Isordia-Salas Irma, Sainz Irma M, Pixley Robin A, Martínez-Murillo Carlos, Colman Robert W
The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Rev Invest Clin. 2005 Nov-Dec;57(6):802-13.
The plasma kallikrein-kinin system (KKS) participates in the pathogenesis of inflammatory reactions involved in cellular injury, coagulation, fibrinolysis, kinin formation, complement activation, cytokine secretion and release of proteases. It has been shown that KKS activation in the systemic inflammatory response syndrome results in decrease of its component plasma proteins. Similar changes have been documented in diabetes, sepsis, children with vasculitis, allograft rejection, disseminated intravascular coagulation, patients with recurrent pregnancy losses, hereditary angioedema, adult respiratory distress syndrome and coronary artery disease. Direct involvement of the KKS in the pathogenesis of experimental acute arthritis and acute and chronic enterocolitis has been documented by previous studies from our laboratory using experimental animal models. It has been found that in HK deficient Lewis rats, experimental IBD was much less severe. We showed a genetic difference in kininogen structure between resistant Buffalo and susceptible Lewis rats, which results in accelerated cleavage of HK and it is responsible for the susceptibility to the inflammatory process in the Lewis rats. It has been demostrated that therapy with a specific plasma kallikrein inhibitor (P8720) modulated the experimental enterocolitis, arthritis and systemic inflammation. Furthermore, it has been shown that a bradykinin 2 receptor (B2R) antagonist attenuates the inflammatory changes in the same animal model. We have showed that a monoclonal antibody targeting HK decreases angiogenesis and arrests tumor growth in a syngeneic animal model. In summary, these results indicate that the plasma KKS plays a central role in the pathogenesis of chronic intestinal inflammation, arthritis and angiogenesis.
血浆激肽释放酶 - 激肽系统（KKS）参与细胞损伤、凝血、纤维蛋白溶解、激肽形成、补体激活、细胞因子分泌以及蛋白酶释放等炎症反应的发病机制。研究表明，全身炎症反应综合征中KKS的激活会导致其组成血浆蛋白减少。在糖尿病、脓毒症、血管炎患儿、同种异体移植排斥反应、弥散性血管内凝血、复发性流产患者、遗传性血管性水肿、成人呼吸窘迫综合征和冠状动脉疾病中也记录到了类似变化。我们实验室先前使用实验动物模型的研究已证明KKS直接参与实验性急性关节炎以及急性和慢性肠炎的发病机制。研究发现，在缺乏高分子量激肽原（HK）的Lewis大鼠中，实验性炎症性肠病的严重程度要低得多。我们发现抗性水牛大鼠和易感Lewis大鼠之间激肽原结构存在遗传差异，这导致HK的裂解加速，也是Lewis大鼠易患炎症过程的原因。已证明用特异性血浆激肽释放酶抑制剂（P8720）进行治疗可调节实验性肠炎、关节炎和全身炎症。此外，研究表明缓激肽2受体（B2R）拮抗剂可减轻同一动物模型中的炎症变化。我们已表明，在同基因动物模型中，靶向HK的单克隆抗体可减少血管生成并阻止肿瘤生长。总之，这些结果表明血浆KKS在慢性肠道炎症、关节炎和血管生成的发病机制中起核心作用。
