Buerke M, Weyrich A S, Murohara T, Queen C, Klingbeil C K, Co M S, Lefer A M
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
J Pharmacol Exp Ther. 1994 Oct;271(1):134-42.
Polymorphonuclear leukocytes (i.e. neutrophils) significantly mediate damage in myocardial ischemia followed by reperfusion. In the present study, the cardioprotective effects of a humanized form of a monoclonal antibody directed against L-selectin designated monoclonal antibody (mAb) HuDREG-200 were examined in a feline model of 90-min myocardial ischemia followed by 270 min of reperfusion. In preliminary studies, flow cytometric analysis indicated that HuDREG-200 binds to feline neutrophils. In vitro administration of mAb HuDREG-200 significantly inhibited (P < .01) adherence of unstimulated neutrophils to ischemic-reperfused coronary endothelium in a concentration-dependent manner. Humanized DREG-200 (2 mg/kg) administered 10 min before reperfusion significantly attenuated myocardial necrosis compared to an isotype-matched humanized control mAb (HuABL364) which does not bind to L-selectin (14 +/- 3 vs. 29 +/- 3% necrosis/area-at-risk, P < .01), representing a 52% reduction in myocardial necrosis. This myocardial preservation also was related to reduced creatine kinase release and improved recovery of cardiac contractility (i.e. left ventricular dP/dtmax). Moreover, endothelial function, as assessed by relaxation to acetylcholine, also was significantly preserved in ischemic-reperfused coronary arteries isolated from cats treated with mAb HuDREG-200 compared to mAb HuABL364 (68 +/- 6 vs. 18 +/- 5, P < .01). Thus, a humanized anti-L-selectin mAb appears to be an effective means of preserving the ischemic myocardium from reperfusion injury and of preserving myocardial contractile function, at least during the early reperfusion period.
多形核白细胞（即中性粒细胞）在心肌缺血再灌注后显著介导损伤。在本研究中，在猫的90分钟心肌缺血继以270分钟再灌注模型中，检测了一种针对L-选择素的人源化单克隆抗体（单克隆抗体[mAb]HuDREG-200）的心脏保护作用。在初步研究中，流式细胞术分析表明HuDREG-200与猫中性粒细胞结合。体外给予mAb HuDREG-200以浓度依赖方式显著抑制（P <.01）未刺激的中性粒细胞与缺血再灌注冠状动脉内皮的黏附。再灌注前10分钟给予人源化DREG-200（2 mg/kg）与不与L-选择素结合的同型匹配人源化对照mAb（HuABL364）相比，显著减轻心肌坏死（坏死/危险面积分别为14±3% vs. 29±3%，P <.01），心肌坏死减少52%。这种心肌保护还与肌酸激酶释放减少和心脏收缩功能恢复改善（即左心室dP/dtmax）有关。此外，与mAb HuABL364相比，在用mAb HuDREG-200治疗的猫分离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功能也得到显著保留（68±6 vs. 18±5，P <.01）。因此，人源化抗L-选择素单克隆抗体似乎是保护缺血心肌免受再灌注损伤以及保护心肌收缩功能的有效手段，至少在再灌注早期是如此。
