Dreyer W J, Michael L H, West M S, Smith C W, Rothlein R, Rossen R D, Anderson D C, Entman M L
Section of Cardiovascular Sciences, Methodist Hospital, Houston, Tex.
Circulation. 1991 Jul;84(1):400-11. doi: 10.1161/01.cir.84.1.400.
We have previously demonstrated that chemotactic factors released from the ischemic canine myocardium peak early during reperfusion and that they elicit neutrophil adherence reactions in vitro that are dependent on the CD18 glycoprotein family. In this study we investigated the hypothesis that neutrophil localization in ischemic canine myocardium in vivo occurs over a similar time course during early reperfusion and involves a CD18-dependent mechanism.
We occluded the circumflex coronary artery for 1 hour in acute, open-chest dogs, followed by reperfusion for 1, 2, 3, or 4 hours. Regional myocardial blood flow was determined using radiolabeled microspheres, and localization was traced using technetium-99m-labeled autologous neutrophils. In the first hour of reperfusion, neutrophil localization occurred preferentially within the subendocardial region and was inversely related to flow. Neutrophil localization diminished across the ischemic myocardium from endocardium to epicardium but remained negatively related to flow in the midmyocardial region. Regardless of flow, little neutrophil localization occurred in the subepicardial region. Neutrophil localization was greatest in the first hour of reperfusion and diminished thereafter. By 4 hours of reperfusion, the rate of localization was markedly attenuated relative to 1 hour. Dogs given anti-CD18 monoclonal antibody R15.7 (1 mg/kg i.v.) before occlusion underwent 1 hour of occlusion followed by 1 hour of reperfusion. When compared with 1-hour reperfusion controls, the R15.7-treated dogs demonstrated significant attenuation of neutrophil localization in the subendocardial region.
These data support the concepts that rapid neutrophil localization during reperfusion occurs within regions of previous myocardial ischemia and that neutrophils preferentially localize within the subendocardial region. The rate of neutrophil localization is greatest within the first hour after the initiation of reperfusion, and localization is, at least in part, CD18 dependent. Therapies directed against neutrophil-mediated reperfusion injury should be initiated with these considerations in mind.
我们先前已证明，缺血犬心肌释放的趋化因子在再灌注早期达到峰值，且它们在体外引发的中性粒细胞黏附反应依赖于CD18糖蛋白家族。在本研究中，我们调查了这样一种假说，即体内缺血犬心肌中的中性粒细胞定位在再灌注早期的相似时间进程内发生，且涉及一种依赖于CD18的机制。
我们在急性开胸犬中闭塞左旋冠状动脉1小时，随后再灌注1、2、3或4小时。使用放射性标记的微球测定局部心肌血流量，并使用锝-99m标记的自体中性粒细胞追踪定位情况。在再灌注的第1小时，中性粒细胞定位优先发生在心内膜下区域，且与血流量呈负相关。中性粒细胞定位从心内膜到心外膜在整个缺血心肌中逐渐减少，但在心肌中层区域仍与血流量呈负相关。无论血流量如何，心外膜下区域几乎没有中性粒细胞定位。中性粒细胞定位在再灌注的第1小时最大，此后逐渐减少。到再灌注4小时时，定位率相对于1小时明显降低。在闭塞前给予抗CD18单克隆抗体R15.7（1毫克/千克静脉注射）的犬，闭塞1小时后再灌注1小时。与1小时再灌注对照组相比，接受R15.7治疗的犬在心内膜下区域的中性粒细胞定位明显减弱。
这些数据支持以下概念，即再灌注期间中性粒细胞的快速定位发生在先前心肌缺血区域内，且中性粒细胞优先在心内膜下区域定位。中性粒细胞定位率在再灌注开始后的第1小时内最大，且定位至少部分依赖于CD18。针对中性粒细胞介导的再灌注损伤的治疗应考虑到这些因素而启动。
