Multiscale model for the assessment of autonomic dysfunction in human endotoxemia

Abstract

Severe injury and infection are associated with autonomic dysfunction. The realization that a dysregulation in autonomic function may predispose a host to excessive inflammatory processes has renewed interest in understanding the role of central nervous system (CNS) in modulating systemic inflammatory processes. Assessment of heart rate variability (HRV) has been used to evaluate systemic abnormalities and as a predictor of the severity of illness. Dissecting the relevance of neuroimmunomodulation in controlling inflammatory processes requires an understanding of the multiscale interplay between CNS and the immune response. A vital enabler in that respect is the development of a systems-based approach that integrates data across multiple scales, and models the emerging host response as the outcome of interactions of critical modules. Thus, a multiscale model of human endotoxemia, as a prototype model of systemic inflammation in humans, is proposed that integrates processes across the host from the cellular to the systemic host response level. At the cellular level interacting components are associated with elementary signaling pathways that propagate extracellular signals to the transcriptional response level. Further, essential modules associated with the neuroendocrine immune crosstalk are considered. Finally, at the systemic level, phenotypic expressions such as HRV are incorporated to assess systemic decomplexification indicative of the severity of the host response. Thus, the proposed work intends to associate acquired endocrine dysfunction with diminished HRV as a critical enabler for clarifying how cellular inflammatory processes and neural-based pathways mediate the links between patterns of autonomic control (HRV) and clinical outcomes.

Fig. 1.

Basic topological interactions composing the multilevel model of endotoxin induced human inflammation. At the cellular level, interacting components involve the propagation of LPS signaling on the transcriptional response level (P, A, E) through the activation of endotoxin signaling receptor (R) and elementary signaling pathways (NF-κB signaling module). At the level of circulating hormones, essential modules are associated with the release of endocrine stress hormones from neuroendocrine axis (HPA, SNS) coupled with their anti-inflammatory influence on the host. The dynamics of cortisol and epinephrine (EPI) signaling involve components interacting at the cellular level. At the systemic level, physiological deterioration of the host is quantified by heart rate variability (HRV).

Fig. 2.

Estimation of relevant model parameters intending to reproduce available experimental data associated with transcriptional signatures (A) and plasma counterregulatory hormones including EPI and cortisol (F) as well as clinical data (HRV). Solid lines (-) correspond to model predictions under conditions of low-dose endotoxin, while ● refers to experimental data expressed as means ± SE. The initial condition of endotoxin [LPS (t = 0 h) = 1] refers to LPS concentration relative to 2 ng/kg body weight.

Fig. 3.

A: plasma cortisol levels (F); B: steroid active signal, FR(N) under conditions of acute endotoxin injury (w_Fex = 0); C: simulated F; D: steroid active signals FR(N) under conditions of prior steroid infusion (w_Fex = 1), which is initiated at t = −6 h before LPS and continued for 6 h after LPS. Solid lines correspond to model predictions, while solid markers represent experimental data expressed as means ± SE.

Fig. 4.

Simulation of an unresolved inflammatory response due to high endotoxin concentration [LPS (t = 0 h) = 4]. Such high concentration of LPS (4 times greater than the nominal value) deregulates the NF-κB signaling module giving rise to an unconstrained immune response followed by abnormal hormonal responses that macroscopically are translated into diminished physiological variability.

Fig. 5.

Simulating the effect of acute EPI infusion (w_EPI,ex = 1), which is initiated 3 h prior to the main endotoxin challenge [LPS (t = 0 h) = 4] and continued for 6 h after LPS (R_in,EPI = 15), under conditions of severe inflammation. Dashed and solid lines represent the progression of a balanced (due to system's pre-exposure into EPI infusion) and unconstrained inflammatory response (due to high inflammatory challenge), [LPS (t = 0 h) = 4], respectively. Acute pre-exposure of the host to EPI attenuates the aberrant proinflammatory response (P) induced by high LPS concentration, which allows for recovery in HRV dynamics (restoration in autonomic balance).

Fig. 6.

The effect of low-dose steroid administration initiated 6 h prior to endotoxin challenge (dashed lines) and continued for another 6 h after LPS (w_Fex = 1) under conditions of high LPS concentration (solid lines). Solid lines simulate the progression of a systemic inflammatory response syndrome (due to high LPS concentration), [LPS (t = 0 h) = 4], while dashed lines reflect the protective effect that can be exerted by hormonal(steroid) replacement therapy. The acute pre-exposure of the host to exogenous cortisol dampens the excessive proinflammatory effects induced by high LPS concentration, which allows for restoration in autonomic balance (HRV).

Fig. 7.

The effect of exogenously induced hypercortisolemia on autonomic dysfunction under the systemic inflammatory manifestations mediated by low-dose endotoxin. Solid lines simulate the progression of a self-limited endotoxin-induced inflammatory response, while dashed lines reflect the antecedent period of exogenously induced hypercortisolemia initiated 6 h prior to LPS administration and continued for 6 h after endotoxin (w_Fex = 1). Solid markers and ○ refer to experimental data (expressed as means ± SE) under conditions of acute endotoxin injury and prior hydrocortisone infusion, respectively, which do not vary across the 2 experimental conditions (LPS, Cort-6 h + LPS). Such prior cortisol infusion modulates cytokine responses (P, A) and hormonal responses (EPI), but there is no change in overall system adaptability as assessed by HRV (solid and dashed HRV lines overlap).

Fig. 8.

Dose-dependent modulation in the progression of the inflammatory reaction due to short-term EPI infusion (w_EPI,ex = 1), initiated 3 h before LPS and continued for 6 h after LPS at increasing values of the parameter R_in,EPI = 5, 10, 20. Such intervention potentiates, in a dose-dependent manner (dashed and dotted lines), the secretion of EPI from SNS that through cAMP anti-inflammatory signaling can protect, in part, the host response attenuating the proinflammatory response (P). Such attenuation in the proinflammatory response relative to endotoxin administration (solid lines) does not extend to changes in autonomic balance (HRV) as represented by the superimposition of predicted HRV dynamics (solid and dashed lines overlap). Solid markers and ○ refer to relevant experimental data (expressed as means ± SE) under conditions of low-dose endotoxin administration and prior EPI infusion, respectively. These data have not been used as a training dataset but rather to validate the structure of the proposed model. Descriptive statistics in the original analysis (40) show that there was no significant variation between these experimental measurements (solid markers vs. open circles) from 0 h until 24 h after LPS exposure.