Myocardial reperfusion injury: etiology, mechanisms, and therapies.
Myocardial reperfusion injury: etiology, mechanisms, and therapies.
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DOI：
10.1051/ject/2004364391
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发表时间：
2004-12-01
期刊：
影响因子：
--
通讯作者：
Silldorff, Erik P
中科院分区：
文献类型：
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作者：
Hoffman, John W Jr;Gilbert, Timothy B;Silldorff, Erik P
缺血心肌的再灌注是组织存活所必需的，然而，再灌注会导致病理后果。心肌再灌注损伤是一个多方面的过程，其部分由氧自由基、嗜酸性粒细胞-内皮细胞相互作用、细胞凋亡和细胞内钙超载介导。氧悖论描述了向缺血组织输送氧的矛盾需求和由此产生的氧减少以形成自由基，自由基参与大分子氧化、膜功能障碍、细胞凋亡和受损的钙螯合能力，这导致过度挛缩。中性粒细胞的过度活化会放大这些细胞损伤危机，从而促进促炎介质、氧自由基的形成和内皮一氧化氮形成的减少，导致嗜中性粒细胞-内皮相互作用增加和毛细血管闭塞。然而，神经再生作用是双重的，因为它是严重缺血后清除坏死碎片所必需的。中性粒细胞、内皮细胞和肌细胞产生的氧自由基也可能在激活凋亡级联反应中发挥作用。虽然细胞凋亡在再灌注损伤中的作用是有争议的，但在梗死组织中发现了凋亡细胞。关键介质之一可能是线粒体内膜通透性增加，导致ATP形成减少，细胞色素c释放和半胱天冬酶激活，这是促进细胞凋亡的关键。线粒体膜通透性增加发生在暴露于超生理钙浓度。这是由于代偿性Na+/Ca 2+交换以去除由缺血期间Na+/K+泵送减少和再灌注后Na+/H+交换增加引起的过量细胞内钠。超生理性钙离子诱发肌挛缩和细胞损伤。为减少心肌再灌注损伤而开发的各种疗法包括抑制上述过程以及其他过程。虽然单一疗法已经显示出一些前景，但对再灌注反应的复杂性使得戏剧性的改善变得难以捉摸。有效的治疗将很可能需要多方面的拮抗作用的许多病理级联反应引发的再灌注。
Reperfusion of ischemic myocardium is required for tissue survival; however, reperfusion elicits pathologic consequences. Myocardial reperfusion injury is a multifarious process that is mediated in part by oxygen free radicals, neutrophil-endothelium interactions, apoptosis, and intracellular calcium overload. The oxygen paradox describes the contradictory need to delivery oxygen to ischemic tissue and the resultant reduction of oxygen to form free radicals that are involved in macromolecule oxidation, membrane disfunction, apoptosis, and damaged calcium sequestering ability, which results in hypercontracture. These cell-damaging crises are amplified by the excessive activation of neutrophils, which promote the formation of proinflammatory mediators, oxygen radicals, and the reduction of endothelial nitric oxide formation, leading to increased neutrophil-endothelium interactions and capillary occlusion. Neutrophil action is twofold, however, because it is required for necrotic debris removal after severe ischemia. The oxygen radicals produced by neutrophils, endothelium, and myocytes may also play a role in activating the apoptotic cascade. Although the role of apoptosis in reperfusion injury is controversial, apoptotic cells are found in infarcted tissue. One of the key mediators may be increased inner mitochondrial membrane permeability, resulting in reduced ATP formation, release of cytochrome c, and caspase activation, which is key to promotion of apoptosis. Increased mitochondrial membrane permeability occurs during exposure to supraphysiological calcium concentrations. This occurs because of compensatory Na+/Ca2+ exchange to remove the excess intracellular sodium resulting from decreased Na+/K+ pumping during ischemia and increased Na+/H+ exchange following reperfusion. Supraphysiological calcium elicits hypercontracture and cellular damage. The various therapies being developed to diminish myocardial reperfusion injury involve inhibition of the processes described above as well as others. Although single therapies have shown some promise, the complexity of the response to reperfusion has made dramatic improvement elusive. Effective treatment will most likely require multifaceted antagonism of the numerous pathological cascades initiated by reperfusion.