• Circadian rhythm
• Cushing's syndrome
• Glucocorticoids
• Hypercortisolism
• Immune system

• Adult
• Female
• Humans
• Male
• Middle Aged
• Case-Control Studies
• Circadian Clocks
• Circadian Rhythm
• Cushing Syndrome/genetics
• Cushing Syndrome/immunology
• Gene Expression Profiling
• Gene Expression Regulation
• Leukocytes, Mononuclear/metabolism
• Leukocytes, Mononuclear/immunology
• Machine Learning
• Prospective Studies

• CIRCI
• adrenal
• cortisol
• critical illness
• glucocorticoid receptor
• sepsis

• canine parvoviral enteritis
• cortisol
• epinephrine
• human dialyzable leucocytes extract
• lymphocytes
• neutrophils
• norepinephrine

• Consejo Nacional de Ciencia y Tecnología

• COVID-19
• Cushing’s syndrome
• IVIg
• hypercortisolism
• immunomodulation
• immunosuppression

• Adrenocorticotropic Hormone
• Aged
• COVID-19/complications
• Cushing Syndrome/complications
• Cushing Syndrome/diagnosis
• Cushing Syndrome/drug therapy
• Female
• Humans
• Immunoglobulins, Intravenous/therapeutic use
• Pandemics
• COVID-19 Drug Treatment

• COVID-19
• GCR
• HPA
• critical illness

• COVID-19/metabolism
• Critical Illness
• Glucocorticoids/metabolism
• Humans
• Hypothalamo-Hypophyseal System/metabolism
• Hypothalamo-Hypophyseal System/virology
• Pituitary-Adrenal System/metabolism
• Pituitary-Adrenal System/virology
• Receptors, Glucocorticoid/metabolism
• Stress, Physiological

The glucocorticoid receptor (GCR) and the mineralocorticoid receptor (MR) are members of the steroid receptor superfamily of hormone-dependent transcription factors. The receptors are structurally and functionally related. They are localized in the cytosol and translocate into the nucleus after ligand binding. GCRs and MRs can be co-expressed within the same cell, and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation. In critical illness, the hypothalamic-pituitary-adrenal axis is activated, and as a consequence, serum cortisol concentrations are high. However, a number of patients exhibit relatively low cortisol levels for the degree of illness severity. Glucocorticoid (GC) actions are facilitated by GCR, whose dysfunction leads to GC tissue resistance. The MR is unique in this family in that it binds to both aldosterone and cortisol. Endogenous GCs play a critical role in controlling inflammatory responses in critical illness. Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes, type 1 and type 2. 11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone. The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues. In this review, we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness.

• Mineralocorticoid receptor
• Glucocorticoid receptor, Critical illness
• 11beta-hydroxysteroid dehydrogenase
• Aldosterone
• Cortisol

• Cushing’s syndrome
• hypercortisolism
• immune system
• inflammation

• Animals
• Cushing Syndrome/metabolism
• Humans
• Immune System/metabolism
• Inflammation/metabolism
• Interleukin-1/metabolism
• Interleukin-6/metabolism

• cortisol
• critical illness
• glucocorticoid receptors
• mRNA expression
• real-time PCR
• sepsis

• glucocorticoids
• inflammation
• innate immunity
• neutrophils

Sepsis, a life-threatening organ dysfunction, results from a dysregulated host response to invading pathogens that may be characterized by overwhelming systemic inflammation or some sort of immune paralysis. Sepsis remains a major cause of morbidity and mortality. Treatment is nonspecific and relies on source control and organ support. Septic shock, the most severe form of sepsis is associated with the highest rate of mortality. Two large multicentre trials, undertaken 15 years apart, found that the combination of hydrocortisone and fludrocortisone significantly reduces mortality in septic shock. The corticosteroids family is composed of several molecules that are usually characterized according to their glucocorticoid and mineralocorticoid power, relative to hydrocortisone. While the immune effects of glucocorticoids whether mediated or not by the intracellular glucocorticoid receptor have been investigated for several decades, it is only very recently that potential immune effects of mineralocorticoids via non-renal mineralocorticoid receptors have gained popularity. We reviewed the respective role of glucocorticoids and mineralocorticoids in counteracting sepsis-associated dysregulated immune systems.

• NF-κB
• animal models
• clinical trials
• glucocorticoids
• mineralocorticoids
• organ function
• sepsis
• septic shock

The purposes of this study are to examine if the human glucocorticoid receptor (hGR) isoform-α mRNA and hGR protein expressions are deficient in the acute phase of sepsis (S) compared to systemic inflammatory response syndrome (SIRS) and healthy subjects (H) and to evaluate if the hGRα and hGR alterations are associated with cortisol changes and if they are related to (1) extracellular and intracellular heat shock proteins (HSP) 72 and 90α; (2) ACTH, prolactin, and interleukins (ILs); and (3) outcome.

Patients consecutively admitted to a university hospital intensive care unit (ICU) with S (n = 48) or SIRS (n = 40) were enrolled in the study. Thirty-five H were also included. Total mRNA was isolated from peripheral blood samples and cDNA was prepared. RT-PCR was performed. Intracellular hGR and HSP expression in monocytes and/or neutrophils was evaluated using four-colour flow cytometry. Serum prolactin, ACTH, and cortisol concentrations were also measured. ELISA was used to evaluate serum ILs and extracellular (e) HSPs (eHSP72, eHSP90α).

hGR protein was higher in S compared to H and SIRS; hGRα mRNA was higher in S compared to H (p < 0.05). In sepsis, hGR protein and eHSP72 were higher among non-survivors compared to survivors (p < 0.05). The hGR MFI and hGRα mRNA fold changes were significantly related to each other (r_s = 0.64, p < 0.001). Monocyte hGR protein expression was positively correlated with extracellular and intracellular HSPs, cortisol, and ILs and negatively to organ dysfunction (p < 0.05). HSPs, hGR, and cortisol were able to discriminate sepsis from SIRS (AUROC > 0.85, p < 0.05). In sepsis, monocyte-hGR protein and eHSP72 were strong predictors of mortality (AUROC > 0.95, p < 0.04).

Acute-phase sepsis is associated with increased hGR expression and cortisol concentrations, possibly implying no need for exogenous steroids. At this stage, hGR is able to predict sepsis and outcome and is related to stress-activated bio-molecules and organ dysfunction.

• Cortisol
• Glucocorticoid receptor (GR)
• HSP90α
• Heat shock protein 72
• SIRS
• Sepsis