Molecular intercommunication between the complement and coagulation systems.
Molecular intercommunication between the complement and coagulation systems.
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DOI：
10.4049/jimmunol.0903678
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发表时间：
2010-11-01
期刊：
影响因子：
--
通讯作者：
Huber-Lang M
中科院分区：
文献类型：
--
作者：
Amara U;Flierl MA;Rittirsch D;Klos A;Chen H;Acker B;Brückner UB;Nilsson B;Gebhard F;Lambris JD;Huber-Lang M
补体系统以及凝血系统在危及生命的组织损伤和炎症的背景下具有基本的临床意义。这两个级联之间的关联已被提出，但精确的分子机制仍然未知。目前的研究报告了多种因素的凝血和纤溶级联与中央补体成分C3和C5在体外和离体。发现凝血酶、人凝血因子（F）XIa、Xa和IXa以及纤溶酶都能有效切割C3和C5。质谱分析将裂解产物鉴定为C3 a和C5 a，显示与天然过敏毒素C3 a和C5 a相同的分子量。裂解产物还分别表现出对人肥大细胞和中性粒细胞的强烈化学吸引。所研究的凝血和纤维蛋白溶解因子对C3裂解的酶活性按以下顺序定义：FXa >纤溶酶>凝血酶> FIXa > FXIa >对照。此外，在选择性FXA抑制剂磺达肝癸钠和依诺肝素的存在下，FXA诱导的C3切割以浓度依赖性方式被显着抑制。向人血清或血浆中添加FXa离体激活补体，表现为C3 a、C5 a和末端补体复合物的产生，以及补体溶血血清活性降低，其定义了导致50%致敏绵羊红细胞补体介导裂解的确切血清浓度。此外，在多发性损伤患者（n = 12）的血浆中，目前的数据表明，凝血/纤溶蛋白酶可能作为天然的C3和C5转化酶，产生生物活性过敏毒素，在复杂的丝氨酸蛋白酶系统中通过多个直接相互作用连接两个级联。
The complement system as well as the coagulation system has fundamental clinical implications in the context of life-threatening tissue injury and inflammation. Associations between both cascades have been proposed, but the precise molecular mechanisms remain unknown. The current study reports multiple links for various factors of the coagulation and fibrinolysis cascades with the central complement components C3 and C5 in vitro and ex vivo. Thrombin, human coagulation factors (F) XIa, Xa, and IXa, and plasmin were all found to effectively cleave C3 and C5. Mass spectrometric analyses identified the cleavage products as C3a and C5a, displaying identical molecular weights as the native anaphylatoxins C3a and C5a. Cleavage products also exhibited robust chemoattraction of human mast cells and neutrophils, respectively. Enzymatic activity for C3 cleavage by the investigated clotting and fibrinolysis factors is defined in the following order: FXa > plasmin > thrombin > FIXa > FXIa > control. Furthermore, FXa-induced cleavage of C3 was significantly suppressed in the presence of the selective FXa inhibitors fondaparinux and enoxaparin in a concentration-dependent manner. Addition of FXa to human serum or plasma activated complement ex vivo, represented by the generation of C3a, C5a, and the terminal complement complex, and decreased complement hemolytic serum activity that defines exact serum concentration that results in complement-mediated lysis of 50% of sensitized sheep erythrocytes. Furthermore, in plasma from patients with multiple injuries (n = 12), a very early appearance and correlation of coagulation (thrombin–antithrombin complexes) and the complement activation product C5a was found. The present data suggest that coagulation/fibrinolysis proteases may act as natural C3 and C5 convertases, generating biologically active anaphylatoxins, linking both cascades via multiple direct interactions in terms of a complex serine protease system.
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DOI：
10.1097/ta.0b013e318169cd3c
发表时间：
2008-05-01
影响因子：
--
作者：
Brohi, Karim;Cohen, Mitchell J.;Pittet, Jean-Francois
通讯作者：
Pittet, Jean-Francois
影响因子：
20.3
作者：
Hartmann, K;Henz, BM;Zuberbier, T
通讯作者：
Zuberbier, T
影响因子：
7.5
作者：
Esmon, CT
通讯作者：
Esmon, CT
影响因子：
4.8
作者：
Flierl, Michael A.;Rittirsch, Daniel;Ward, Peter A.
通讯作者：
Ward, Peter A.
影响因子：
82.9
作者：
Huber-Lang, Markus;Sarma, J. Vidya;Ward, Peter A.
通讯作者：
Ward, Peter A.