Abstract
Critical illness initiates a cascade of systemic disturbances—including energy deficits,
oxidative stress, endothelial injury, and intestinal barrier dysfunction. Mitochondria,
the vascular endothelium, and the intestinal barrier are three critical interfaces
that facilitate the restoration of homeostasis. These processes are regulated by the
glucocorticoid (GC) signaling system, specifically through the glucocorticoid receptor
α (GRα), which coordinates cellular metabolism, immune modulation, and vascular integrity.
This integrated signaling network offers therapeutic targets to prevent or reduce
organ dysfunction and damage. Mitochondria function as metabolic hubs, transforming
substrates mobilized by GC–GRα into adenosine triphosphate (ATP) via oxidative phosphorylation
(OXPHOS), while also regulating calcium homeostasis, reactive oxygen species (ROS)
signaling, and apoptosis. However, excessive ROS generation during critical illness
can disrupt cellular energetics, leading to systemic inflammation and critical illness-related
corticosteroid insufficiency (CIRCI). GC–GRα signaling helps mitigate mitochondrial
dysfunction by promoting mitochondrial biogenesis, enhancing antioxidant defenses,
and maintaining redox balance, which is essential for metabolic recovery and survival.
The vascular endothelium and the intestinal barrier are the two most extensive and
vulnerable surfaces affected during critical illness, and their preservation or restoration
is vital for recovery. These active interfaces are essential for maintaining vascular
integrity, immune balance, and metabolic stability—functions that are often severely
impaired in critical illness. The vascular endothelium, which lines the entire circulatory
system, plays a crucial role in regulating vascular tone, permeability, and immune
cell recruitment through mediators like nitric oxide and prostacyclin. In conditions
such as sepsis and acute respiratory distress syndrome (ARDS), inflammatory injury
damages the endothelial glycocalyx and tight junctions, leading to microvascular leakage
and widespread inflammation. Activation of GC–GRα pathways helps restore endothelial
integrity by inhibiting nuclear factor-κB (NF-κB), lowering proinflammatory cytokine
production, increasing tight junction proteins, and boosting endothelial nitric oxide
synthase (eNOS) activity—mechanisms that collectively prevent thrombosis and edema.
The intestinal barrier, maintained by tight junctions and gut microbiota, is essential
for nutrient absorption and mucosal immune defense. During critical illness, gut dysbiosis—marked
by a depletion of beneficial commensals and overgrowth of pathogenic species—compromises
barrier integrity, increases intestinal permeability, and promotes bacterial translocation.
GC–GRα signaling plays a key role in preserving the intestinal barrier by regulating
tight junctions, lowering permeability, and affecting microbiota composition. Combining
GC therapy with microbiota-focused interventions offers hope for reducing inflammation,
supporting recovery, and improving survival in critically ill patients.
Keywords
critical illness - glucocorticoid receptor-α - endothelium - intestinal barrier -
mitochondria - oxidative stress
