抗粘附分子ICAM-1单克隆抗体CL18/6对犬缺血/再灌注心肌的保护作用

Protection of ischemic/reperfused canine myocardium by CL18/6, a monoclonal antibody to adhesion molecule ICAM-1.

作者信息

Hartman J C, Anderson D C, Wiltse A L, Lane C L, Rosenbloom C L, Manning A M, Humphrey W R, Wall T M, Shebuski R J

机构信息

Upjohn Company, Kalamazoo, MI 49001, USA.

出版信息

Cardiovasc Res. 1995 Jul;30(1):47-54.

PMID:7553723

Abstract

OBJECTIVE

A blocking monoclonal antibody to intercellular adhesion molecule-1 (ICAM-1), CL18/6, previously has been demonstrated to inhibit neutrophil attachment to isolated vascular endothelium and cardiomyocytes. Due to the well known participation of ICAM-1 in the inflammatory responses associated with myocardial ischemia/reperfusion injury, we investigated if CL18/6 could attenuate myocardial ischemia/reperfusion injury in vivo.

METHODS

Saline (3-5 ml, i.v., n = 6), non-blocking control MAb CL18/1D8 or CL18/6 (both 0.5 mg kg-1, i.v., n = 4) were administered prior to coronary occlusion (1 h) and subsequent reperfusion (5 h) produced by inflation of a coronary balloon angioplasty catheter in isoflurane-anesthetized, closed-chest dogs. Heart rate and arterial pressure were measured, and regional myocardial blood flow (rMBF), and myeloperoxidase activity (MPO) to index local neutrophil sequestration, were determined. Myocardial infarct size (IS) was evaluated using the tetrazolium staining technique and expressed as a percent of area at risk (AR).

RESULTS

Changes in heart rate and arterial pressure were insignificant throughout the experiment. rMBF (mean +/- s.e.m.) in the ischemic subendocardium for each treatment group was: Saline (0.07 +/- 0.02 ml min-1 g-1); CL18/1D8 (0.04 +/- 0.02); CL18/6 (0.06 +/- 0.02). IS/AR% was: saline (37 +/- 3%); CL18/1D8 (39 +/- 9%); CL18/6 (15 +/- 4%*); * = significantly different from CL18/1D8 and saline, P < 0.05. MPO assayed from AR immediately adjacent to the infarct was significantly reduced below infarct MPO only in the CL18/6 treated group-36%).

CONCLUSIONS

The results indicate that CL18/6 antagonism of ICAM-1 provided cardioprotection associated with reduced neutrophil activity in vulnerable myocardium, and suggest that ICAM-1 mediated neutrophil sequestration in endangered cardiac tissue is an important mechanism of myocardial ischemia/reperfusion injury.

摘要

目的

一种针对细胞间黏附分子-1（ICAM-1）的阻断性单克隆抗体CL18/6，先前已被证明可抑制中性粒细胞与分离的血管内皮细胞和心肌细胞的黏附。由于ICAM-1在与心肌缺血/再灌注损伤相关的炎症反应中的作用已广为人知，我们研究了CL18/6是否能在体内减轻心肌缺血/再灌注损伤。

方法

在异氟烷麻醉、开胸犬中，通过冠状动脉球囊血管成形术导管充气造成冠状动脉闭塞（1小时）及随后的再灌注（5小时）之前，静脉注射生理盐水（3 - 5毫升，n = 6）、非阻断性对照单克隆抗体CL18/1D8或CL18/6（均为0.5毫克/千克，静脉注射，n = 4）。测量心率和动脉压，并测定局部心肌血流量（rMBF）以及用于指示局部中性粒细胞滞留的髓过氧化物酶活性（MPO）。使用四氮唑染色技术评估心肌梗死面积（IS），并表示为危险区域（AR）面积的百分比。

结果

在整个实验过程中，心率和动脉压的变化不显著。各治疗组缺血性心内膜下的rMBF（平均值±标准误）为：生理盐水组（0.07±0.02毫升/分钟/克）；CL18/1D8组（0.04±0.02）；CL18/6组（0.06±0.02）。IS/AR%为：生理盐水组（37±3%）；CL18/1D8组（39±9%）；CL18/6组（15±4%*）；*与CL18/1D8组和生理盐水组有显著差异，P < 0.05。仅在CL18/6治疗组中，紧邻梗死灶的AR区域的MPO测定值显著低于梗死灶MPO（降低36%）。