17β-雌二醇可减少大鼠心肌缺血再灌注损伤中心脏白细胞的积聚。

17Beta-oestradiol reduces cardiac leukocyte accumulation in myocardial ischaemia reperfusion injury in rat.

作者信息

Squadrito F, Altavilla D, Squadrito G, Campo G M, Arlotta M, Arcoraci V, Minutoli L, Serrano M, Saitta A, Caputi A P

机构信息

Institute of Pharmacology, School of Medicine, University of Messina, Italy.

出版信息

Eur J Pharmacol. 1997 Sep 24;335(2-3):185-92. doi: 10.1016/s0014-2999(97)01201-6.

DOI:10.1016/s0014-2999(97)01201-6

PMID:9369372

Abstract

We investigated whether oestrogens modulate the phenomenon of leukocyte accumulation during ischaemia and reperfusion of the myocardium. Anaesthetized rats were subjected to total occlusion (1 h) of the left main coronary artery followed by 1 h reperfusion. Sham myocardial ischaemia-reperfusion rats (Sham) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity, serum creatinine phosphokinase activity, serum and macrophages tumour necrosis factor (TNF-alpha) and the myocardial staining of intercellular adhesion molecule-1 (ICAM-1) were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum creatinine phosphokinase activity (348 +/- 38 U/ml) and cardiac myeloperoxidase activity, a marker of polymorphonuclear leukocyte accumulation, both in the area at risk and in the necrotic area (MPO 9 +/- 1.1 mU/g tissue and 8.2 +/- 1 mU/g tissue, respectively), and induced a marked increase in the macrophage (156 +/- 14 U/ml at the end of reperfusion) and serum (344 +/- 12 U/ml, at the end of reperfusion) levels of TNF-alpha. Finally, myocardial ischaemia-reperfusion injury increased ICAM-1 staining in the myocardium. Administration of 17beta-oestradiol (5, 10 and 20 microg/kg, i.m. 5 min after induction of myocardial ischaemia-reperfusion injury), lowered myocardial necrosis and myeloperoxidase activity in the area at risk and in the necrotic area, reduced serum and macrophages TNF-alpha (20 +/- 3 U/ml and 9 +/- 3 U/ml, respectively) and decreased serum creatinine phosphokinase activity (67 +/- 3 U/ml). Oestrogen treatment also blunted the increased staining of ICAM-1 in the injured myocardium. Finally, 17beta-oestradiol added in vitro to peritoneal macrophages collected from untreated rats subjected to myocardial ischaemia-reperfusion injury, significantly reduced TNF-alpha production. Our results suggest that 17beta-oestradiol, by inhibiting TNF-alpha production, limits the deleterious ICAM-1-mediated binding of leukocytes to injured myocardium and protects against myocardial ischaemia-reperfusion injury.

摘要

我们研究了雌激素是否能调节心肌缺血再灌注过程中的白细胞聚集现象。将麻醉的大鼠左主冠状动脉完全闭塞1小时，然后再灌注1小时。假心肌缺血再灌注大鼠（假手术组）作为对照。评估心肌坏死、心肌髓过氧化物酶活性、血清肌酸磷酸激酶活性、血清和巨噬细胞肿瘤坏死因子（TNF-α）以及细胞间黏附分子-1（ICAM-1）的心肌染色情况。未处理大鼠的心肌缺血加再灌注导致明显的心肌坏死，血清肌酸磷酸激酶活性增加（348±38 U/ml），以及心肌髓过氧化物酶活性增加，髓过氧化物酶是多形核白细胞聚集的标志物，在危险区域和坏死区域均有增加（分别为9±1.1 mU/g组织和8.2±1 mU/g组织），并导致巨噬细胞（再灌注结束时为156±14 U/ml）和血清（再灌注结束时为344±12 U/ml）中TNF-α水平显著升高。最后，心肌缺血再灌注损伤增加了心肌中ICAM-1的染色。给予17β-雌二醇（5、10和20μg/kg，在心肌缺血再灌注损伤诱导后5分钟肌肉注射），可降低危险区域和坏死区域的心肌坏死和髓过氧化物酶活性；降低血清和巨噬细胞中的TNF-α（分别为20±3 U/ml和9±3 U/ml）；降低血清肌酸磷酸激酶活性（67±3 U/ml）。雌激素治疗还减弱了受损心肌中ICAM-1染色的增加。最后，将17β-雌二醇体外添加到从经历心肌缺血再灌注损伤的未处理大鼠收集的腹腔巨噬细胞中，可显著降低TNF-α的产生。我们的结果表明，17β-雌二醇通过抑制TNF-α的产生，限制了ICAM-1介导的白细胞与受损心肌的有害结合，并预防心肌缺血再灌注损伤。