Wilson I, Gillinov A M, Curtis W E, DiNatale J, Burch R M, Gardner T J, Cameron D E
Division of Cardiac Surgery, Johns Hopkins Hospital, Baltimore, MD 21287.
Circulation. 1993 Nov;88(5 Pt 2):II372-9.
Reduction of the leukocyte population during postischemic coronary reperfusion results in decreased neutrophil-mediated tissue injury. However, the importance of leukocyte adhesion to coronary endothelium for postischemic ventricular dysfunction after global hypothermic myocardial ischemia is unknown. Neutrophil integrins (CD11b/CD18) upregulate in response to cardiopulmonary bypass and ischemic stress, and their role in generating postoperative ventricular dysfunction was examined in this study.
An in vivo, in situ model of neonatal cardiac surgery was established in which neutrophil adherence was manipulated by administering NPC 15669 (an inhibitor of neutrophil CD11b/CD18 surface receptor upregulation). Seventeen 3- to 5-day-old piglets (8 controls and 9 NPC 15669-treated animals) were instrumented with a coronary sinus catheter, sonomicrometry crystals across the short axis of the left ventricle (LV), and a micromanometer positioned in the LV. Hearts were subjected to 90 minutes of hypothermic ischemia after a single dose of cold crystalloid cardioplegia. Myocardial granulocyte accumulation during ischemia and reperfusion was reduced in NPC animals compared with controls (myeloperoxidase activity, 43.4 +/- 2.6 and 75.8 +/- 6.3 mumol/10 mg tissue, respectively; P < or = .005). This was associated with a reduction in coronary vascular resistance in NPC animals compared with controls (P < or = .02) and decreased release of myocardial creatine phosphokinase throughout reperfusion (P < or = .05). NPC animals demonstrated an improved preservation of the end-systolic pressure-volume relation after discontinuation of cardiopulmonary bypass (71 +/- 6% and 96 +/- 6% at 60 minutes, respectively; P < or = .05). There was no difference in ventricular compliance between groups.
These data demonstrate that inhibition of neutrophil CD11b/CD18 surface adherence receptor upregulation reduces granulocyte accumulation in myocardium after hypothermic global ischemia, reduces myocyte damage, and improves ventricular systolic function.
缺血后冠状动脉再灌注期间白细胞数量减少可导致中性粒细胞介导的组织损伤减轻。然而，在全身性低温心肌缺血后，白细胞黏附于冠状动脉内皮对缺血后心室功能障碍的重要性尚不清楚。中性粒细胞整合素（CD11b/CD18）会因体外循环和缺血应激而上调，本研究对其在导致术后心室功能障碍中的作用进行了检测。
建立了一种新生仔猪心脏手术的体内原位模型，通过给予NPC 15669（一种中性粒细胞CD11b/CD18表面受体上调抑制剂）来控制中性粒细胞黏附。17只3至5日龄仔猪（8只作为对照，9只接受NPC 15669治疗）植入冠状窦导管、横跨左心室（LV）短轴的超声心动图晶体以及置于LV内的微测压计。在单次给予冷晶体心脏停搏液后，心脏经历90分钟的低温缺血。与对照组相比，接受NPC治疗的动物在缺血和再灌注期间心肌粒细胞积聚减少（髓过氧化物酶活性分别为43.4±2.6和75.8±6.3μmol/10mg组织；P≤0.005）。这与接受NPC治疗的动物相比对照组冠状动脉血管阻力降低（P≤0.02）以及在整个再灌注过程中心肌肌酸磷酸激酶释放减少（P≤0.05）有关。接受NPC治疗的动物在体外循环停止后表现出收缩末期压力-容积关系的保存改善（60分钟时分别为71±6%和96±6%；P≤0.05）。两组之间心室顺应性无差异。
这些数据表明，抑制中性粒细胞CD11b/CD18表面黏附受体上调可减少低温全身性缺血后心肌中的粒细胞积聚，减少心肌细胞损伤，并改善心室收缩功能。
