Maroko P R, Carpenter C B, Chiariello M, Fishbein M C, Radvany P, Knostman J D, Hale S L
J Clin Invest. 1978 Mar;61(3):661-70. doi: 10.1172/JCI108978.
Components of the complement system are known to play an important role in the cytolytic process and in chemotaxis of leukocytes. Cobra venom factor specifically cleaves C3 activity via activation of the alternative (properdin) complement pathway. It does not act directly on C3. If C3 is involved in tissue necrosis after ischemic injury, cobra venom factor might reduce tissue damage after acute coronary occlusion. Accordingly, in 14 control dogs occlusion of the left anterior descending artery was carried out for 24 h. Epicardial electrograms were recorded 15 min after occlusion, and 24 h later transmural specimens for creatine phosphokinase activity (CPK) and for histological analysis were obtained from the same sites. In another 14 experimental dogs, 20 U/kg cobra venom factor was given intravenously 30 min after occlusion. Serum complement levels fell within 2-4 h to <20% of normal. In the control dogs, the relationship between ST-segment elevation and CPK activity 24 h later was: log CPK = -0.06 ST + 1.48 (n = 111 specimens, 14 dogs, r = 0.77). In the experimental dogs, log CPK = -0.024 ST + 1.46 (n = 111 specimens, 14 dogs, r = 0.60), showing significantly different slopes (P < 0.001), i.e., less CPK depression for any level of ST-segment elevation. Histologically, 69 of 71 sites (97%) with ST-segment elevation exceeding 2 mV in the control dogs showed signs of necrosis 24 h later, whereas in the experimental group only 43 of 79 sites (54%) with abnormal ST-segment elevations showed signs of necrosis (P < 0.0005). At the same time, it was shown that the administration of cobra venom factor did not alter cardiac performance, collateral blood flow to the ischemic myocardium or the clotting system, but infiltration of polymorphonuclear leukocytes into the myocardium was decreased. It is concluded that cobra venom factor, by reducing the amount of C3 and C5 substrate available for chemotactic factor generation, or other as yet undefined mechanisms, protects the ischemic myocardium from undergoing necrosis, as judged by histology and local CPK activity. Hence, a new approach to limiting the extent of myocardial infarcts after experimental coronary occlusion, based upon inhibition of complement-dependent inflammatory processes, is demonstrated.
已知补体系统的成分在细胞溶解过程和白细胞趋化作用中发挥重要作用。眼镜蛇毒因子通过激活替代（备解素）补体途径特异性地裂解C3活性。它不直接作用于C3。如果C3参与缺血性损伤后的组织坏死，那么眼镜蛇毒因子可能会减轻急性冠状动脉闭塞后的组织损伤。因此，对14只对照犬进行左前降支动脉闭塞24小时。闭塞后15分钟记录心外膜电图，24小时后从相同部位获取用于肌酸磷酸激酶活性（CPK）和组织学分析的透壁标本。在另外14只实验犬中，闭塞后30分钟静脉注射20 U/kg眼镜蛇毒因子。血清补体水平在2 - 4小时内降至正常水平的<20%。在对照犬中，24小时后ST段抬高与CPK活性之间的关系为：log CPK = -0.06 ST + 1.48（n = 111个标本，14只犬，r = 0.77）。在实验犬中，log CPK = -0.024 ST + 1.46（n = 111个标本，14只犬，r = 0.60），显示斜率有显著差异（P < 0.001），即对于任何程度的ST段抬高，CPK降低程度较小。组织学上，对照犬中71个ST段抬高超过2 mV的部位中有69个（97%）在24小时后显示坏死迹象，而在实验组中，79个ST段异常抬高的部位中只有43个（54%）显示坏死迹象（P < 0.0005）。同时，研究表明给予眼镜蛇毒因子不会改变心脏功能、缺血心肌的侧支血流或凝血系统，但多形核白细胞向心肌的浸润减少。结论是，通过减少可用于产生趋化因子的C3和C5底物量或其他尚未明确的机制，眼镜蛇毒因子可保护缺血心肌免于坏死，这从组织学和局部CPK活性判断得出。因此，展示了一种基于抑制补体依赖性炎症过程来限制实验性冠状动脉闭塞后心肌梗死范围的新方法。
