Qing Ma, Wöltje Michael, Schumacher Kathrin, Sokalska Magdalena, Vazquez-Jimenez Jaime F, Minkenberg Ralf, Seghaye Marie-Christine
Department of Pediatric Cardiology, Aachen University Hospital, Aachen, Germany.
Crit Care. 2006;10(2):R57. doi: 10.1186/cc4886.
The use of moderate hypothermia during experimental cardiac surgery is associated with decreased expression of tumour necrosis factor (TNF)-alpha in myocardium and with myocardial protection. In order to identify the cellular mechanisms that lead to that repression, we investigated the effect of hypothermia during cardiac surgery on both main signalling pathways involved in systemic inflammation, namely the nuclear factor-kappaB (NF-kappaB) and activating protein-1 pathways.
Twelve female pigs were randomly subjected to standardized cardiopulmonary bypass with moderate hypothermia or normothermia (temperature 28 degrees C and 37 degrees C, respectively; six pigs in each group). Myocardial probes were sampled from the right ventricle before, during and 6 hours after bypass. We detected mRNA encoding TNF-alpha by competitive RT-PCR and measured protein levels of TNF-alpha, inducible nitric oxide synthase and cyclo-oxygenase-2 by Western blotting. Finally, we assessed the activation of NF-kappaB and activating protein-1, as well as phosphorylation of p38 mitogen-activated protein kinase by electrophoretic mobility shift assay with super shift and/or Western blot.
During and after cardiac surgery, animals subjected to hypothermia exhibited lower expression of TNF-alpha and cyclo-oxygenase-2 but not of inducible nitric oxide synthase. This was associated with lower activation of p38 mitogen-activated protein kinase and of its downstream effector activating protein-1 in hypothermic animals. In contrast, NF-kappaB activity was no different between groups.
These findings indicate that the repression of TNF-alpha associated with moderate hypothermia during cardiac surgery is associated with inhibition of the mitogen-activated protein kinase p38/activating protein-1 pathway and not with inhibition of NF-kappaB. The use of moderate hypothermia during cardiac surgery may mitigate the perioperative systemic inflammatory response and its complications.
在实验性心脏手术中使用适度低温与心肌中肿瘤坏死因子（TNF）-α表达降低及心肌保护有关。为了确定导致这种抑制的细胞机制，我们研究了心脏手术期间低温对全身炎症所涉及的两个主要信号通路，即核因子-κB（NF-κB）和激活蛋白-1通路的影响。
将12只雌性猪随机分为两组，分别进行适度低温或常温的标准化体外循环（温度分别为28℃和37℃；每组6只猪）。在体外循环前、期间和结束后6小时从右心室采集心肌样本。通过竞争性逆转录聚合酶链反应（RT-PCR）检测编码TNF-α的mRNA，并通过蛋白质印迹法测量TNF-α、诱导型一氧化氮合酶和环氧化酶-2的蛋白水平。最后，我们通过超迁移和/或蛋白质印迹的电泳迁移率变动分析评估NF-κB和激活蛋白-1的激活以及p38丝裂原活化蛋白激酶的磷酸化。
在心脏手术期间及术后，接受低温治疗的动物TNF-α和环氧化酶-2的表达较低，但诱导型一氧化氮合酶的表达没有降低。这与低温动物中p38丝裂原活化蛋白激酶及其下游效应物激活蛋白-1的较低激活有关。相比之下，两组之间NF-κB活性没有差异。
这些发现表明，心脏手术期间与适度低温相关的TNF-α抑制与丝裂原活化蛋白激酶p38/激活蛋白-1通路的抑制有关，而与NF-κB的抑制无关。心脏手术期间使用适度低温可能减轻围手术期全身炎症反应及其并发症。
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