Bryant J W, Shariat-Madar Z
University of Mississippi, University, MS 38677-1848, USA.
Cardiovasc Hematol Agents Med Chem. 2009 Jul;7(3):234-50. doi: 10.2174/187152509789105444.
The plasma kallikrein-kinin system (KKS) plays a critical role in human physiology. The KKS encompasses coagulation factor XII (FXII), the complex of prekallikrein (PK) and high molecular weight kininogen (HK). The conversion of plasma prekallikrein to kallikrein by the activated FXII and in response to numerous different stimuli leads to the generation of bradykinin (BK) and activated HK (HKa, an antiangiogenic peptide). BK is a proinflammatory peptide, a pain mediator and potent vasodilator, leading to robust accumulation of fluid in the interstitium. Systemic production of BK, HKa with the interplay between BK bound-BK receptors and the soluble form of HKa are key to angiogenesis and hemodynamics. KKS has been implicated in the pathogenesis of inflammation, hypertension, endotoxemia, and coagulopathy. In all these cases increased BK levels is the hallmark. In some cases, the persistent production of BK due to the deficiency of the blood protein C1-inhibitor, which controls FXII, is detrimental to the survival of the patients with hereditary angioedema (HAE). In others, the inability of angiotensin converting enzyme (ACE) to degrade BK leads to elevated BK levels and edema in patients on ACE inhibitors. Thus, the mechanisms that interfere with BK liberation or degradation would lead to blood pressure dysfunction. In contrast, anti-kallikrein treatment could have adverse effects in hemodynamic changes induced by vasoconstrictor agents. Genetic models of kallikrein deficiency are needed to evaluate the quantitative role of kallikrein and to validate whether strategies designed to activate or inhibit kallikrein may be important for regulating whole-body BK sensitivity.
血浆激肽释放酶-激肽系统（KKS）在人体生理过程中发挥着关键作用。KKS包括凝血因子XII（FXII）、前激肽释放酶（PK）和高分子量激肽原（HK）的复合物。活化的FXII在多种不同刺激作用下将血浆前激肽释放酶转化为激肽释放酶，进而导致缓激肽（BK）和活化的HK（HKa，一种抗血管生成肽）的生成。BK是一种促炎肽、疼痛介质和强效血管扩张剂，可导致间质中液体大量积聚。BK、HKa的全身产生以及BK结合的BK受体与可溶性HKa之间的相互作用是血管生成和血液动力学的关键。KKS与炎症、高血压、内毒素血症和凝血病的发病机制有关。在所有这些情况下，BK水平升高是其标志。在某些情况下，由于控制FXII的血液蛋白C1抑制剂缺乏导致BK持续产生，对遗传性血管性水肿（HAE）患者的生存有害。在其他情况下，血管紧张素转换酶（ACE）无法降解BK会导致服用ACE抑制剂的患者BK水平升高和水肿。因此，干扰BK释放或降解的机制会导致血压功能障碍。相比之下，抗激肽释放酶治疗可能会对血管收缩剂引起的血液动力学变化产生不利影响。需要激肽释放酶缺乏的遗传模型来评估激肽释放酶的定量作用，并验证旨在激活或抑制激肽释放酶的策略对于调节全身BK敏感性是否重要。
