Shibata N, Akagami H, Sanma H, Goshima K
Department Internal Medicine, Osaka, Japan.
Jpn Circ J. 1988 Jul;52(7):673-83. doi: 10.1253/jcj.52.673.
The dissolution of infarcted myocardium occurs after the infiltration of leukocytes. In the search for a mechanism of the leukocyte infiltration, we measured the production of lipoxygenase metabolites of arachidonic acid in the canine myocardium after ligation of the circumflex branch of the left coronary artery. At least 2 lipoxygenase products, namely 5- and 12-hydroxyeicosatetraenoic acids (HETEs), were augmented in myocardium subjected to ischemia lasting more than 6 hours, with levels of the latter being raised much more than the former. Augmentation of the HETEs in ischemic myocardium appeared to occur prior to any significant infiltration of leukocytes. More than 12 hours after coronary ligation, the infiltration of leukocytes became prominent and an increase in 12-HETE was observed. Calcium content in the infarcted myocardium appeared to be increased several hours before the increase in 12-HETE. These data suggest that the initial increment in 12-HETE may result from it being a product of infarcted myocardium, where Ca2+ is accumulated in the cell, and that the increased HETEs work as a leukocyte chemoattractant in infarcted myocardium. This hypothesis is supported by the independent experiment which showed that cultured cardiomyocytes produced lipoxygenase metabolites of arachidonic acid, including 12-HETEs etc, which exhibited neutrophil-chemoattractant activity when they were challenged by calcium ionophore and/or arachidonic acid. Azelastine-HCl, a lipoxygenase inhibitor, attenuated not only the above production of HETEs from the cardiomyocytes, but also production of HETEs and infiltration of neutrophils in ischemic myocardium, resulting in attenuation of the fibrous scar of infarcted myocardium.
梗死心肌的溶解发生在白细胞浸润之后。为了探寻白细胞浸润的机制，我们在结扎犬左冠状动脉回旋支后，测量了犬心肌中花生四烯酸的脂氧合酶代谢产物的生成情况。在经历持续超过6小时缺血的心肌中，至少两种脂氧合酶产物，即5-和12-羟基二十碳四烯酸（HETEs）增加，其中后者的水平升高幅度远大于前者。缺血心肌中HETEs的增加似乎发生在白细胞出现任何显著浸润之前。冠状动脉结扎超过12小时后，白细胞浸润变得明显，同时观察到12-HETE增加。梗死心肌中的钙含量似乎在12-HETE增加前数小时就已升高。这些数据表明，12-HETE的初始增加可能是由于它是梗死心肌的产物，梗死心肌细胞中积累了Ca2+，并且增加的HETEs在梗死心肌中作为白细胞趋化剂起作用。这一假设得到了独立实验的支持，该实验表明培养的心肌细胞产生花生四烯酸的脂氧合酶代谢产物，包括12-HETEs等，当它们受到钙离子载体和/或花生四烯酸刺激时，表现出中性粒细胞趋化活性。盐酸氮卓斯汀，一种脂氧合酶抑制剂，不仅减弱了心肌细胞中上述HETEs的生成，还减弱了缺血心肌中HETEs的生成和中性粒细胞的浸润，从而导致梗死心肌纤维瘢痕的减轻。
