Frangogiannis N G, Lindsey M L, Michael L H, Youker K A, Bressler R B, Mendoza L H, Spengler R N, Smith C W, Entman M L
Department of Medicine, The Methodist Hospital and the DeBakey Heart Center, Baylor College of Medicine, Houston, Tex 77030-3498, USA.
Circulation. 1998 Aug 18;98(7):699-710. doi: 10.1161/01.cir.98.7.699.
Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1-CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM- 1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium. We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion.
Constitutive expression of TNF-alpha and not IL-1beta was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-alpha in the cardiac lymph after myocardial ischemia. Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium. Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-alpha in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion. Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-alpha.
Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-alpha. We suggest that mast cell-derived TNF-alpha may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophil-induced injury.
中性粒细胞诱导的心肌细胞损伤需要心肌细胞细胞间黏附分子（ICAM）-1的表达以及ICAM-1与CD11b/CD18的黏附。我们之前已证实在缺血后心脏淋巴液中存在白细胞介素（IL）-6活性；IL-6是诱导心肌细胞ICAM-1的主要刺激因子。此外，我们发现梗死心肌再灌注后IL-6 mRNA的诱导在很早的时候就出现了。我们推测，一种预先形成的上游细胞因子的释放会在再灌注时浸润的白细胞中诱导IL-6的产生。
正常犬心肌中存在肿瘤坏死因子（TNF）-α的组成性表达，而白细胞介素-1β（IL-1β）则没有，且TNF-α主要定位于心脏肥大细胞。通过证实心肌缺血后心脏淋巴液中组胺和TNF-α的快速释放，记录了缺血心肌中肥大细胞的脱颗粒现象。用异硫氰酸荧光素（FITC）标记抗生物素蛋白进行的组织化学研究表明，脱颗粒的肥大细胞仅存在于犬心肌的缺血样本中。免疫组织化学显示，脱颗粒的肥大细胞是缺血心肌中TNF-α的主要来源。对再灌注心肌的原位杂交研究表明，IL-6 mRNA定位于浸润的单核细胞以及再灌注后15分钟内出现在缺血后心脏淋巴液中的单核细胞中。此外，将分离的犬单核细胞与缺血后心脏淋巴液一起孵育，显示IL-6 mRNA有显著诱导，而用抗TNF-α中和抗体可部分阻断这种诱导。
心肌缺血后心脏肥大细胞脱颗粒，释放预先形成的介质，如组胺和TNF-α。我们认为，肥大细胞衍生的TNF-α可能是上调浸润白细胞中IL-6并启动负责诱导心肌细胞ICAM-1及随后中性粒细胞诱导损伤的细胞因子级联反应的关键因素。
