Cain B S, Meldrum D R, Dinarello C A, Meng X, Banerjee A, Harken A H
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
J Surg Res. 1998 May;76(2):117-23. doi: 10.1006/jsre.1998.5304.
Myocardial tumor necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury (I/R), sepsis, chronic heart failure, and cardiac allograft rejection. Cardiac resident macrophages and cardiomyocytes themselves produce TNF-alpha. In this regard, adenosine (ADO) has been reported to reduce macrophage TNF-alpha production. Our purposes were to determine whether (1) I/R induces rat myocardial TNF-alpha production; (2) ADO decreases ischemia-induced rat myocardial TNF-alpha production; (3) ADO functionally protects human myocardium against I/R; and (4) TNF-alpha-binding protein (TNFBP; p55) confers similar protection when substituted for ADO pretreatment. To study this, human atrial trabeculae were obtained during cardiac surgery and suspended in organ baths, paced at 1 Hz, and force development was recorded during I/R (45/120 min) with or without ADO pretreatment (125 microM x 10 min), or TNFBP (1 microgram/ml) during I/R. Isolated rat hearts were perfused using the Langendorff method undergoing I/R (20/40 min) with or without ADO pretreatment (125 microM x 2 min) and rat myocardial expression of TNF-alpha was assessed by ELISA. Results demonstrated that I/R increased rat myocardial TNF-alpha levels from 324 +/- 36 to 902 +/- 77 pg/g (P < 0.05; ANOVA and Bonferroni/Dunn) and decreased human myocardial developed force (DF) to 18 +/- 2% of baseline (%BDF; P < 0.05). ADO pretreatment decreased ischemia-induced rat myocardial TNF-alpha production (356 +/- 107 pg/g; P < 0.05) and increased postischemic DF of human myocardium to 39 +/- 3% BDF (P < 0.05. Further substantiating the link between ischemia-induced TNF-alpha production and injury, TNFBP administration similarly improved post-I/R function of human myocardium (55 +/- 5% BDF; P < 0.05 vs. I/R alone). We conclude that (1) I/R induces rat myocardial TNF-alpha production; (2) ADO pretreatment decreases I/R-induced rat myocardial TNF-alpha production; (3) ADO improves human myocardial function; (4) TNFBP confers similar protection; and (5) inhibition/neutralization of TNF-alpha represents a novel strategy for protecting human myocardium against ischemia and reperfusion injury.
心肌肿瘤坏死因子-α（TNF-α）在缺血再灌注损伤（I/R）、脓毒症、慢性心力衰竭及心脏移植排斥反应中，是导致心肌功能障碍和心肌细胞死亡的自分泌因素。心脏驻留巨噬细胞和心肌细胞自身均可产生TNF-α。就此而言，已有报道称腺苷（ADO）可减少巨噬细胞TNF-α的产生。我们的目的是确定：（1）I/R是否会诱导大鼠心肌产生TNF-α；（2）ADO是否会降低缺血诱导的大鼠心肌TNF-α的产生；（3）ADO是否能在功能上保护人心肌免受I/R损伤；（4）TNF-α结合蛋白（TNFBP；p55）在替代ADO预处理时是否能提供类似的保护作用。为研究此问题，在心脏手术期间获取人房小梁，将其悬于器官浴槽中，以1 Hz频率起搏，在有或无ADO预处理（125 μM×10分钟）的情况下，或在I/R期间给予TNFBP（1 μg/ml），记录I/R（45/120分钟）期间的肌力发展情况。采用Langendorff方法灌注离体大鼠心脏，使其经历I/R（20/40分钟），有或无ADO预处理（125 μM×2分钟），并通过酶联免疫吸附测定法评估大鼠心肌TNF-α的表达。结果表明，I/R使大鼠心肌TNF-α水平从324±36 pg/g升高至902±77 pg/g（P<0.05；方差分析和Bonferroni/Dunn检验），并使人心肌发展力（DF）降至基线的18±2%（%BDF；P<0.05）。ADO预处理可降低缺血诱导的大鼠心肌TNF-α的产生（356±107 pg/g；P<0.05），并使人心肌缺血后DF升高至39±3%BDF（P<0.05）。进一步证实缺血诱导的TNF-α产生与损伤之间的联系，给予TNFBP同样可改善人心肌I/R后的功能（55±5%BDF；与单独I/R相比，P<0.05）。我们得出结论：（1）I/R诱导大鼠心肌产生TNF-α；（2）ADO预处理可降低I/R诱导的大鼠心肌TNF-α的产生；（3）ADO可改善人心肌功能；（4）TNFBP可提供类似的保护作用；（5）抑制/中和TNF-α是保护人心肌免受缺血和再灌注损伤的一种新策略。
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