Youker K A, Hawkins H K, Kukielka G L, Perrard J L, Michael L H, Ballantyne C M, Smith C W, Entman M L
Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX.
Trans Assoc Am Physicians. 1993;106:145-54.
Acute inflammation has been suggested as a potential mechanism for some of the injury associated with reperfusion of the ischemic myocardium. This hypothesis implies that viable myocardial cells adjacent to the lethally injured cells are vulnerable to injury induced by the neutrophil influx observed to attend reperfusion. In our previous work, we demonstrated that the presence of ICAM-1 on the surface of cardiac myocytes is required for neutrophils to directly damage them; blocking monoclonal antibodies to either ICAM-1 on cardiac myocytes or Mac-1 on activated neutrophils completely precluded neutrophil-induced myocyte injury. We also demonstrated that postischemic cardiac lymph (cardiac extracellular fluid) contained leukotactic factors (primarily C5a) and cytokines present in concentrations sufficient to maximally induce Mac-1 on the surface of neutrophils and ICAM-1 on the surface of isolated dog cardiac myocytes. The present study sought to further these observations by examining the site of potential ICAM-1 induction as a function of time of reperfusion, degree of ischemia, and viability of myocardial cells. Our evidence suggests that ICAM-1 mRNA is induced very early after reperfusion only in the previously ischemic myocardium and is not seen in the nonischemic myocardium during the early hours of reperfusion. Moreover, ICAM-1 mRNA induction is seen most intensely in the ischemic area directly bordering the necrotic area (which, after 1-hr reperfusion, does not contain any ICAM-1 mRNA) and immediately abutting the site of maximal influx of neutrophils. Thus, the induction of ICAM-1 and the influx of neutrophils (presumably activated by the chemotactic factors that guided their migration) exists on the border between viable and necrotic cells. This provides the first direct molecular evidence for a jeopardized border zone on the edge of myocardial infarction during reperfusion. As previously demonstrated, this reaction is wholly dependent upon tissue injury of the ischemic myocardium and therefore represents an example of a mechanism of injury extension induced as a reaction to a primary injury. The degree of specificity of this reaction demonstrated by the subendocardial sparing directly adjacent to ischemic cells suggests finely modulated mechanisms by which this process is controlled.
急性炎症被认为是与缺血心肌再灌注相关的一些损伤的潜在机制。这一假说意味着，与致死性损伤细胞相邻的存活心肌细胞易受再灌注时观察到的中性粒细胞流入所诱导的损伤。在我们之前的研究中，我们证明心肌细胞表面存在细胞间黏附分子-1（ICAM-1）是中性粒细胞直接损伤它们所必需的；针对心肌细胞上的ICAM-1或活化中性粒细胞上的Mac-1的阻断单克隆抗体完全排除了中性粒细胞诱导的心肌细胞损伤。我们还证明，缺血后心脏淋巴液（心脏细胞外液）含有趋化因子（主要是C5a）和细胞因子，其浓度足以最大程度地诱导中性粒细胞表面的Mac-1和分离的犬心肌细胞表面的ICAM-1。本研究旨在通过检查潜在的ICAM-1诱导位点作为再灌注时间、缺血程度和心肌细胞活力的函数来进一步验证这些观察结果。我们的证据表明，ICAM-1 mRNA仅在再灌注后非常早期在先前缺血的心肌中被诱导，而在再灌注早期的非缺血心肌中未见。此外，ICAM-1 mRNA诱导在直接毗邻坏死区域（再灌注1小时后，该区域不含任何ICAM-1 mRNA）且紧邻中性粒细胞最大流入部位的缺血区域最为强烈。因此，ICAM-1的诱导和中性粒细胞的流入（可能由引导其迁移的趋化因子激活）存在于存活细胞和坏死细胞的边界。这为再灌注期间心肌梗死边缘的濒危边界区提供了首个直接的分子证据。如先前所示，这种反应完全依赖于缺血心肌的组织损伤，因此代表了作为对原发性损伤的反应而诱导的损伤扩展机制的一个例子。紧邻缺血细胞的内膜下 sparing所显示的这种反应的特异性程度表明，该过程受到精细调节的机制控制。
