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.
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.
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.)
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.
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。
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）。
P-选择素的功能阻断导致心脏功能更好地恢复，并减轻了再灌注早期的中性粒细胞聚集。阻断P-选择素介导的中性粒细胞黏附的策略可能在改善再灌注早期心肌功能方面有临床应用价值。
