Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI).
Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI).
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DOI：
10.1016/j.molimm.2008.07.010
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发表时间：
2008-10
影响因子：
3.6
通讯作者：
Robinson, William H.
中科院分区：
文献类型：
--
作者：
Leung, Lawrence L. K.;Myles, Timothy;Nishimura, Toshihiko;Song, Jason J.;Robinson, William H.
关键词：
凝血酶活化羧肽酶原B（proCP B或凝血酶活化纤维蛋白溶解抑制剂或TAFI）是一种血浆羧肽酶原，由血管内皮表面上的凝血酶-血栓调节蛋白复合物活化。激活的CPB去除部分消化的纤维蛋白凝块中新暴露的羧基末端赖氨酸，减少组织纤溶酶原激活剂和纤溶酶原结合，并保护凝块免受过早溶解。我们最近已经表明，CPB是催化更有效的比血浆CPN，主要的血浆过敏毒素抑制剂，在抑制缓激肽，激活补体C3 a，C5 a，和凝血酶裂解骨桥蛋白在体外。使用凝血酶突变体（E229 K），具有最小的促凝血特性，但保留了在体内激活蛋白C和proCPB的能力，我们表明，输注E229 K凝血酶到野生型小鼠降低缓激肽诱导的低血压，但在proCPB缺陷小鼠中没有效果，表明E229 K凝血酶的有益作用是通过其激活proCPB而不是蛋白C介导的。类似地，proCPB缺陷小鼠在C5 a诱导的肺泡炎模型中表现出增强的肺部炎症，并且E229 K凝血酶改善了野生型但proCPB缺陷小鼠中肺泡炎的程度。ProCPB缺陷小鼠在炎性关节炎模型中也显示出增强的关节炎。因此，我们的体外和体内数据支持凝血酶激活的CPB具有广泛的抗炎特性的论点。通过从C3 a、C5 a、缓激肽和凝血酶裂解的骨桥蛋白特异性裂解羧基末端丝氨酸，它使这些活性炎症介质失活。沿着蛋白C的活化，内皮凝血酶-血栓调节蛋白复合物对proCPB的活化代表了体内调节凝血酶促炎功能的稳态反馈机制。
Thrombin-activatable procarboxypeptidase B (proCPB or thrombin-activatable fibrinolysis inhibitor or TAFI) is a plasma procarboxypeptidase that is activated by the thrombin-thrombomodulin complex on the vascular endothelial surface. The activated CPB removes the newly exposed carboxyl terminal lysines in the partially digested fibrin clot, diminishes tissue plasminogen activator and plasminogen binding, and protects the clot from premature lysis. We have recently shown that CPB is catalytically more efficient than plasma CPN, the major plasma anaphylatoxin inhibitor, in inhibiting bradykinin, activated complement C3a, C5a, and thrombin-cleaved osteopontin in vitro. Using a thrombin mutant (E229K) that has minimal procoagulant properties but retains the ability to activate protein C and proCPB in vivo, we showed that infusion of E229K thrombin into wild type mice reduced bradykinin-induced hypotension but it had no effect in proCPB-deficient mice, indicating that the beneficial effect of E229K thrombin is mediated through its activation of proCPB and not protein C. Similarly proCPB-deficient mice displayed enhanced pulmonary inflammation in a C5a-induced alveolitis model and E229K thrombin ameliorated the magnitude of alveolitis in wild type but not proCPB-deficient mice. ProCPB-deficient mice also displayed enhanced arthritis in an inflammatory arthritis model. Thus, our in vitro and in vivo data support the thesis that thrombin-activatable CPB has broad anti-inflammatory properties. By specific cleavage of the carboxyl terminal arginines from C3a, C5a, bradykinin and thrombin-cleaved osteopontin, it inactivates these active inflammatory mediators. Along with the activation of protein C, the activation of proCPB by the endothelial thrombin-thrombomodulin complex represents a homeostatic feedback mechanism in regulating thrombin’s pro-inflammatory functions in vivo.
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