Abstract
Glucocorticoid (GC)–activated glucocorticoid receptor α (GRα) signaling—underpins
survival and recovery during severe physiological stress. Rooted in evolution, these
adjustments are not mere damage control; they constitute a coordinated, dynamic, phase-specific
program that integrates metabolic, immune (innate and adaptive), cardiovascular, neuroendocrine,
and organ functions. By boosting mitochondrial energy production and regulating inflammatory
and hemostatic pathways, the GC–GRα axis enables adaptation to the demands of critical
illness. These mechanisms operate across tissues and time to sustain systemic stability.
This program unfolds in three phases. In the priming phase, innate immunity is rapidly
mobilized, bioenergetic reserves are secured, and cardiovascular function is enhanced
to build resilience. With the immediate threat contained, the modulatory phase suppresses
excessive inflammation and oxidative stress and restores and preserves vascular integrity.
In the restorative phase, resolution of injury enables structural and functional repair,
re-establishing tissue architecture and function for long-term recovery. Failure to
enter or complete the modulatory phase prolongs dysregulated responses that impede
recovery. GRα is central: beyond anti-inflammatory actions, it shapes pro-inflammatory
and metabolic programs. Through context-dependent co-regulation with nuclear factor-κB
and activator protein-1, GRα directs cell-specific responses, drives chromatin remodeling,
and orchestrates phase-specific gene expression to maintain a dynamic balance essential
for survival. When transition to the modulatory phase fails, persistent stress signaling
depletes neuroendocrine reserves, impairs bioenergetics, and exhausts key micronutrients,
increasing allostatic load and mortality risk. Clinical modifiers—including critical
illness-related corticosteroid insufficiency (CIRCI), mitochondrial dysfunction, hypovitaminosis,
and oxidative stress—accelerate metabolic strain and decline toward organ failure.
Mechanism-aligned care targeting GRα and synchronizing therapy with recovery phases
enables individualized CIRCI correction, tempering of dysregulated inflammation, and
organ recovery. Recognizing GC–GRα as the coordinator of homeostatic corrections highlights
its evolutionary importance and guides strategies that complement the body's capacity
to restore homeostasis.
Keywords
critical illness - glucocorticoids - GRα - GC–GRα signaling - homeostatic adaptation
- phase-specific response - endothelial homeostasis - NF-κB
