Bidirectional role of tumor necrosis factor-α in coronary microembolization -: Progressive contractile dysfunction versus delayed protection against infarction
Bidirectional role of tumor necrosis factor-α in coronary microembolization -: Progressive contractile dysfunction versus delayed protection against infarction
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DOI：
10.1161/01.res.0000255031.15793.86
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发表时间：
2007-01-05
影响因子：
20.1
通讯作者：
Heusch, Gerd
中科院分区：
文献类型：
--
作者：
Skyschally, Andreas;Gres, Petra;Heusch, Gerd
在不稳定型心绞痛患者中，斑块破裂和冠状动脉微栓塞（ME）可先于冠状动脉完全闭塞和即将发生的梗死。ME诱导的微梗死引发炎症反应，肿瘤坏死因子-α（TNF-α）表达增加，导致进行性收缩功能障碍。然而，TNF-α不仅是一种负性肌力药，而且还可以保护心肌免受梗死。在麻醉的猪中，我们研究了当TNF-α表达增加时ME是否能防止梗死。ME（组1; n = 7）通过冠状动脉内输注微球（42 μ m; 3000/mL/min流入）诱导。对照组（第2组; n = 8）接受生理盐水。第3组和第4组（每组n = 4）分别在ME或安慰剂前30分钟用绵羊TNF-α抗体（25 mg/kg体重）预处理。在ME后6小时，当TNF-α增加（66 +/-21 pg/g湿重;平均值+/- SEM）或在安慰剂后（TNF-α，21 +/-10 pg/g; P < 0.05）诱导缺血（90分钟）。在再灌注2小时后测定血管大小（风险面积百分比）（氯化三苯基四唑染色）。ME在6小时内逐渐减少收缩期室壁增厚（第1组与第2组，65 +/- 4%与90 +/- 1%;基线百分比; P < 0.05）。TNF-α抗体减弱了ME后收缩期室壁增厚的进行性减少（第3组，基线的77 +/- 5%;与第1组相比P < 0.05），而对照组无影响（第4组;基线的90 +/- 8%）。ME组梗死面积减少至18 ± 4%，而第2组为33 ± 4%（P < 0.05）。TNF-α抗体消除了梗死面积的减少（第3组与第4组，29 +/- 3%与35 +/- 5%）。在ME中，TNF-α负责进行性收缩功能障碍和延迟的梗死保护。
In patients with unstable angina, plaque rupture and coronary microembolization (ME) can precede complete coronary artery occlusion and impending infarction. ME-induced microinfarcts initiate an inflammatory reaction with increased tumor necrosis factor-alpha (TNF-alpha) expression, resulting in progressive contractile dysfunction. However, TNF-alpha is not only a negative inotrope but can also protect the myocardium against infarction. In anesthetized pigs, we studied whether ME protects against infarction when TNF-alpha expression is increased. ME (group1; n = 7) was induced by intracoronary infusion of microspheres (42 mu m; 3000 per mL/min inflow). Controls (group 2; n = 8) received saline. Groups 3 and 4 (n = 4 each) were pretreated with ovine TNF-alpha antibodies (25 mg/kg body weight) 30 minutes before ME or placebo, respectively. Ischemia ( 90 minutes) was induced 6 hours after ME when TNF-alpha was increased (66 +/- 21 pg/g wet weight; mean +/- SEM) or after placebo (TNF-alpha, 21 +/- 10 pg/g; P < 0.05). Infarct size ( percentage area at risk) was determined after 2 hours of reperfusion ( triphenyl tetrazolium chloride staining). ME decreased systolic wall thickening progressively over 6 hours ( group 1 versus group 2, 65 +/- 4% versus 90 +/- 1%; percentage of baseline; P < 0.05). TNF-alpha antibodies attenuated the progressive decrease in systolic wall thickening following ME (group 3, 77 +/- 5% of baseline; P < 0.05 versus group 1) with no effect in controls (group 4; 90 +/- 8% of baseline). With ME, infarct size was decreased to 18 +/- 4% versus 33 +/- 4% in group 2 (P < 0.05). The infarct size reduction was abolished by TNF-alpha antibodies (group 3 versus group 4, 29 +/- 3% versus 35 +/- 5%). In ME, TNF-alpha is responsible for both progressive contractile dysfunction and delayed protection against infarction.