子VII在寒冷环境中的”自发”活化是由于血浆蛋白酶抑制剂C1 INH的失活和XII的表面活化的共同作用。凝血因子VII的冷激活在服用口服避孕药的女性的血浆中更为突出，因为她们的血浆增加了XII并降低了Cl INH（34）。与自身活化或Xa活化相比，由XIIf接触活化VII的贡献尚不清楚。最后，XIIf已被证明（35）激活补体的第一组分（Cl）。
XIIa also converts PK to K on the surface at an accelerated rate compared with fluid-phase activation. K, in the fluid phase, has a variety of substrates besides HMWK. K directly converts plasminogen to plasmin (19), although the rate of reaction is too slow to account for the acceleration ofclot lysis after exposure of plasma to activating surfaces. XIIa (20) and XIa (21) can also catalyze this reaction, but at well above plasma concentrations. The physiological or pathological significance ofsurface-activated fibrinolysisremains to be established. In vitro plasma K also converts PR to renin (R). However, this reaction requires prior exposure of plasma to acid to render the PR susceptible to K (22), which suggests that this pathway may not be physiologic. The susceptibility is not merely due to removal of inhibitors, since in plasma deficient in inhibitors of K (C1 inhibitor (Cl INH) and a2-macroglobulin) no conversion of PR to R is observed when PK was activated to K or when K is added directly to plasma (23).A function of K that may be more relevant for defensive reactions is its ability to activate neutrophils. Early studies (24) suggested that K was chemotactic for neutrophils and that an intact active site was required. More recently, K was demonstrated to aggregate neutrophils and stimulate oxygen consumption of these cells (25). Although in the rabbit the cleavage of C5to C5a by K (26) has been shown to be the mechanism of activation, in the human system the aggregation of neutrophils by K is independent of C5a (25). The release of elastase from neutrophils in recalcified plasma (27) has recently been shown to be due tothe ability of K to stimulate elastase secretion from neutrophil azurophilic granules (28). K also stimulates super-oxide and H202 formation in human neutrophils (29). These observations expand the potential role for the contact system in pathologic states involving neutrophil activation. XII in plasma is not only converted to XIIa, but also to XII fragments (XIIf), which retain the active site of XIIa while losing the surface-binding domain. Thus, XIIfdiffuses back into plasma where it may encounter three potential substrates, PK, Factor VII, and C1. Like XIIa, XIIfcan cleave PK to K. Factor VII coagulant activity is enhanced 40-fold by XIIfwhich cleaves it into a two-chain molecule (30). However, unlike Xa (31), XIIf does not subsequently inactivateVIla by further cleavage to a three-chain molecule. The shortening of the prothrombin time in glass compared with plastic (32) is due to Factor VII activation by activated XII. The" spontaneous" activation of Factor VII in the cold (33) isdue to a combination of inactivation ofthe plasma protease inhibitor Ci INH and surface activation of XII. Cold activation of FactorVII is more prominent in the plasma from women taking oral contraceptives, since their plasma has increased XII and decreased Cl INH (34). The contribution of contact activation of VII by XIIf, compared with autoactivation or activation by Xa, is not known. Finally, XIIf has been demonstrated (35) to activate the first component of complement (Cl).