Weyrich A S, Ma X Y, Lefer D J, Albertine K H, Lefer A M
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-6799.
J Clin Invest. 1993 Jun;91(6):2620-9. doi: 10.1172/JCI116501.
The cardioprotective effects of an mAb to P-selectin designated mAb PB1.3 was examined in a feline model of myocardial ischemia (MI) and reperfusion. PB1.3 (1 mg/kg), administered after 80 min of ischemia (i.e., 10 min before reperfusion), significantly attenuated myocardial necrosis compared to a non-blocking mAb (NBP1.6) for P-selectin (15 +/- 3 vs 35 +/- 3% of area at risk, P < 0.01). Moreover, endothelial release of endothelium derived relaxing factor, as assessed by relaxation to acetylcholine, was also significantly preserved in ischemic-reperfused coronary arteries isolated from cats treated with mAb PB1.3 compared to mAb NBP1.6 (67 +/- 6 vs 11 +/- 3, P < 0.01). This endothelial preservation was directly related to reduced endothelial adherence of PMNs in ischemic-reperfused coronary arteries. Immunohistochemical localization of P-selectin was significantly upregulated in the cytoplasm of endothelial cells that lined coronary arteries and veins after 90 min of ischemia and 20 min of reperfusion. The principal site of intracytoplasmic expression was in venous vessels. mAb PB1.3 significantly decreased (P < 0.01) adherence of unstimulated PMNs to thrombin and histamine stimulated endothelial cells in a concentration-dependent manner in vitro. These results demonstrate that PMN adherence to endothelium by P-selectin is an important early consequence of reperfusion injury, and a specific monoclonal antibody to P-selectin exerts significant endothelial preservation and cardioprotection in myocardial ischemia and reperfusion.
研究了一种针对P-选择素的单克隆抗体（mAb PB1.3）在猫心肌缺血（MI）和再灌注模型中的心脏保护作用。在缺血80分钟后（即再灌注前10分钟）给予PB1.3（1毫克/千克），与针对P-选择素的非阻断性单克隆抗体（NBP1.6）相比，可显著减轻心肌坏死（危险区域面积的15±3%对35±3%，P<0.01）。此外，与mAb NBP1.6相比，在用mAb PB1.3治疗的猫分离出的缺血再灌注冠状动脉中，通过对乙酰胆碱的舒张反应评估的内皮衍生舒张因子的内皮释放也得到了显著保留（67±6对11±3，P<0.01）。这种内皮保留与缺血再灌注冠状动脉中PMN内皮黏附的减少直接相关。在缺血90分钟和再灌注20分钟后，冠状动脉和静脉内皮细胞胞质中P-选择素的免疫组化定位显著上调。胞质内表达的主要部位是静脉血管。mAb PB1.3在体外以浓度依赖的方式显著降低（P<0.01）未刺激的PMN对凝血酶和组胺刺激的内皮细胞的黏附。这些结果表明，P-选择素介导的PMN与内皮的黏附是再灌注损伤的一个重要早期后果，一种针对P-选择素的特异性单克隆抗体在心肌缺血和再灌注中具有显著的内皮保护和心脏保护作用。
