Review
The role of adrenal gland microenvironment in the HPA axis function and dysfunction during sepsis

https://doi.org/10.1016/j.mce.2014.12.019Get rights and content

Highlights

  • Homeostatic activation of the HPA axis is pivotal to survive sepsis and septic shock.

  • In many critically ill patients plasma ACTH and cortisol levels are often dissociated.

  • Dissociation of the HPA axis during sepsis is associated with chronic adrenal inflammation.

  • Chronic inflammation and increased adrenal cell death may contribute the HPA axis dysfunction.

  • Disruption of the adrenal gland vascular homeostasis may lead to dysregulation of the HPA axis.

Abstract

Sepsis and septic shock in response to bacterial or viral infections remain the major health problem worldwide. Despite decades of intensive research and improvements in medical care, severe sepsis is associated with high mortality. Rapid activation of the adrenal gland glucocorticoid and catecholamine production is a fundamental component of the stress response and is essential for survival of the host. However, in many critically ill patients this homeostatic function of the adrenal gland is often impaired. In these patients, plasma levels of adrenocorticotropic hormone (ACTH) and cortisol are often dissociated. This has been attributed to the stimulatory action of non-ACTH factors within the adrenal gland such as cytokines, and recently with decreased cortisol metabolism and suppressed ACTH synthesis. Regulation of the hypothalamus–pituitary–adrenal (HPA) axis function during sepsis is a complex process which involves various immune and neuroendocrine interactions occurring at the levels of the central nervous system (CNS) and the adrenal gland. A coordinated interaction of numerous cell types and systems within the adrenal gland is involved in the sustained adrenal glucocorticoid production. This review article describes and discusses recent experimental findings regarding the role of adrenal gland microenvironment including the adrenal vasculature and the immune-adrenal crosstalk in the disregulated HPA axis during sepsis conditions. In summary, in addition to the reduced cortisol breakdown and related ACTH suppression, sepsis-mediated chronic activation of the immune-adrenal crosstalk and vascular dysfunction may contribute to the HPA axis dysregulation found in septic patients.

Introduction

Sepsis and septic shock in response to bacterial or viral infections remain the major health problem worldwide (Angus, Wax, 2001, Mayr et al, 2014). It is characterized by systemic activation of multiple inflammatory pathways, including cytokine networks and coagulation (van der Poll, 2001), and by activation and dysfunction of innate and adaptive branches of the immune system, that often leads to secondary infections (Boomer et al, 2011, Russell, 2006). Despite decades of intensive research and improvements in medical care, severe sepsis is associated with high mortality (Russell, 2006).

Rapid activation of the HPA axis resulting in increased production of glucocorticoids is crucial to survive sepsis (Goodwin et al., 2013). Although in a number of critically ill patients, this homeostatic function of the HPA axis is disregulated, knowledge about the underlying mechanisms and predisposing factors leading to this dysregulation is scarce (Annane et al, 1996, Bornstein, 2009). In many of these patients, dissociation between low ACTH levels and either relatively normal or elevated cortisol levels is being diagnosed at the time of admission to the intensive care unit stations (ICU). Increased cortisol levels were attributed traditionally to action of non-ACTH factors such as e.g. local intra-adrenal cytokines and recently to reduced cortisol breakdown (Boonen et al, 2013, Ehrhart-Bornstein et al, 1998).

Regulation of the HPA axis during sepsis is still not fully understood process which requires a complex interaction between neuroendocrine and immune systems. Numerous experimental data support the key role of cytokines and other inflammatory mediators in the initial activation of corticotrophin releasing hormone (CRH) and ACTH release from hypothalamus and pituitary gland during microbial infection (Turrin and Rivest, 2004). Simultaneously, a coordinated interaction of numerous cell types and systems within the adrenal microenvironment is involved in the sustained adrenal glucocorticoid production (Ehrhart-Bornstein et al., 1998).

Since the role of reduced cortisol metabolism and sepsis-mediated suppression of ACTH production on HPA axis function in critically ill patients was recently a subject of many excellent review articles (Boonen, Van den Berghe, 2015, Boonen et al, 2014), this review focuses predominantly on the importance of an intact adrenal microenvironment, especially the adrenal–immune crosstalk and adrenal vasculature in this process.

Section snippets

Regulation of the HPA axis during stress-free conditions

The adrenal gland is the key effector organ of the HPA axis (Chrousos, 1995). Activation of the HPA axis is not only an essential component of the general adaptation to stress but also contributes to the maintenance of homeostasis at stress free conditions. In the latter conditions, the dynamics of glucocorticoid production is characterized by both, circadian and ultradian rhythms of hormone secretion. Glucocorticoids are secreted in a highly pulsatile fashion through a 24 hour cycle with its

Dys(-function) of the HPA axis during sepsis

Rapid activation of adrenal steroid production is crucial to survive sepsis (Goodwin et al., 2013). It has been demonstrated in human and rodents that defects in adrenal hormone production initiated either by pharmacologic (Chan et al, 2012, Hawes et al, 1992), genetic or by surgical intervention (Bosmann et al., 2013) result in an increased mortality rate due to the sepsis. In general, glucocorticoids are required to ensure the proper cardiovascular reactivity to angiotensin II and

The role of adrenal gland microenvironment in the adrenal gland function and dysfunction during systemic inflammation

A coordinated interaction of numerous cell types and systems within adrenal microenvironment was found to be involved in sustained adrenal glucocorticoid production during sepsis. Among these, adrenocortical–chromaffin cell interactions, the immune–adrenal crosstalk, adrenal vascular system as well as the innervation play the major role (Ehrhart-Bornstein et al., 1998). Consequently, any impairment in function of one of these systems, as depicted in Fig. 1, can lead to alterations of adrenal

Summary and perspective

Sepsis and septic shock are serious threats to body homeostasis. Activation of adrenal stress system, including the HPA axis, is pivotal to survive these adverse conditions. However in many critically ill patients, this homeostatic function of the adrenal gland is impaired. In these patients dissociation between plasma ACTH and cortisol levels is often diagnosed. As for a mechanism of this discrepancy, reduced cortisol metabolism, cytokine-mediated suppression of ACTH synthesis and activation

Acknowledgements

This work was supported by grants of the Deutsche Forschungsgemeinschaft (DFG) to WK (KA 3013/2-2), SRB (BO 1141/11-2) and KZ (ZA 234/12-2) of the Clinical Research Unit KFO 252/1.

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