ReviewThe role of adrenal gland microenvironment in the HPA axis function and dysfunction during sepsis
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.
References (97)
The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome
Blood
(2003)- et al.
Endothelial factors mediate aldosterone release via PKA-independent pathways
Mol. Cell. Endocrinol
(2009) - et al.
Cytokines and steroidogenesis
Mol. Cell. Endocrinol
(2004) - et al.
Dissociation of ACTH and glucocorticoids
Trends Endocrinol. Metab
(2008) - et al.
Regulation of IL-17 family members by adrenal hormones during experimental sepsis in mice
Am. J. Pathol
(2013) - et al.
Neutrophils in development of multiple organ failure in sepsis
Lancet
(2006) - et al.
Defect in neutrophil killing and increased susceptibility to infection with nonpathogenic gram-positive bacteria in peptidoglycan recognition protein-S (PGRP-S)-deficient mice
Blood
(2003) - et al.
Differential expression and action of Toll-like receptors in human adrenocortical cells
Mol. Cell. Endocrinol
(2009) - et al.
Characterization of the LPS-induced inflammation of the adrenal gland in mice
Mol. Cell. Endocrinol
(2013) - et al.
Unresponsiveness of MyD88-deficient mice to endotoxin
Immunity
(1999)
Insufficient activation of adrenocortical but not adrenomedullary hormones during stress in rats subjected to repeated immune challenge
J. Neuroimmunol
Interleukins 1α and 1β as regulators of steroidogenesis in human NCI-H295R adrenocortical cells
Steroids
Immunotherapy of sepsis
Lancet Infect. Dis
Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children
N. Engl. J. Med
Interleukin-1 beta enhances corticosterone secretion by acting directly on the rat adrenal gland
Endocrinology
Epidemiology of sepsis: an update
Crit. Care Med
The hypothalamo-pituitary axis in septic shock
Br. J. Intens. Care
Diagnosis of adrenal insufficiency in severe sepsis and septic shock
Am. J. Respir. Crit. Care Med
Aldosterone secretagogues increase adrenal blood flow in male rats
Endocrinology
Longitudinal assessment of adrenal function in the early and prolonged phases of critical illness in septic patients: relations to cytokine levels and outcome
J. Clin. Endocrinol. Metab
Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis
Science
Migration inhibitory factor expression in experimentally induced endotoxemia
Am. J. Pathol
Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis
J. Endotoxin Res
Network of immune-neuroendocrine interactions
Clin. Exp. Immunol
Immunosuppression in patients who die of sepsis and multiple organ failure
JAMA
Understanding the HPA response to critical illness: novel insights with clinical implications
Intensive Care Med
Reduced cortisol metabolism during critical illness
N. Engl. J. Med
Impact of duration of critical illness on the adrenal glands of human intensive care patients
J. Clin. Endocrinol. Metab
Predisposing factors for adrenal insufficiency
N. Engl. J. Med
Clinical review 104: adrenocorticotropin (ACTH)- and non-ACTH-mediated regulation of the adrenal cortex: neural and immune inputs
J. Clin. Endocrinol. Metab
Structure and dynamics of adrenal mitochondria following stimulation with corticotropin releasing hormone
Anat. Rec
Impaired adrenal stress response in Toll-like receptor 2-deficient mice
Proc. Natl. Acad. Sci. U.S.A.
The role of toll-like receptors in the immune-adrenal crosstalk
Ann. N. Y. Acad. Sci
Regulation of adrenal medullary and cortical blood flow
Am. J. Physiol
Etomidate is associated with mortality and adrenal insufficiency in sepsis: a meta-analysis
Crit. Care Med
Endothelial dysfunction: a critical determinant in inflammation-associated adrenal insufficiency?
Eur. J. Clin. Invest
Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment
Science
The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation
N. Engl. J. Med
Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood
Nat. Med
Immune cells and cytokine circuits: toward a working model for understanding direct immune-to-adrenal communication pathways
Endocrinology
Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012
Crit. Care Med
Orexinergic activity modulates altered vital signs and pituitary hormone secretion in experimental sepsis
Crit. Care Med
Intraadrenal interactions in the regulation of adrenocortical steroidogenesis
Endocr. Rev
Splanchnic nerve stimulation modulates steroid secretion in hypophysectomized dogs
Neuroendocrinology
Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland
Endocrinology
Regulation of hypothalamic corticotropin-releasing hormone transcription by elevated glucocorticoids
Mol. Endocrinol
Defective inflammatory response in interleukin 6-deficient mice
J. Exp. Med
The complement anaphylatoxin C5a induces apoptosis in adrenomedullary cells during experimental sepsis
PLoS ONE
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