Meldrum D R
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
Am J Physiol. 1998 Mar;274(3):R577-95. doi: 10.1152/ajpregu.1998.274.3.R577.
The heart is a tumor necrosis factor (TNF)-producing organ. Both myocardial macrophages and cardiac myocytes themselves synthesize TNF. Accumulating evidence indicates that myocardial TNF is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury, sepsis, chronic heart failure, viral myocarditis, and cardiac allograft rejection. Indeed, locally (vs. systemically) produced TNF contributes to postischemic myocardial dysfunction via direct depression of contractility and induction of myocyte apoptosis. Lipopolysaccharide or ischemia-reperfusion activates myocardial P38 mitogen-activated protein (MAP) kinase and nuclear factor kappa B, which lead to TNF production. TNF depresses myocardial function by nitric oxide (NO)-dependent and NO-independent (sphingosine dependent) mechanisms. TNF activation of TNF receptor 1 or Fas may induce cardiac myocyte apoptosis. MAP kinases and TNF transcription factors are feasible targets for anti-TNF (i.e., cardioprotective) strategies. Endogenous anti-inflammatory ligands, which trigger the gp130 signaling cascade, heat shock proteins, and TNF-binding proteins, also control TNF production and activity. Thus modulation of TNF in cardiovascular disease represents a realistic goal for clinical medicine.
心脏是一个产生肿瘤坏死因子（TNF）的器官。心肌巨噬细胞和心肌细胞本身都能合成TNF。越来越多的证据表明，心肌TNF在缺血再灌注损伤、脓毒症、慢性心力衰竭、病毒性心肌炎和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。事实上，局部（相对于全身）产生的TNF通过直接抑制收缩力和诱导心肌细胞凋亡，导致缺血后心肌功能障碍。脂多糖或缺血再灌注可激活心肌P38丝裂原活化蛋白（MAP）激酶和核因子κB，进而导致TNF的产生。TNF通过一氧化氮（NO）依赖性和NO非依赖性（鞘氨醇依赖性）机制降低心肌功能。TNF受体1或Fas的激活可能诱导心肌细胞凋亡。MAP激酶和TNF转录因子是抗TNF（即心脏保护）策略的可行靶点。内源性抗炎配体可触发gp130信号级联反应、热休克蛋白和TNF结合蛋白，也能控制TNF的产生和活性。因此，调节心血管疾病中的TNF是临床医学的一个现实目标。
