Corticosteroid resistance in sepsis is influenced by microRNA-124–induced downregulation of glucocorticoid receptor-α*

Ledderose, Carola; Möhnle, Patrick; Limbeck, Elisabeth; Schütz, Stefanie V.; Weis, Florian; Rink, Jessica; Briegel, Josef; Kreth, Simone

doi:10.1097/ccm.0b013e31825b8ebc

Cited by 119 publications

(105 citation statements)

References 64 publications

(30 reference statements)

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“…Glucocorticoid resistance is also recognized as a potential complication of critical illness, with most of the evidence originating from the sepsis and ARDS clinical and experimental literature [75][76][77][78][79][80][81]. Critical illness is associated with reduced GR-α density and transcription [7,25,82,83] and increased GR-β (dominant negative activity on GR-induced transcription) [80,83,84]. These changes are considered maladaptive, since GR-α upregulation was shown to augment the effects of available glucocorticoids [81].…”

Section: Tissue Resistance To Glucocorticoidsmentioning

confidence: 99%

Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

et al. 2017

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Section: Tissue Resistance To Glucocorticoidsmentioning

confidence: 99%

Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

et al. 2017

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“…It was found that miR-124 specifi cally downregulated GR-α, and a slight increase of miR-124 and a reduction of GR-α were observed in patient T cells compared with healthy controls [ 108 ]. In addition, Tessel and colleagues [ 109 ] identifi ed and characterized miR-130b as an important downregulator of GR in a GC-resistant multiple myeloma cell line: The overexpression of this miRNA was also associated with a decreased regulation of GILZ , a downstream GC-controlled gene (Table 2 ).…”

Section: Mirnas Involved In Gr Regulation and Their Potential Rolementioning

confidence: 95%

Glucocorticoids in Pediatric Gastrointestinal Disorders

Iudicibus

Martelossi

Decorti

2015

Systemic Corticosteroids for Inflammatory Disorders in Pediatrics

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Pediatric Inflammatory Bowel Disease\ud Inflammatory bowel diseases (IBDs) are the most frequent chronic gastrointestinal disorders in pediatric age. They include two disease entities – Crohn’s disease (CD) and ulcerative colitis (UC) – which, although different in their pathogenesis, show common clinical characteristics such as chronic inflammation at different levels of the gastrointestinal tract and alternation between active and inactive phases. The incidence of IBD is increasing in recent years, particularly among children and adolescents, and it is currently estimated that 20–30 % of patients with IBD experience the onset of symptoms when they are under 20 years of age [1–3]. In childhood, IBDs are gener- ally more extended, more severe, and progress more rapidly than in adulthood. Moreover, therapy in children with IBD is more aggressive than in adults: Indeed, about 80 % of children need steroids, and about 30 % are subjected to an intestinal resection during a 5-year follow-up. Quality of life is severely affected in IBD, espe- cially for pediatric patients, owing to the chronic character of the disease that implies frequent hospitalizations and aggressive therapies, with a significant risk of side effects and a considerable impact on health care costs. IBD can result in loss of education and difficulty in gaining employment or insurance; overall, 15 % of patients with IBD are unable to work after 5–10 years of disease. Depressive disorders and low social func- tioning are also common among these patients, and the disease can also cause growth failure or retarded sexual development in young people [4–7]. It was recently reported that the mean individual annual costs in European countries amount to US$6,000 for CD and $4,600 for UC, and pediatric cases cost even more than adult ones [8]

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“…Even in the presence of high levels of cortisol, a relative insufficiency can occur due to reduced levels or impaired function of GR. This may be a consequence of GR downregulation by cytokines (31,55), decreased ligand affinity (62), or an altered expression profile of the GR isoforms (31). Finally, in retrospect, measurements of DHEA, DHEAS, CRH, and the renin-angiotensin system may have added valuable information.…”

Section: Discussionmentioning

confidence: 99%

Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia

Cortés‐Puch

Hicks

Sun

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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The clinical significance and even existence of critical illness-related corticosteroid insufficiency is controversial. Here, hypothalamic-pituitary-adrenal (HPA) function was characterized in severe canine Staphylococcus aureus pneumonia. Animals received antibiotics and titrated life-supportive measures. Treatment with dexamethasone, a glucocorticoid, but not desoxycorticosterone, a mineralocorticoid, improves outcome in this model. Total and free cortisol, adrenocorticotropic hormone (ACTH). and aldosterone levels, as well as responses to exogenous ACTH were measured serially. At 10 h after the onset of infection, the acute HPA axis stress response, as measured by cortisol levels, exceeded that seen with high-dose ACTH stimulation but was not predictive of outcome. In contrast to cortisol, aldosterone was largely autonomous from HPA axis control, elevated longer, and more closely associated with survival in early septic shock. Importantly, dexamethasone suppressed cortisol and ACTH levels and restored ACTH responsiveness in survivors. Differing strikingly, nonsurvivors, sepsis-induced hypercortisolemia, and high ACTH levels as well as ACTH hyporesponsiveness were not influenced by dexamethasone. During septic shock, only serial measurements and provocative testing over a well-defined timeline were able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identify a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies. septic shock; sepsis; corticosteroids; adrenal insufficiency; cortisol; adrenocorticotropic hormone; aldosterone "RELATIVE ADRENAL DEFICIENCY" in critically ill patients with otherwise normal hypothalamic-pituitary-adrenal (HPA) function was recently renamed "critical illness-related corticosteroid insufficiency" (CIRCI) (33). However, there are no widely accepted criteria for the diagnosis and treatment of this hypothetical condition (40,41,57,58). No test of HPA function reliably predicts outcome, and the relative importance of endogenous glucocorticoid (cortisol) vs. mineralocorticoid (aldosterone) activity to survival is not known. Importantly, patient selection for corticosteroid therapy in sepsis has varied in clinical practice and across randomized trials, in which benefit has not been reproducible (4,40,41,57).To date, HPA testing in patients with septic shock has focused primarily on criteria for inadequate cortisol production using both random cortisol levels and adrenocorticotropic hormone (ACTH)-stimulated adrenal responsiveness. However, both low and high cortisol levels have been associated with worst outcomes (5, 23, 39, 52). Total cortisol increases of less than 9 g/dl in response to high-dose ACTH (250 g) (5) or a random total cortisol below an arbitrary cutoff (e.g., Ͻ10 to Ͻ25 g/dl) (6,20,23,(33)(34)(35) have been proposed to define CIRCI (33). However, neither high-nor low-dose (1 g) ACTH stimulation testing has been shown to identify sept...

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Corticosteroid resistance in sepsis is influenced by microRNA-124–induced downregulation of glucocorticoid receptor-α*

Abstract: Glucocorticoid treatment induces expression of miR-124, which downregulates glucocorticoid receptor-α thereby limiting anti-inflammatory effects of glucocorticoids. Steroid treatment might aggravate glucocorticoid resistance in patients with high glucocorticoid receptor-β levels.

Cited by 119 publications

References 64 publications

Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

Glucocorticoids in Pediatric Gastrointestinal Disorders

Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia

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