This study explored the relationship between GR expression and immune alteration in the early period after ROSC in patients who experienced CA, by observing GR expression in circulatory T and B lymphocytes, NK cells, and Treg cells and changes in cell counts and plasma total cortisol and ACTH levels. We found that GR expression, cell counts, and ratios rapidly decreased and plasma total cortisol levels increased in these patients.
After ROSC, the immune response of patients who experienced CA is impaired, and the systemic inflammatory response is increased [7, 27]. In this study, the T and B lymphocyte, NK cell, and Treg cell counts as well as the CD3+CD4+/T, CD3+CD8+/T, and Treg cell/CD4+T lymphocyte ratios were significantly reduced after ROSC. NK cells, which are special innate immune cells that have cytotoxic functions similar to CD3+CD8+ T lymphocytes, mainly distinguish infected and stressed cells from healthy cells and eliminate intracellular infection as well as dysfunctional cells [28, 29]. T lymphocytes are also important because of their function as adaptive immune cells for the control and elimination of infection [28]. Moreover, B and T lymphocytes mediate humoral and cellular immunity, respectively. Compared with previous studies, this study further performed an earlier and more comprehensive assessment of the immune system of patients who experienced CA, and our findings more substantially supported the rapid emergence of immune dysfunction in these patients after ROSC compared to that of previous reports.
The effectiveness of GC use in these patients during and after resuscitation has been controversial due to insufficient evidence. However, the use of GC during resuscitation improves the survival rate of patients who experienced CA due to its direct anti-inflammatory, immunosuppressive effects, hemodynamic, and positive inotropic effects. All of this ultimately leads to increased stress capacity of the body [19, 20]. GC can activate GRs in cells when the body is under stress, thereby increasing both the effectiveness of resuscitation and the discharge survival rate. This study is the first to explore GR expression in circulating immune cells in patients who experienced CA after ROSC. We observed that GR expression in B and T lymphocytes, NK cells, and CD3+CD8+ T lymphocytes decreased significantly in patients who experienced CA, while the percentage of GR+ Treg cells and CD3+CD4+ T lymphocytes showed a slight decrease. Moreover, we observed a more significant 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 insufficient binding of GRs and GCs, GC insensitivity, and the inability of GCs to effectively exert anti-inflammatory and immunosuppressive effects. These findings may also explain why different results of the clinical application of GCs have appeared in previous studies and support the possibility of using GCs in the clinical treatment of patients who experienced CA.
In this study, we also found that the total plasma cortisol levels were significantly higher in patients who experienced CA but ACTH levels were not. High levels of inflammatory cytokines inhibit ACTH release [19]. During critical illness, the body does not sufficiently metabolize cortisol [31]. In addition, the continuous increase in plasma cortisol levels may trigger the negative feedback pathway of the hypothalamic-pituitary-adrenal axis, inhibiting the release of ACTH and cortisol and eventually leading to adrenal insufficiency. These factors may explain the opposite trends of plasma ACTH and cortisol levels in the patients who were included in this study and experienced CA. Notably, this result suggests that low GR expression levels cannot be matched with high plasma total cortisol levels. Previous studies have found that GC use during resuscitation may benefit patients who experienced CA [14–17]. The benefits, such as direct anti-inflammatory and anti-shock effects, improvement of vascular endothelial permeability, and other mechanisms may be related to the effects of using a high dose of GC, or GCs may work through other non-GR pathways. It is also possible that the immune function of patients who experienced CA is suppressed due to ischemia-reperfusion injury, which requires a large dose of GC to stimulate GRs to function. This study did not provide data on plasma GC levels and GR expression in a group of patients who were administered GCs and successfully resuscitated; therefore, further studies are required to explore the exact mechanisms of GCs.
Our study has several limitations. First, to assess obvious changes, we only enrolled patients who experienced CA and had obvious signs of systemic ischemic hypoxia, such as GCS < 8 after ROSC. The patients were not stratified by age, gender, occurrence of comorbidities or mild systemic ischemic hypoxia. Second, since this was a preliminary observational study, we were only observing early changes. A dynamic observation for a longer duration would be helpful to understand the significance of GR expression in evolving immunity during the clinical course of CA after ROSC. Third, the samples used in this study were from the clinical laboratory, so the plasma total cortisol and ACTH in the samples were at a risk of degradation before we collected the samples. Finally, we did not discuss the changes in and the roles of GR isoforms, free cortisol, and corticosteroid-binding globulin. Therefore, future studies on these aspects are warranted to better understand the immunosuppressive effects of ROSC among patients who experienced CA.