Decreased glucocorticoid receptor expression during critical illness

Abstract

Introduction In critically ill patients, the hypothalamic‐pituitary‐adrenal axis is activated, resulting in increased serum cortisol concentrations. However, in some patients, especially those with sepsis, cortisol levels are relatively low for the degree of illness severity. Therefore, in the present project, we aim to characterize the time course of glucocorticoid receptor (GCR) alpha and beta expression in peripheral polymorphonuclear cells of critically ill septic or nonseptic patients using real‐time PCR. Design A prospective observational study conducted on 32 critically ill adults not receiving steroids, in a university‐affiliated, multidisciplinary intensive care unit (ICU). Blood samples were collected for measurement of glucocorticoid receptor expression within 24‐48 hours of admission to the ICU and at days 4, 8 and 13 after admission, reflecting the acute and chronic phase of the illness. Results During ICU stay, patients expressed over time reduced levels of both GCR‐α and GCR‐β mRNA. More specifically, GCR‐α mRNA expression was decreased fourfold 4 days after admission (P < 0.0001) and remained low up to 2 weeks after admission (P < 0.001). On the other hand, GCR‐β mRNA levels remained stable shortly after admission, but approx. one week after admission, its levels decreased threefold (P < 0.01) and remained reduced up to 2 weeks after admission (P < 0.001). Discussion Our results suggest that critically ill patients have highly variable expression of alpha and beta GCR, and moreover, the levels of both receptors decrease during ICU stay. Taken together, these might explain the differential responsiveness of patients to exogenous steroid administration or to endogenous cortisol secretion.

Expression of Glucocorticoid Receptors in the Early Period After the Return of Spontaneous Circulation Among Patients Who Experienced Cardiac Arrest : A Retrospective Observational Study

“…Moreover, we observed a more signi cant decrease in the MFI of GR expression in Treg cells and CD3 + CD4 + T lymphocytes but none in the percentage of GR expression. Previous studies have found decreased expression of GRs in peripheral polymorphonuclear cells in critically ill patients [22], and antagonism to GRs aggravates viral and bacterial infections [30]. The results of this study suggest that the decrease in intracellular GR expression in patients who experienced CA may be one of the causes of GC resistance, due to insu cient binding of GRs and GCs, GC insensitivity, and the inability of GCs to effectively exert anti-in ammatory and immunosuppressive effects.…”

“…The a nity of GRs to GC in circulating monocytes is decreased in patients with acquired immunode ciency syndrome [21]. The expression of GR is decreased in critical illness [22], pediatric septic shock, and patients with high serum cortisol [23]. However, hitherto, no study has reported on the GR expression after ROSC in patients who experienced CA.…”

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

“…GRβ homodimers can interact with glucocorticoid response elements (GRE) in the DNA, however their binding does not activate transcription (69). Generally, GRβ is expressed at very low levels compared to GRα; however, its expression is increased in inflammatory diseases, including critical illness, and this might be associated with decreased sensitivity to GCs and CIRCI (79).…”

“…Clinical studies, including autopsies, in patients with severe sepsis and septic shock have reported a significant reduction in GRα expression in circulating cells (79,(134)(135)(136)(137); heart (125), liver and skeletal muscle (125,138), and a significant increase in GRβ expression in the heart and liver (125). GRα mRNA in neutrophils correlates negatively with plasma IL-6 levels and shows gradual recovery overtime in survivors (135).…”

Glucocorticoid and mineralocorticoid receptor expression in critical illness: A narrative review

“…Finally, our group was able to demonstrate that critically-ill steroid-free patients have a highly variable expression of both GCR isoforms in peripheral polymorphonuclear cells. Moreover, GCR expression and HPA axis function undergo a biphasic response during acute or subacute critical illness; this dissociation of reduced GCR expression and elevated cortisol might imply an abnormal stress response[ 42 , 43 ].…”