抗P-选择素单克隆抗体对冷停搏缺血后新生羔羊心脏恢复的影响。

Nagashima M, Shin'oka T, Nollert G, Shum-Tim D, Hickey P R, Roth S J, Kirchhoff A, Springer T A, Burke P R, Mayer J E

Department of Cardiovascular Surgery, Children's Hospital, Boston, MA 02115, USA.

Circulation. 1998 Nov 10;98(19 Suppl):II391-7; discussion II397-8.

BACKGROUND

The interaction between endothelium and leukocytes plays a crucial role in ischemia-reperfusion injury. P-selectin, which is expressed on activated endothelium, mediates the first step in leukocyte adherence to the endothelium. This study examined the effects of a monoclonal antibody (mAb) against P-selectin on the recovery of cardiac function and myocardial neutrophil infiltration after ischemia.

METHODS AND RESULTS

Thirteen blood-perfused, isolated neonatal lamb hearts underwent 2 hours of hypothermic cardioplegic arrest and 2 hours of reperfusion. Immediately before reperfusion, mAb to P-selectin was administered to the perfusate (15 micrograms/mL) in 6 hearts (group P-sel). In control (n = 7), the same volume of saline was added. Isovolumic left ventricular function and coronary blood flow were measured. At 2 hours after reperfusion, myocardial myeloperoxidase activity, an index of neutrophil accumulation, was assayed. At 30 minutes of reperfusion, hearts treated with mAb to P-selectin achieved significantly greater recovery of maximum developed pressure (70 +/- 4% in control versus 77 +/- 2% in group P-sel, P < 0.01), maximum positive first derivative of pressure (dP/dt) (64 +/- 7% in control versus 73 +/- 5% in group P-sel, P < 0.05), and maximum negative dP/dt (61 +/- 6% in control versus 70 +/- 6% in group P-sel, P < 0.05) compared with control. Percent baseline of coronary blood flow was also significantly increased in group P-sel (135 +/- 40% in control versus 205 +/- 43% in group P-sel, P < 0.05). Myocardial myeloperoxidase activity was significantly lower (P < 0.05) in group P-sel (4.7 +/- 3.2) versus control (16.0 +/- 10.1). (Units are change in absorbance/min/g tissue.)

CONCLUSIONS

The functional blockade of P-selectin resulted in better recovery of cardiac function and attenuated neutrophil accumulation during early reperfusion. Strategies to block P-selectin mediated neutrophil adherence may have clinical application in improving myocardial function at early reperfusion.

背景

内皮细胞与白细胞之间的相互作用在缺血再灌注损伤中起关键作用。P-选择素表达于活化的内皮细胞上，介导白细胞黏附于内皮细胞的第一步。本研究检测了抗P-选择素单克隆抗体（mAb）对缺血后心脏功能恢复及心肌中性粒细胞浸润的影响。

方法与结果

13个血液灌注的离体新生羔羊心脏经历2小时低温心脏停搏及2小时再灌注。在再灌注前即刻，给6个心脏的灌注液中加入抗P-选择素mAb（15微克/毫升）（P-sel组）。对照组（n = 7）加入相同体积的生理盐水。测量等容左心室功能及冠状动脉血流量。再灌注2小时后，检测心肌髓过氧化物酶活性，这是中性粒细胞聚集的一个指标。再灌注30分钟时，与对照组相比，用抗P-选择素mAb处理的心脏在最大舒张压力恢复方面显著更好（对照组为70±4%，P-sel组为77±2%，P < 0.01），最大压力一阶正导数（dP/dt）（对照组为64±7%，P-sel组为73±5%，P < 0.05），以及最大压力一阶负导数（对照组为61±6%，P-sel组为70±6%，P < 0.05）。P-sel组冠状动脉血流量占基线的百分比也显著增加（对照组为135±40%，P-sel组为205±43%，P < 0.05）。P-sel组心肌髓过氧化物酶活性显著低于对照组（P < 0.05）（4.7±3.2）与（16.0±10.1）。（单位为吸光度变化/分钟/克组织）。