Department of Pediatric Cardiology, Charité Universitaetsmedizin, Berlin, Germany.
Vascul Pharmacol. 2009 Oct;51(4):246-52. doi: 10.1016/j.vph.2009.06.006. Epub 2009 Jul 1.
To protect immature organ systems during corrective cardiac surgery, patients are cooled to a minimal temperature of 17 degrees C during cardiopulmonary bypass (CPB). However hypothermic CPB triggers the whole body inflammatory response and results in unwanted prolonged inflammation. The present study was designed to clarify the hypothermia and rewarming induced mechanisms and examine interventional pharmacological strategies that could prevent prolonged inflammation. Stimulated primary human umbilical vein endothelial cells (HUVECs) were exposed to a dynamic temperature protocol analogous to clinical settings. Furthermore endothelial cells were pretreated with methylprednisolone and/or tacrolimus as well as with MAPK inhibitors (SB203580, U0126 and SP600125). Cell viability, expression of IL-6 and ERK 1/2, p38 and SAPK/JNK were investigated. Stimulated endothelial cells secreted significantly higher IL-6 protein 2h after rewarming in comparison to normothermic control cells. Moreover, dynamic temperature changes lead to increased MAPK phosphorylation. Only the combined pre-treatment with MP and TAC served to inhibit the IL-6 secretion. As intracellular signalling pathway we could demonstrate that SB203580 as specific p38 inhibitor most effectively down regulated the unwanted IL-6 release after cooling and rewarming. Therefore inhibition of p38 or components of the p38 pathway could be a promising and selective antiinflammatory therapeutic target after hypothermic CPB.
为了在心脏矫正手术中保护未成熟的器官系统，患者在体外循环（CPB）期间被冷却至 17 摄氏度的最低温度。然而，低温 CPB 会引发全身炎症反应，导致不必要的炎症持续时间延长。本研究旨在阐明低温和复温诱导的机制，并研究可预防炎症持续时间延长的干预性药理策略。刺激原代人脐静脉内皮细胞（HUVEC）暴露于类似于临床环境的动态温度方案中。此外，将内皮细胞用甲基强的松龙和/或他克莫司以及 MAPK 抑制剂（SB203580、U0126 和 SP600125）预处理。研究了细胞活力、IL-6 和 ERK1/2、p38 和 SAPK/JNK 的表达。与正常体温对照细胞相比，复温后 2 小时，受刺激的内皮细胞分泌的 IL-6 蛋白明显更高。此外，动态温度变化导致 MAPK 磷酸化增加。只有 MP 和 TAC 的联合预处理才能抑制 IL-6 的分泌。作为细胞内信号通路，我们可以证明，作为特异性 p38 抑制剂的 SB203580 最有效地抑制了冷却和复温后不必要的 IL-6 释放。因此，抑制 p38 或 p38 途径的成分可能是低温 CPB 后有希望和选择性的抗炎治疗靶点。
