Dynamic pituitary-adrenal interactions in response to cardiac surgery.
Dynamic pituitary-adrenal interactions in response to cardiac surgery.
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DOI：
10.1097/ccm.0000000000000773
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发表时间：
2015-04
影响因子：
8.8
通讯作者：
Lightman SL
中科院分区：
文献类型：
--
作者：
Gibbison B;Spiga F;Walker JJ;Russell GM;Stevenson K;Kershaw Y;Zhao Z;Henley D;Angelini GD;Lightman SL
表征冠状动脉旁路移植术 (CABG) 过程中泵和停泵过程中垂体-肾上腺相互作用的动态特征。由于我们的数据表明肾上腺对 ACTH 的反应性发生了重大变化，因此我们使用反向翻译方法来研究危重病大鼠模型中这种变化背后的分子机制。临床研究：前瞻性观察研究 动物研究：对照实验研究 临床研究：心脏手术手术室和重症监护病房 动物研究：大学研究实验室 临床研究：20 名男性患者 动物研究：成年雄性 Sprague-Dawley 大鼠。临床研究：冠状动脉旁路移植术 - 开泵和关泵动物研究：通过颈静脉插管注射脂多糖 (LPS) 或生理盐水（对照）临床研究：从放置第一个静脉通路起 24 小时内采集血样。分别每10分钟和60分钟测量一次皮质醇和ACTH，并在24小时开始和结束以及手术结束时测量皮质类固醇结合球蛋白（CBG）。在手术结束时，ACTH 和皮质醇水平最初上升至超正常值。随后 ACTH 水平恢复至术前值。所有个体在整个围手术期都保持促肾上腺皮质激素和皮质醇的超电脉动。手术后 8 小时左右，肾上腺对 ACTH 的敏感性显着增加，面对“基础”水平的 ACTH，皮质醇保持非常高的水平。在 24 小时采样期结束时，这种敏感性开始恢复到术前值。动物研究：通过颈静脉插管给予成年雄性 Sprague-Dawley 大鼠脂多糖 (LPS) 或无菌盐水。随后每小时收集血样用于 ACTH 和皮质酮测量。注射后6小时处死大鼠，收集肾上腺，分别使用RTqPCR和Western免疫印迹法测量StAR、SF-1和DAX1 mRNA和蛋白质。还通过 RTqPCR 测量了 ACTH 受体 (MC2R) mRNA 及其辅助蛋白 (MRAP) 的肾上腺水平。大鼠对 LPS 的反应显示出与接受 CABG 的患者相似的 ACTH 和皮质酮模式。我们还能够证明，注射 LPS 6 小时后，肾上腺内皮质酮水平增加，StAR、SF-1 和 MRAP mRNA 和 StAR 蛋白增加，DAX1 和 MC2R mRNA 减少。严重的炎症刺激会激活 HPA 轴，导致肾上腺皮质中的类固醇生成活性增加，并导致血液中皮质醇水平升高。 CABG 后，ACTH 和皮质醇的分泌大量增加。尽管随后 ACTH 下降至基础水平，皮质醇仍然升高，并且 ACTH - 皮质醇的协调搏动得以维持。这表明肾上腺对 ACTH 的敏感性增加，我们在 HPA 轴免疫激活的动物模型中证实了这一点。使用该模型，我们能够证明肾上腺敏感性的增加是由于刺激性和抑制性肾上腺内信号通路的调节变化所致。进一步了解正常 HPA 对大手术反应的动态将为我们提供更合理的危重患者糖皮质激素治疗方法。
To characterize the dynamics of the pituitary-adrenal interaction during the course of coronary artery bypass grafting (CABG) both on and off pump. Since our data pointed to a major change in adrenal responsiveness to ACTH we used a reverse translation approach to investigate the molecular mechanisms underlying this change in a rat model of critical illness. Clinical studies: Prospective observational study Animal studies: Controlled experimental study Clinical studies: Cardiac surgery operating rooms and critical care units Animal studies: University research laboratory Clinical studies: Twenty, male patients Animal studies: Adult, male Sprague-Dawley rats. Clinical studies: Coronary artery bypass graft - both on and off pump Animal studies: Injection of either lipopolysaccharide (LPS) or saline (controls) via a jugular vein cannula Clinical studies: Blood samples were taken for 24 hours from placement of the first venous access. Cortisol and ACTH were measured every 10 and 60 minutes respectively, and corticosteroid binding globulin (CBG) was measured at the beginning and end of the 24 hour period and at the end of operation. There was an initial rise in both levels of ACTH and cortisol to supra-normal values at around the end of surgery. ACTH levels then returned towards pre-operative values. Ultradian pulsatility of both ACTH and cortisol was maintained throughout the peri-operative period in all individuals. The sensitivity of the adrenal gland to ACTH increased markedly at around 8 hours after surgery maintaining very high levels of cortisol in the face of ‘basal’ levels of ACTH. This sensitivity began to return towards pre-operative values at the end of the 24-hour sampling period. Animal studies: Adult, male Sprague-Dawley rats were either given lipopolysaccharide (LPS) or sterile saline via a jugular vein cannula. Hourly blood samples were subsequently collected for ACTH and corticosterone measurement. Rats were sacrificed 6 hours after the injection and the adrenal glands were collected for measurement of StAR, SF-1 and DAX1 mRNA and protein using RTqPCR and Western immunoblotting, respectively. Adrenal levels of the ACTH receptor (MC2R) mRNA and its accessory protein (MRAP) were also measured by RTqPCR. In response to LPS, rats showed a pattern of ACTH and corticosterone that was similar to patients undergoing CABG. We were also able to demonstrate increased intra-adrenal corticosterone levels and an increase in StAR, SF-1 and MRAP mRNAs and StAR protein, and a reduction in DAX1 and MC2R mRNAs, 6h after LPS injection. Severe inflammatory stimuli activate the HPA axis resulting in increased steroidogenic activity in the adrenal cortex and an elevation of cortisol levels in the blood. Following CABG there is a massive increase in both ACTH and cortisol secretion. Despite a subsequent fall of ACTH to basal levels, cortisol remains elevated and co-ordinated ACTH - cortisol pulsatility is maintained. This suggested that there is an increase in adrenal sensitivity to ACTH, which we confirmed in our animal model of immune activation of the HPA axis. Using this model we were able to show that this increased adrenal sensitivity results from changes in the regulation of both stimulatory and inhibitory intra-adrenal signaling pathways. Increased understanding of the dynamics of normal HPA responses to major surgery will provide us with a more rational approach to glucocorticoid therapy in critically ill patients.