Glucocorticoid receptor function is decreased in neutrophils during endotoxic shock - 29/06/14

Doi : 10.1016/j.jinf.2014.03.011

Maria Bergquist ^a,^b,^⁎ , Pernilla Jirholt ^b, Merja Nurkkala ^b, Christian Rylander ^c, Göran Hedenstierna ^a, Catharina Lindholm ^b
^a Department of Medical Sciences, The Hedenstierna Laboratory, Uppsala University, Sweden
^b Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Sweden
^c Department of Anaesthesia & Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden

^∗Corresponding author. Uppsala University, The Hedenstierna Laboratory, University Hospital, Entr 40^III, S-75185 Uppsala, Sweden. Tel.: +46 (0) 18 6115165; fax: +46 (0) 18 611 41 53.

Summary

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.

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Keywords : Lipopolysaccharide, Endotoxin, Glucocorticoid receptor, Sepsis, Dexamethasone