Meldrum D R, Dinarello C A, Shames B D, Cleveland J C, Cain B S, Banerjee A, Meng X, Harken A H
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
Circulation. 1998 Nov 10;98(19 Suppl):II214-8; discussion II218-9.
Tumor necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion (I/R) injury, sepsis, chronic heart failure, and cardiac allograft rejection. Cardiac resident macrophages, infiltrating leukocytes, and cardiomyocytes themselves produce TNF-alpha. Although adenosine reduces macrophage TNF-alpha production and protects myocardium against I/R, it remains unknown whether ischemic preconditioning, which is mediated by adenosine, decreases postischemic myocardial TNF-alpha production.
Isolated rat hearts were crystalloid perfused with the Langendorff method and subjected to global, normothermic I/R (20/40 minutes), with or without prior transient ischemic preconditioning (5 minutes) or adenosine pretreatment. Postischemic cardiac TNF-alpha (ELISA) and function were determined (Langendorff). I/R increased cardiac TNF-alpha and impaired myocardial function. Ischemic preconditioning or adenosine decreased myocardial TNF-alpha and improved postischemic functional recovery. Sequestration of myocardial TNF-alpha (TNF binding protein) during the I/R experiments similarly improved postischemic myocardial function.
This study constitutes the initial demonstration that in addition to its other beneficial effects, preconditioning decreases postischemic myocardial TNF-alpha, an autocrine contributor to postischemic myocardial dysfunction. Reduced myocardial TNF-alpha production may represent the distal effector mechanism of preconditioning.
肿瘤坏死因子-α（TNF-α）是导致心肌功能障碍和心肌细胞死亡的自分泌因子，在缺血再灌注（I/R）损伤、脓毒症、慢性心力衰竭及心脏移植排斥反应中均发挥作用。心脏驻留巨噬细胞、浸润的白细胞以及心肌细胞自身均可产生TNF-α。尽管腺苷可减少巨噬细胞TNF-α的产生并保护心肌免受I/R损伤，但由腺苷介导的缺血预处理是否能降低缺血后心肌TNF-α的产生仍不清楚。
采用Langendorff法对离体大鼠心脏进行晶体灌注，使其经历整体常温I/R（20/40分钟），同时给予或不给予先前短暂的缺血预处理（5分钟）或腺苷预处理。测定缺血后心脏TNF-α（酶联免疫吸附测定）及功能（Langendorff法）。I/R增加了心脏TNF-α水平并损害了心肌功能。缺血预处理或腺苷可降低心肌TNF-α水平并改善缺血后功能恢复。在I/R实验期间阻断心肌TNF-α（TNF结合蛋白）同样可改善缺血后心肌功能。
本研究首次证明，除了其他有益作用外，预处理还可降低缺血后心肌TNF-α水平，TNF-α是导致缺血后心肌功能障碍的自分泌因子。心肌TNF-α产生的减少可能代表预处理的远端效应机制。
