Glucocorticoid receptor expression and binding capacity in patients with burn injury

Bergquist, Maria; Huss, Fredrik; Hästbacka, Johanna; Lindholm, Catharina; Martijn, Cécile; Rylander, Christian; Hedenstierna, Göran; Fredén, Filip

doi:10.1111/aas.12604

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…Glucocorticoid receptor (GR) signaling has been shown to induce monocyte differentiation that shares the phenotypical characterization of EBIMØs (32). However, in the setting of burn injury, GR expression and binding capacity were increased in circulating leukocytes compared to healthy subjects (33) eliminating the probability of GR signaling as Siglec1 is down regulated in EBIMØ after a burn injury.…”

Section: Discussionmentioning

confidence: 99%

A Shift in Myeloid Cell Phenotype via Down Regulation of Siglec-1 in Island Macrophages of Bone Marrow Is Associated With Decreased Late Erythroblasts Seen in Anemia of Critical Illness

et al. 2019

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Burn injury has been shown to significantly dampen erythropoiesis in both burn patients and in murine models. Our previous findings elucidated the erythropoietin independent defects in red cell development stages involving erythroid progenitor production and late stage erythroblast enucleation processes. We hypothesized that macrophages (MØ) in erythroblast islands (EBI) could be yet another roadblock impeding erythropoiesis following burn injury. Here we highlight that the methodology to study EBI can be achieved with single cell suspensions using a simple technique such as flow cytometry, as obtaining the central erythroblast island macrophages (EBIMØs) of interest is a delicate process. We elucidated the requisite of EBIMØ from the erythroblast as well as the MØ perspective. In addition to the primary erythropoiesis organ, the bone marrow (BM), spleens were also examined for extra-medullary erythropoiesis. Femurs and spleens were harvested from adult mice (B6D2F1) subjected to 15% total body surface area (TBSA) scald burn (B) or sham burn (S). Total bone marrow cells (TBM) and splenocytes were probed for total erythrons, early and late erythroblasts and EBIMØ by flow cytometry. There was only a marginal increase in the number of EBIMØ after burn, but, between the signatures of EBIMØ, Siglec-1 expression (MFI) was reduced by 40% in B with and a parallel 44% decrease in TBM erythrons in the BM. There were more (2.5-fold) EEBs and less LEBs (2.4-fold) per million TBM cells in B; with a corresponding decrease in Siglec-1 and Ly6G expressions in EBIMØ associated with EEB. Conversely, extra-medullary erythropoiesis was robust in spleens from B. Not only were the numbers of EBIMØs increased in B (p < 0.002), both EEBs and LEBs associated with EBIMØ were higher by 30 and 75%, respectively. Importantly, an increase in Siglec-1 and Vcam1 expressing F480+ splenic macrophages was observed after burn injury. Therefore, stagnant EEBs in the BM after burn injury could be due to low Siglec1 expressing EBIMØ, which perhaps impede their maturation into LEBs and reticulocytes. Repercussion of myeloid cell phenotype specific to BM after burn injury could plausibly account for a defective late stage RBC maturation resulting in anemia of critical illness.Summary Sentence: Characterization of erythroblast island macrophages (EBIMØ) in the bone marrow and spleen at different stages of erythropoiesis after burn injury.

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Section: Discussionmentioning

confidence: 99%

A Shift in Myeloid Cell Phenotype via Down Regulation of Siglec-1 in Island Macrophages of Bone Marrow Is Associated With Decreased Late Erythroblasts Seen in Anemia of Critical Illness

et al. 2019

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“…The receptor is involved in the adaptation to physiological stress, with the receptor-glucocorticoid complex regulating the expression of anti-inflammatory proteins in the nucleus or suppressing the expression of pro-inflammatory proteins in the cytosol. Inflammation and cytokines significantly affect glucocorticoid receptor number and function (72)(73)(74). A decrease in both binding activity and glucocorticoid receptor-mediated transcription, have been shown in acute respiratory distress syndrome (75).…”

Section: Cortisol Metabolism Tissue Glucocorticoid Activity and Sensi...mentioning

confidence: 99%

CIRMI—a new term for a concept worthy of further exploration: a narrative review

Nethathe¹,

Lipman²,

Anderson³

et al. 2022

Ann Transl Med

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Background and Objective: Critical illness-related corticosteroid insufficiency (CIRCI) describes hypothalamic-pituitary-axis impairment during critical illness associated with three major pathophysiological events; dysregulation of the hypothalamic-pituitary-axis, altered cortisol metabolism, and tissue corticosteroid resistance. Similar changes are evident with regard to mineralocorticoid dysfunction in critical illness. Hyperreninemic hypoaldosteronism describes a sub-population of critically ill patients with an impaired adrenal aldosterone response to increased levels of renin. In the light of the recent demonstration of significant mortality improvements associated with adjunctive glucocorticoid treatment in combination with fludrocortisone in septic shock, and the suggestion that angiotensin II is effective in treating vasodilatory shock, the clinical relevance of mineralocorticoid dysfunction in critical illness requires further exploration. This interpretative review considers hyperreninemic hypoaldosteronism, a concept worth re-examining in the light of the potential mortality benefit of mineralocorticoid supplementation in critical illness. We compare the pathophysiological and clinical characteristics of CIRCI and hyperreninemic hypoaldosteronism, two syndromes that represent corticosteroid and mineralocorticoid dysfunction in critical illness. We highlight gaps in the literature and give novel insights into the limitations of assessment, diagnosis and treatment.Methods: English language abstracts and articles published before June 2021 were identified through PubMed and Google Scholar. Randomized trials, observational studies, basic sciences studies, systematic and narrative reviews were considered. Reference lists of articles were searched for further relevant material.Key Content and Findings: Difficulties are encountered in interpreting measures of gluco-and mineralocorticoid activity in critical illness. Aldosterone levels, like cortisol, have been shown to be increased in sepsis and hemorrhagic shock. The finding of hyperreninemia and hyperaldosteronism with an aldosterone/plasma renin activity ratio below 2 should prompt consideration of hyperreninemic hypoaldosteronism, a finding, which likely signifies the loss of negative feedback control of the renin-angiotensin-aldosterone system.Conclusions: As there is evidence to suggest that in acute critical illness, hyperreninemic hypoaldosteronism, is associated with poor outcomes, co-administration of hydrocortisone with fludrocortisone in patients with septic shock should be considered. In keeping with the concept of CIRCI, we suggest the term critical illness-related mineralocorticoid insufficiency as a more appropriate description ^ ORCID: Gladness Dakalo Nethathe,

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“…Cells were run on a FACS Calibur ow cytometer. 24,25 The relative quantity of GR protein (mean uorescence) was expressed as MFI.…”

Section: Gr-mab-fcm Analysis and Fitc Labelled-dex-fcm Analysismentioning

confidence: 99%

Combination of icariin and oleanolic acid attenuatesin vivoandin vitroglucocorticoid resistance through protecting dexamethasone-induced glucocorticoid receptor impairment

Tang

Chen

et al. 2018

RSC Adv.

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Glucocorticoid resistance (GCR) remains a significant problem and is the most important reason for treatment failure of glucocorticoids (GCs). How to increase the sensitivity to GCs and exploring new agents to overcome GCR is of great significance. Herein, we report for the first time that the effects of combination of icariin and oleanolic acid (OA) on dexamethasone (Dex)-induced glucocorticoid receptor (GR) impairment in vivo and in vitro. Compared with the use of Dex or combination of icariin and OA alone, co-administration resulted in a significant increase in apoptosis, GR protein, GR binding and GRa protein both in GC-sensitive CEM-C7 and GC-resistant CEM-C1 cells and a decrease in GRb protein and GRb/GRa only in CEM-C1 cells. Furthermore, an ovalbumin-induced rat asthma model was chosen to evaluate the effects of co-administration of Dex and combination of icariin and OA in vivo. Compared with the use of Dex alone, co-administration could protect blood lymphocyte from excessive apoptosis, significantly increasing GR binding, GR protein and mRNA of GRa while decreasing GRb protein and mRNA of GRb. The results suggested that combination of icariin and OA could increase sensitivity to GCs through attenuating in vivo and in vitro Dex-induced GR impairment.

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Glucocorticoid receptor expression and binding capacity in patients with burn injury

Abstract: GR expression and binding capacity are increased in most types of circulating leucocytes of severely burned patients on their admission to specialized burn care. If sepsis is present after 1 week, it is associated with higher GR expression in T lymphocytes and NK cells.

Cited by 5 publications

References 25 publications

A Shift in Myeloid Cell Phenotype via Down Regulation of Siglec-1 in Island Macrophages of Bone Marrow Is Associated With Decreased Late Erythroblasts Seen in Anemia of Critical Illness

A Shift in Myeloid Cell Phenotype via Down Regulation of Siglec-1 in Island Macrophages of Bone Marrow Is Associated With Decreased Late Erythroblasts Seen in Anemia of Critical Illness

CIRMI—a new term for a concept worthy of further exploration: a narrative review

Combination of icariin and oleanolic acid attenuatesin vivoandin vitroglucocorticoid resistance through protecting dexamethasone-induced glucocorticoid receptor impairment

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