Increased glucocorticoid receptor expression in sepsis is related to heat shock proteins, cytokines, and cortisol and is associated with increased mortality

Konstantinos Vardas; Stavroula Ilia; Amalia Sertedaki; Evangelia Charmandari; Efrossini Briassouli; Dimitris Goukos; Kleovoulos Apostolou; Katerina Psarra; Efthimia Botoula; Stylianos Tsagarakis; Eleni Magira; Christina Routsi; Constantine A Stratakis; Serafim Nanas; George Briassoulis

doi:10.1186/s40635-017-0123-8

Increased glucocorticoid receptor expression in sepsis is related to heat shock proteins, cytokines, and cortisol and is associated with increased mortality

Intensive Care Med Exp. 2017 Dec;5(1):10. doi: 10.1186/s40635-017-0123-8. Epub 2017 Feb 21.

Authors

Konstantinos Vardas^{1

2}, Stavroula Ilia², Amalia Sertedaki³, Evangelia Charmandari³, Efrossini Briassouli⁴, Dimitris Goukos⁴, Kleovoulos Apostolou¹, Katerina Psarra⁵, Efthimia Botoula⁶, Stylianos Tsagarakis⁶, Eleni Magira¹, Christina Routsi¹, Constantine A Stratakis⁷, Serafim Nanas¹, George Briassoulis⁸

Affiliations

¹ First Critical Care Department, National and Kapodistrian University of Athens, Athens, Greece.
² Pediatric Intensive Care Unit, University Hospital, University of Crete, 71500, Heraklion, Crete, Greece.
³ Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, 'Aghia Sophia' Children's Hospital and Division of Endocrinology and Metabolism, Biomedical Research Foundation of the Academy of Athens, National and Kapodistrian University of Athens, Athens, Greece.
⁴ First Department of Internal Medicine-Propaedeutic, National and Kapodistrian University of Athens, Athens, Greece.
⁵ Immunology-Histocompatibility Department, Evangelismos Hospital, Athens, Greece.
⁶ Department of Endocrinology-Diabetes, Evangelismos Hospital, Athens, Greece.
⁷ Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD, 20892, USA.
⁸ Pediatric Intensive Care Unit, University Hospital, University of Crete, 71500, Heraklion, Crete, Greece. ggbriass@otenet.gr.

Abstract

Background: The purposes of this study are to examine if the human glucocorticoid receptor (hGR) isoform-α mRNA and hGR protein expressions are deficient in the acute phase of sepsis (S) compared to systemic inflammatory response syndrome (SIRS) and healthy subjects (H) and to evaluate if the hGRα and hGR alterations are associated with cortisol changes and if they are related to (1) extracellular and intracellular heat shock proteins (HSP) 72 and 90α; (2) ACTH, prolactin, and interleukins (ILs); and (3) outcome.

Methods: Patients consecutively admitted to a university hospital intensive care unit (ICU) with S (n = 48) or SIRS (n = 40) were enrolled in the study. Thirty-five H were also included. Total mRNA was isolated from peripheral blood samples and cDNA was prepared. RT-PCR was performed. Intracellular hGR and HSP expression in monocytes and/or neutrophils was evaluated using four-colour flow cytometry. Serum prolactin, ACTH, and cortisol concentrations were also measured. ELISA was used to evaluate serum ILs and extracellular (e) HSPs (eHSP72, eHSP90α).

Results: hGR protein was higher in S compared to H and SIRS; hGRα mRNA was higher in S compared to H (p < 0.05). In sepsis, hGR protein and eHSP72 were higher among non-survivors compared to survivors (p < 0.05). The hGR MFI and hGRα mRNA fold changes were significantly related to each other (r _s = 0.64, p < 0.001). Monocyte hGR protein expression was positively correlated with extracellular and intracellular HSPs, cortisol, and ILs and negatively to organ dysfunction (p < 0.05). HSPs, hGR, and cortisol were able to discriminate sepsis from SIRS (AUROC > 0.85, p < 0.05). In sepsis, monocyte-hGR protein and eHSP72 were strong predictors of mortality (AUROC > 0.95, p < 0.04).

Conclusions: Acute-phase sepsis is associated with increased hGR expression and cortisol concentrations, possibly implying no need for exogenous steroids. At this stage, hGR is able to predict sepsis and outcome and is related to stress-activated bio-molecules and organ dysfunction.

Keywords: Cortisol; Glucocorticoid receptor (GR); HSP90α; Heat shock protein 72; SIRS; Sepsis.