Tofukuji M, Stahl G L, Agah A, Metais C, Simons M, Sellke F W
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Division, Beth Israel-Deaconess Medical Center, Boston, MA 02215, USA.
J Thorac Cardiovasc Surg. 1998 Dec;116(6):1060-8. doi: 10.1016/S0022-5223(98)70059-5.
Because C5a induces tissue injury by activating polymorphonuclear leukocytes, the hypothesis was that inhibition of C5a activity would reduce cardioplegia-related injury.
Pigs were placed on cardiopulmonary bypass. The hearts were arrested for 1 hour with hyperkalemic cardioplegia. Pigs were then separated from bypass, and the hearts were reperfused for 2 hours. Anti-porcine C5a monoclonal antibody (1.6 mg/kg, intravenously; n = 6) was administered 20 minutes before the onset of cardiopulmonary bypass. Six pigs received saline solution vehicle. Reactivity of coronary arterioles was studied in vitro with videomicroscopy. Microvessels from uninstrumented pigs served as controls for vascular studies.
Endothelium-dependent relaxation to adenosine diphosphate (percent relaxation of precontraction) was reduced after cardioplegic reperfusion (63% +/- 14% vs 77% +/- 10% in control at 10 micromol/L; P =.01). This impairment in endothelium-dependent relaxation was improved with anti-porcine C5a monoclonal antibody (80% +/- 22%; P =.01 vs saline solution), as was the impaired endothelium-dependent relaxation to clonidine (64% +/- 12% control; 26% +/- 17% saline solution; 55% +/- 24% anti-porcine C5a monoclonal antibody at 10 micromol/L; P =.01 saline solution vs control or anti-porcine C5a monoclonal antibody). Myeloperoxidase activity was significantly decreased (0.2 +/- 0.2 units/g protein; P =.04) in the anti-porcine C5a monoclonal antibody group compared with 5.2 +/- 2.7 in the saline solution group. CH50 2 hours after bypass was not statistically different (0.57 +/- 0.41 unit and 0.65 +/- 0.41 unit, respectively) between the anti-porcine C5a monoclonal antibody and saline solution groups. Despite less myocardial polymorphonuclear leukocyte infiltration after C5a inhibition, maximum rate of rise of left ventricular pressure, percent segmental shortening, and blood flow through the left anterior descending coronary artery were similar in the anti-porcine C5a monoclonal antibody and saline solution groups.
Inhibition of C5a limits neutrophil-mediated impairment of endothelium-dependent relaxation after cardiopulmonary bypass and cardioplegic reperfusion, but it has no effect on short-term myocardial functional preservation.
由于C5a通过激活多形核白细胞诱导组织损伤，因此假设抑制C5a活性可减少与心脏停搏相关的损伤。
将猪置于体外循环。用高钾心脏停搏液使心脏停搏1小时。然后将猪脱离体外循环，心脏再灌注2小时。在体外循环开始前20分钟静脉注射抗猪C5a单克隆抗体（1.6mg/kg；n=6）。6头猪接受生理盐水载体。用视频显微镜在体外研究冠状动脉小动脉的反应性。来自未插管猪的微血管用作血管研究的对照。
心脏停搏再灌注后，内皮依赖性舒张对二磷酸腺苷的反应（预收缩舒张百分比）降低（10μmol/L时，对照组为77%±10%，心脏停搏再灌注组为63%±14%；P=0.01）。抗猪C5a单克隆抗体改善了内皮依赖性舒张的这种损害（80%±22%；与生理盐水相比，P=0.01），对可乐定的内皮依赖性舒张损害也有改善（对照组为64%±12%；生理盐水组为26%±17%；10μmol/L时抗猪C5a单克隆抗体组为55%±24%；生理盐水组与对照组或抗猪C5a单克隆抗体组相比，P=0.01）。与生理盐水组的5.2±2.7相比，抗猪C5a单克隆抗体组的髓过氧化物酶活性显著降低（0.2±0.2单位/g蛋白；P=0.04）。体外循环2小时后，抗猪C5a单克隆抗体组和生理盐水组的CH50无统计学差异（分别为0.57±0.41单位和0.65±0.41单位）。尽管抑制C5a后心肌多形核白细胞浸润较少，但抗猪C5a单克隆抗体组和生理盐水组的左心室压力最大上升速率、节段缩短百分比和左前降支冠状动脉血流量相似。
抑制C5a可限制体外循环和心脏停搏再灌注后中性粒细胞介导的内皮依赖性舒张损害，但对短期心肌功能的保存无影响。
