Translational applications of evaluating physiologic variability in human endotoxemia

Abstract

Dysregulation of the inflammatory response is a critical component of many clinically challenging disorders such as sepsis. Inflammation is a biological process designed to lead to healing and recovery, ultimately restoring homeostasis; however, the failure to fully achieve those beneficial results can leave a patient in a dangerous persistent inflammatory state. One of the primary challenges in developing novel therapies in this area is that inflammation is comprised of a complex network of interacting pathways. Here, we discuss our approaches towards addressing this problem through computational systems biology, with a particular focus on how the presence of biological rhythms and the disruption of these rhythms in inflammation may be applied in a translational context. By leveraging the information content embedded in physiologic variability, ranging in scale from oscillations in autonomic activity driving short-term heart rate variability to circadian rhythms in immunomodulatory hormones, there is significant potential to gain insight into the underlying physiology.

Fig. 1

Homeostatic rhythms, at a variety of time scales, which contribute to altered physiologic variability in endotoxemia. TNF-α data: [110]. Sympathetic nervous system activity data: [111]. Circadian cortisol data: [112]. Ultradian cortisol data: [113]. Lung volume, blood pressure, and short-term HR data: [114]. Circadian HR data: [115]. TNF-α is an inflammatory cytokine that has a clear circadian pattern in response to LPS stimulation, and other cytokines also exhibit circadian patterns [110]. Autonomic signaling in inflammation contributes both to changes in cardiac function and modulation of the inflammatory response, and oscillatory activity is inherent in both sympathetic and parasympathetic branches. Cortisol is an anti-inflammatory hormone, with a large circadian rhythm riding on top of an ultradian rhythm. Blood pressure and respiratory rhythms contribute to short-term patterns in HR, which are diminished in endotoxemia.

Fig. 2

Network structure of a model containing the cellular-level responses to LPS, central secretion of immunomodulatory hormones, the production of discrete heart beats, and the modulation of HR patterns by rhythmic autonomic signals. All of the periodic components shown in Fig. 1 are reflected in this network. Most of these interactions are described in more detail in [21].