Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA.
Physiol Genomics. 2012 Feb 1;44(2):121-9. doi: 10.1152/physiolgenomics.00128.2011. Epub 2011 Nov 29.
Endogenous glucocorticoids are secreted by the hypothalamic-pituitary-adrenal (HPA) axis in response to a wide range of stressors. Glucocorticoids exert significant downstream effects, including the regulation of many inflammatory genes. The HPA axis functions such that glucocorticoids are released in a pulsatile manner, producing ultradian rhythms in plasma glucocorticoid levels. It is becoming increasingly evident that this ultradian pulsatility is important in maintaining proper homeostatic regulation and responsiveness to stress. This is particularly interesting from a clinical perspective given that pathological dysfunctions of the HPA axis produce altered ultradian patterns. Modeling this system facilitates the understanding of how glucocorticoid pulsatility arises, how it can be lost, and the transcriptional implications of ultradian rhythms. To approach these questions, we developed a mathematical model that integrates the cyclic production of glucocorticoids by the HPA axis and their downstream effects by integrating existing models of the HPA axis and glucocorticoid pharmacodynamics. This combined model allowed us to evaluate the implications of pulsatility in homeostasis as well as in response to acute stress. The presence of ultradian rhythms allows the system to maintain a lower response to homeostatic levels of glucocorticoids, but diminished feedback within the HPA axis leads to a loss of glucocorticoid rhythmicity. Furthermore, the loss of HPA pulsatility in homeostasis correlates with a decrease in the peak output in response to an acute stressor. These results are important in understanding how cyclic glucocorticoid secretion helps maintain the responsiveness of the HPA axis.
内源性糖皮质激素由下丘脑-垂体-肾上腺 (HPA) 轴响应各种应激源而分泌。糖皮质激素产生显著的下游效应，包括调节许多炎症基因。HPA 轴的功能使得糖皮质激素以脉冲方式释放，在血浆糖皮质激素水平中产生超短周期节律。越来越明显的是，这种超短周期脉动对于维持适当的体内平衡调节和对压力的反应性很重要。从临床角度来看，这一点尤其有趣，因为 HPA 轴的病理性功能障碍会产生改变的超短周期模式。对该系统进行建模有助于理解糖皮质激素脉动是如何产生的、如何失去以及超短周期节律的转录意义。为了研究这些问题，我们开发了一个数学模型，该模型通过整合 HPA 轴中环戊二烯的循环产生及其对糖皮质激素药效动力学的下游影响，整合了现有的 HPA 轴和糖皮质激素药效动力学模型。该综合模型使我们能够评估脉动在体内平衡以及对急性应激反应中的意义。超短周期节律的存在使系统能够维持对糖皮质激素体内平衡水平的较低反应，但 HPA 轴内反馈的减弱导致糖皮质激素节律性的丧失。此外，HPA 轴在体内平衡时失去脉动与对急性应激源的峰值输出减少相关。这些结果对于理解循环糖皮质激素分泌如何有助于维持 HPA 轴的反应性很重要。
