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Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
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2013 (English)In: Journal of Infection, ISSN 0163-4453, E-ISSN 1532-2742, Vol. 67, no 6, 574-583 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Glucocorticoid treatment in septic shock remains controversial after recent trials. We hypothesized that failure to respond to steroid therapy may be caused by decreased expression and/or function of glucocorticoid receptors (GR) and studied this in a mouse model of Staphylococcus aureus sepsis. The impact of timing of dexamethasone treatment was also investigated. Methods: Male C57BL/6J mice were intravenously inoculated with S. aureus and GR expression and binding ability in blood, spleen and lymph nodes were analysed by means of flow cytometry. GR translocation was analysed using Image Stream. Septic mice were administered dexamethasone at 22, 26, 48, 72 and 96 h after inoculation and body weight, as a sign of dehydration, was observed. Results: GR expression was decreased in septic animals, but not the ligand binding capacity. GR translocation was decreased in septic mice compared to control animals. Early dexamethasone treatment (22 and 26 h) improved clinical outcome as studied by weight gain compared to when treatment was started at later time points (48, 72 and 96 h). Conclusion: Our data provide evidence that GR expression is progressively decreased in experimental sepsis and that dexamethasone has a decreased ability to translocate into the cell nucleus. This may explain why steroid treatment is only beneficial when administered early in sepsis and septic shock. 

Place, publisher, year, edition, pages
2013. Vol. 67, no 6, 574-583 p.
Keyword [en]
Sepsis, Glucocorticoid receptor, Corticosteroids, Inflammation, Staphylococcus aureus
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-212302DOI: 10.1016/j.jinf.2013.07.028ISI: 000326588400009OAI: oai:DiVA.org:uu-212302DiVA: diva2:677743
Available from: 2013-12-10 Created: 2013-12-09 Last updated: 2014-09-08Bibliographically approved
In thesis
1. Glucocorticoid receptors in severe inflammation: Experimental and clinical studies
Open this publication in new window or tab >>Glucocorticoid receptors in severe inflammation: Experimental and clinical studies
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Septic shock is one of the most common causes of mortality in intensive care, in spite of antibiotic treatment. Glucocorticoid treatment can be used to blunt an overwhelming immune response in severe inflammation. The varying effects of glucocorticoid treatment in sepsis are poorly understood, with consequences for the clinical guidelines for treatment. Glucocorticoids are potent anti-inflammatory mediators which exert their effects through the glucocorticoid receptor (GR). Deeper understanding about the mechanisms of GR signalling may help to guide and improve glucocorticoid treatment. The aim of this thesis was to analyse GR expression and binding capacity in experimental and human septic shock and severe inflammation with cellular specificity using flow cytometry. In the late phase of a murine sepsis model, we observed decreased GR expression in leukocytes. In a murine model of early endotoxic shock, we observed decreased GR binding capacity in spite of an increased expression, in neutrophils. Glucocorticoid treatment was beneficial only when administered early in both models. Compared to healthy subjects, GR expression was increased in leukocytes from patients during the initial sepsis phase, while GR binding capacity was only increased in lymphocytes and monocytes. In contrast, neutrophils and other leukocyte subsets displayed decreased GR binding capacity. Neutrophil numbers were increased in all patients with sepsis compared to healthy subjects. We also studied patients with burn injury after admission before any infectious event had likely occurred, and on day 7 post admission, when several of the patients had been diagnosed with sepsis. GR expression and binding capacity was increased in leukocytes on admission as compared to healthy subjects, and patients diagnosed with sepsis on day 7 had a further increased GR expression in T lymphocytes. GR binding capacity was decreased in proportion to the extent of the burn injury on day 14 post admission. In conclusion, sepsis and severe inflammation have significant impact on the expression and function of GR, likely to influence the efficiency of glucocorticoid treatment. In addition, glucocorticoid treatment is beneficial only when given early in these models of experimental sepsis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 86 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1016
glucocorticoid receptor, sepsis, inflammation, flow cytometry
National Category
Cell and Molecular Biology
Research subject
Clinical Immunology
urn:nbn:se:uu:diva-229119 (URN)978-91-554-8994-6 (ISBN)
Public defence
2014-09-26, Robergsalen, Ing 40, Uppsala University, Uppsala, 13:00 (English)
Available from: 2014-09-04 Created: 2014-07-31 Last updated: 2014-09-08

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Bergquist, MariaHedenstierna, Göran
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