Abstract
BackgroundA protective role for glucocorticoid therapy in animal models of sepsis was shown many decades ago. In human sepsis, there is new interest in glucocorticoid therapy at a physiological dose after reports of improved response to vasopressor drugs and decreased mortality in a selected group of patients. However, other reports have not confirmed these results. Cellular glucocorticoid resistance could explain a possible cause of that. To evaluate this hypothesis, we evaluated the expression of glucocorticoid receptor beta, the dominant negative isoform of glucocorticoid receptor, in peripheral mononuclear cells of septic patients and the effect of serum septic patients over glucocorticoid receptor expression and glucocorticoid sensitivity in immune cells culture.MethodsA prospective cohort study and an in vitro experimental study with matched controls were developed. Nine patients with septic shock and nine healthy controls were prospectively enrolled. Mononuclear cells and serum samples were obtained from the patients with sepsis on admission to the Intensive Care Unit and on the day of discharge from hospital, and from healthy volunteers matched by age and sex with the patients. Glucocorticoid receptor alpha and beta expression from patients and from immune cell lines cultured in the presence of serum from septic patients were studied by western blot. Glucocorticoid sensitivity was studied in control mononuclear cells cultured in the presence of serum from normal or septic patients. A statistical analysis was performed using a Mann-Whitney test for non-parametric data and analysis of variance for multiple comparison; P < 0.05 was considered significant.ResultsThe patients' glucocorticoid receptor beta expression was significantly higher on admission than on discharge, whereas the alpha receptor was not significantly different. In vitro, septic serum induced increased expression of both receptors in T and B cells in culture, with a greater effect on receptor beta than the control serum. Septic serum induced glucocorticoid resistance in control mononuclear cells.ConclusionThere is a transient increased expression of glucocorticoid receptor beta in mononuclear cells from septic patients. Serum from septic patients induces cell glucocorticoid resistance in vitro. Our findings support a possible cell glucocorticoid resistance in sepsis.
Highlights
Sepsis is a leading cause of death in intensive care units (ICUs) around the world [1]
Our results showed that all patients had significantly increased GR beta (GRb) expression in peripheral blood mononuclear cell (PBMC) obtained at ICU admission compared to their expression at the time of hospital discharge (n = 5, P = 0.037), whereas the expression of GR alpha (GRa) had not significantly changed (Figure 1)
We demonstrated that serum from septic patients influences the expression of glucocorticoid receptor (GR) transcriptional isoforms a and b in cell lines in culture, increasing the dominant negative GRb in T and B cell lines
Summary
Sepsis is a leading cause of death in intensive care units (ICUs) around the world [1]. A protective role for glucocorticoid (GC) therapy in animal models of sepsis was shown many decades ago [6,7], leading to a proposal as early as 1940 for the use of GCs to treat patients with severe sepsis [8]. This therapeutic strategy has had several dramatic shifts with time. The most accepted conclusion from earlier studies was that positive GC effects in sepsis were seen only in a restricted group of patients Until recently, these patients had been identified through a reduced ACTH response, which has been termed adrenal insufficiency or inadequate response to stress [14]. We evaluated the expression of glucocorticoid receptor beta, the dominant negative isoform of glucocorticoid receptor, in peripheral mononuclear cells of septic patients and the effect of serum septic patients over glucocorticoid receptor expression and glucocorticoid sensitivity in immune cells culture
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