Immune Effects of Corticosteroids in Sepsis

Abstract

Sepsis, a life-threatening organ dysfunction, results from a dysregulated host response to invading pathogens that may be characterized by overwhelming systemic inflammation or some sort of immune paralysis. Sepsis remains a major cause of morbidity and mortality. Treatment is nonspecific and relies on source control and organ support. Septic shock, the most severe form of sepsis is associated with the highest rate of mortality. Two large multicentre trials, undertaken 15 years apart, found that the combination of hydrocortisone and fludrocortisone significantly reduces mortality in septic shock. The corticosteroids family is composed of several molecules that are usually characterized according to their glucocorticoid and mineralocorticoid power, relative to hydrocortisone. While the immune effects of glucocorticoids whether mediated or not by the intracellular glucocorticoid receptor have been investigated for several decades, it is only very recently that potential immune effects of mineralocorticoids via non-renal mineralocorticoid receptors have gained popularity. We reviewed the respective role of glucocorticoids and mineralocorticoids in counteracting sepsis-associated dysregulated immune systems.

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

“…Additional co-intervention with critical hormones and mediators involved in homeostatic corrections are also necessary, such as fludrocortisone (174,292,293) or vasopressin (294)(295)(296) in patients with septic shock. Fludrocortisone is a mineralocorticoid and glucocorticoid receptor agonist that binds to cytoplasmic receptors, activates their translocation into the nucleus and subsequently initiates the transcription of mineralocorticoid-and glucocorticoid-responsive genes (297).…”

Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Inhibits Steroidogenesis in Adrenocortical Cell by Macrophage-derived Exosomes in Lipopolysaccharide-induced Septic Shock

“…There was no difference in these variables between WT and Trem2 -/mice at the early stage of septic shock ( g. 6D-F). The immune-modulating proprieties of glucocorticoids give the biologic plausibility that corticosteroids may improve tissue perfusion [8,27]. Thus, we measured plasma lactic acid level.…”

“…Glucocorticoids are steroid hormones synthesized in the adrenal gland from cholesterol precursors [7]. The essential role of endogenous glucocorticoids in regulating homeostatic processes under basal and challenging conditions and protecting the host from detrimental consequences of an overactivated in ammatory immune response including sepsis, has been well established [8]. Genetic defects or surgical interventions in stress response and adrenal gland contributes to the increased mortality rates when suffered from sepsis [9,10], indicating that an intact function of glucocorticoids production in adrenal gland is of pivotal importance for sepsis surviving.…”

Adjunctive Corticosteroid Treatment in Septic Shock

“…A more detailed description of the transcriptomic effect of corticosteroids is beyond the scope of this article, and the interested reader is directed to relevant reviews on the subject. 6 The subject is further complicated by pathophysiological alterations in corticosteroid function that occur in the setting of sepsis. These include changes in concentrations of bound and free cortisol, differential expressions of subtypes of glucocorticoid receptors, and alterations in tissue sensitivity to corticosteroid action.…”