Inhibition of complement neutrophil, and platelet activation by an anti-factor D monoclonal antibody in simulated cardiopulmonary bypass circuits
Inhibition of complement neutrophil, and platelet activation by an anti-factor D monoclonal antibody in simulated cardiopulmonary bypass circuits
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DOI：
10.1067/mtc.2001.114777
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发表时间：
2001-07-01
影响因子：
6
通讯作者：
Fraser, CD
中科院分区：
文献类型：
--
作者：
Fung, M;Loubser, PG;Fraser, CD
目的：接受心肺转流术的患者经常表现出全身性炎症，偶尔表现出严重的多器官衰竭。血液与旁路回路的人工表面接触、手术创伤和缺血再灌注损伤会引发旁路的炎症反应。以体外循环人全血为模拟体外循环模型，研究了抗D因子单克隆抗体（166-32）对补体旁路级联反应的特异性抑制作用。将单克隆抗体166-32以18 μ g/mL的最终浓度加入到儿科心肺转流回路中再循环的新鲜采集的肝素化人血中。将不相关的单克隆抗体用作阴性对照，同一天在平行旁路回路中使用相同的供体血液。结果：单克隆抗体166-32可抑制补体激活，抑制补体Bb、C3 a、sC 5 b-9和C5 a的生成。单克隆抗体166-32也显著抑制中性粒细胞上的CD 11b和血小板上的CD 62 P的上调。这与对嗜中性粒细胞特异性髓过氧化物酶和弹性蛋白酶以及血小板血小板反应蛋白的释放的抑制一致。抗体也抑制了促炎细胞因子白细胞介素8的产生。结论：在体外循环过程中，补体级联反应主要被激活。抗因子D单克隆抗体166-32可有效抑制补体、中性粒细胞和血小板的活化。通过靶向因子D抑制旁路补体途径可能有助于减少接受心肺转流术的患者的全身炎症。
Objectives: Patients undergoing cardiopulmonary bypass frequently manifest generalized systemic inflammation and occasionally manifest serious multiorgan failure. Inflammatory responses of bypass are triggered by contact of blood with artificial surfaces of the bypass circuits, surgical trauma, and ischemia-reperfusion injury. We studied the effects of specific inhibition of the alternative complement cascade by using an anti-factor D monoclonal antibody (166-32) in extracorporeal circulation of human whole blood used as a simulated model of cardiopulmonary bypass.Methods: Five healthy blood donors were used in the study. Monoclonal antibody 166-32 was added to freshly collected, heparinized human blood recirculated in a pediatric cardiopulmonary bypass circuit at a final concentration of 18 mug/mL. An irrelevant monoclonal antibody was used as a negative control with the same donor blood in a parallel bypass circuit on the same day. Blood samples were collected at different time points during recirculation for measurement of activation of complement, neutrophils, and platelets by immunofluorocytometric methods and enzyme-linked immunosorbent assays.Results: Monoclonal antibody 166-32 inhibited the alternative complement activation and the production of Bb, C3a, sC5b-9, and C5a. Upregulation of CD11b on neutrophils and CD62P on platelets was also significantly inhibited by monoclonal antibody 166-32. This is consistent with the inhibition of the release of neutrophil-specific myeloperoxidase and elastase and platelet thrombospondin. The production of proinflammatory cytokine interleukin 8 was also suppressed by the antibody.Conclusions: The alternative complement cascade is predominantly activated during extracorporeal circulation. Anti-factor D monoclonal antibody 166-32 is effective in inhibiting the activation of complement, neutrophils, and platelets. Inhibition of the alternative complement pathway by targeting factor D could be useful in reducing systemic inflammation in patients undergoing cardiopulmonary bypass.