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Glucocorticoid receptors in severe inflammation: Experimental and clinical studies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1016
Keyword [en]
glucocorticoid receptor, sepsis, inflammation, flow cytometry
National Category
Cell and Molecular Biology
Research subject
Clinical Immunology
Identifiers
URN: urn:nbn:se:uu:diva-229119ISBN: 978-91-554-8994-6 (print)OAI: oai:DiVA.org:uu-229119DiVA: diva2:736697
Public defence
2014-09-26, Robergsalen, Ing 40, Uppsala University, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2014-09-04 Created: 2014-07-31 Last updated: 2014-09-08
List of papers
1. Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis
Open this publication in new window or tab >>Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis
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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. 

Keyword
Sepsis, Glucocorticoid receptor, Corticosteroids, Inflammation, Staphylococcus aureus
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-212302 (URN)10.1016/j.jinf.2013.07.028 (DOI)000326588400009 ()
Available from: 2013-12-10 Created: 2013-12-09 Last updated: 2017-12-06Bibliographically approved
2. Glucocorticoid receptor function is decreased in neutrophils during endotoxic shock
Open this publication in new window or tab >>Glucocorticoid receptor function is decreased in neutrophils during endotoxic shock
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2014 (English)In: Journal of Infection, ISSN 0163-4453, E-ISSN 1532-2742, Vol. 69, no 2, 113-122 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: It remains unclear whether glucocorticoid treatment can improve the outcome of sepsis. The aim of the present study was to investigate if glucocorticoid receptor (GR) expression and function is impaired in lipopolysaccharide (LPS) induced shock, and whether the time point for start of glucocorticoid treatment affects the outcome.

METHODS: Male C57BL/6J mice were administered LPS i.p. and GR expression and binding ability in blood and spleen leukocytes were analysed by flow cytometry. GR translocation was analysed using Image Stream technique. The effect of dexamethasone treatment started 2 h before or 2, 12 or 36 h after LPS administration on survival was studied.

RESULTS: Despite increased GR expression in neutrophils after LPS administration, the GR binding capacity was reduced. In addition, GR translocation was decreased in neutrophils and T lymphocytes from endotoxic mice at 12 h compared to control animals. Dexamethasone treatment improved survival only when started early (2 h) after LPS administration.

CONCLUSION: The decreased glucocorticoid responsiveness displayed by neutrophils, in combination with their increased numbers, may explain why survival is increased only when dexamethasone treatment is given early during LPS induced shock.

National Category
Infectious Medicine
Research subject
Clinical Physiology
Identifiers
urn:nbn:se:uu:diva-223346 (URN)10.1016/j.jinf.2014.03.011 (DOI)000339751500002 ()24657243 (PubMedID)
Available from: 2014-04-17 Created: 2014-04-17 Last updated: 2017-12-05Bibliographically approved
3. Glucocorticoid receptor expression and binding capacity during septic shock
Open this publication in new window or tab >>Glucocorticoid receptor expression and binding capacity during septic shock
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(English)Article in journal (Refereed) Submitted
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-229114 (URN)
Available from: 2014-07-31 Created: 2014-07-31 Last updated: 2014-09-08Bibliographically approved
4. Glucocorticoid receptor expression and binding capacity in patients with burn injury
Open this publication in new window or tab >>Glucocorticoid receptor expression and binding capacity in patients with burn injury
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2016 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, no 2, 213-221 p.Article in journal (Refereed) Published
Abstract [en]

Background

Burn injuries are associated with strong inflammation and risk of secondary sepsis which both may affect the function of the glucocorticoid receptor (GR). The aim of this study was to determine GR expression and binding capacity in leucocytes from patients admitted to a tertiary burn center.

Methods

Blood was sampled from 13 patients on admission and days 7, 14 and 21, and once from 16 healthy subjects. Patients were grouped according to the extent of burn and to any sepsis on day 7. Expression and binding capacity of GR were determined as arbitrary units using flow cytometry.

Results

GR expression and binding capacity were increased compared to healthy subjects in most circulating leucocyte subsets on admission irrespective of burn size. Patients with sepsis on day 7 displayed increased GR expression in T lymphocytes (51.8%, < 0.01) compared to admission. There was a negative correlation between GR binding capacity in neutrophils and burn size after 14 days (< 0.05).

Conclusions

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.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-229116 (URN)10.1111/aas.12604 (DOI)000368139700009 ()
Funder
Swedish Research Council, 5315
Available from: 2014-07-31 Created: 2014-07-31 Last updated: 2017-12-05

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