Kukielka G L, Smith C W, Manning A M, Youker K A, Michael L H, Entman M L
Section of Cardiovascular Sciences, Methodist Hospital, DeBakey Heart Center, Houston, Tex, USA.
Circulation. 1995 Oct 1;92(7):1866-75. doi: 10.1161/01.cir.92.7.1866.
Neutrophil-induced injury of myocardial cells requires the expression of intercellular adhesion molecule-1 (ICAM-1) on the myocyte surface and is mediated by ICAM-1-CD11b/CD18 adhesion. We have previously shown that interleukin-6 (IL-6) cytokine activity, present in cardiac lymph, induces ICAM-1 on isolated cardiac myocytes. Furthermore, in previous in vivo studies, we have also shown ICAM-1 mRNA induction in the myocardium within the first hour of reperfusion in the previously ischemic viable zone. We hypothesized that induction of IL-6 synthesis in the myocardium was an integral part of the reaction to injury resulting from ischemia and reperfusion and was associated with induction of ICAM-1 on myocardial cells.
In this study, cloned canine IL-6 cDNA was used as a molecular probe to study the regulation of IL-6 in an awake canine model of myocardial ischemia and reperfusion. IL-6 mRNA was induced in ischemic and reperfused segments of myocardium preferentially in segments previously exposed to severe ischemia. Peak levels of IL-6 mRNA were reached within 3 hours of reperfusion. At the same time, IL-6 mRNA and ICAM-1 mRNA were found in the same myocardial segments. In contrast to hearts that were ischemic for 1 hour and reperfused for 3 hours, nonreperfused hearts after 4 hours of persistent ischemia demonstrated minimal induction of ICAM-1 or IL-6 despite similar degrees of injury and blood flow reductions during ischemia. After 24 hours of persistent ischemia, levels of IL-6 mRNA were comparable to those observed in hearts that were ischemic for 1 hour and subsequently reperfused for 24 hours.
Our results demonstrate induction of IL-6 mRNA in the myocardium and that this synthesis is accelerated by reperfusion. Evidence is also provided to show that peak IL-6 mRNA precedes that of ICAM-1 mRNA. These findings are compatible with our hypothesis that IL-6 is important in the induction of ICAM-1 in the area of ischemia. In addition, these studies suggest that the necessary factors to promote adhesive interactions between transmigrated neutrophils and cardiac myocytes are present in reperfused myocardium.
中性粒细胞诱导的心肌细胞损伤需要心肌细胞表面细胞间黏附分子-1（ICAM-1）的表达，并由ICAM-1-CD11b/CD18黏附介导。我们之前已经表明，存在于心脏淋巴中的白细胞介素-6（IL-6）细胞因子活性可诱导分离的心肌细胞上ICAM-1的表达。此外，在之前的体内研究中，我们还发现在先前缺血的存活区域再灌注的第一小时内心肌中ICAM-1 mRNA的诱导。我们假设心肌中IL-6合成的诱导是对缺血再灌注损伤反应的一个组成部分，并且与心肌细胞上ICAM-1的诱导有关。
在本研究中，克隆的犬IL-6 cDNA被用作分子探针，以研究清醒犬心肌缺血再灌注模型中IL-6的调节。IL-6 mRNA在心肌的缺血和再灌注节段中优先在先前暴露于严重缺血的节段中被诱导。再灌注3小时内达到IL-6 mRNA的峰值水平。同时，在相同的心肌节段中发现了IL-6 mRNA和ICAM-1 mRNA。与缺血1小时并再灌注3小时的心脏相比，持续缺血4小时后的未再灌注心脏尽管在缺血期间损伤程度和血流减少相似，但ICAM-1或IL-6的诱导最小。持续缺血24小时后，IL-6 mRNA水平与缺血1小时随后再灌注24小时的心脏中观察到的水平相当。
我们的结果证明了心肌中IL-6 mRNA的诱导，并且这种合成通过再灌注而加速。还提供了证据表明IL-6 mRNA的峰值先于ICAM-1 mRNA的峰值。这些发现与我们的假设一致，即IL-6在缺血区域ICAM-1的诱导中很重要。此外，这些研究表明再灌注心肌中存在促进迁移的中性粒细胞与心肌细胞之间黏附相互作用的必要因素。
