Abstract
In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GRα) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GRα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GRα and mitochondria number and function. Present understanding of the activated GC-GRα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GRα interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.
Highlights
Reviewed by: Alain Couvineau, Institut National de la Santé et de la Recherche Médicale (INSERM), France Richard G
We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection
Hypovitaminosis D is common in critical illness, despite parallel elevations of PTH [249] with one small study reporting a progressive drop in vitamin D levels in the first week of illness [261], while a low 25(OH)D3 status was significantly associated with all-cause and sepsis mortality [236]
Summary
The reasons behind the evolutionary success of mammals and other multicellular organisms is their extraordinary capacity to adapt to changing environmental conditions and survive by maintaining their homeostasis [1]. Translational research indicates that the type of response (regulated or dysregulated) is established early in critical illness [14, 31, 57], and the previously espoused hypotheses of the second-hit model [14, 22], or the two-phase model (compensatory anti-inflammatory response syndrome) are both considered obsolete [29, 58, 59] Based on this pathophysiological construct, we will focus on emerging evidence indicating the central role played by the activated glucocorticoid receptor-alpha (GRα), the master regulator of NF-κB and homeostatic corrections, in the development and resolution of critical illness. As downregulation of systemic and tissue inflammation continues, the activated GC-GRα engages in a host of pro-resolution mechanisms changing, among others, the phenotype of both granulocytes and macrophages In these immune cells, via genomic mechanisms, GC-GRα increases the expression of AnnexinA1 (AnxA1), AnxA1 receptor (ALXR), and glucocorticoid-induced leucine zipper (GILZ), while via non-genomic mechanisms it increases the secretion of AnxA1. In agreement with microarray data, spontaneous, as well as PMA-induced production of reactive oxygen species, was significantly reduced in GC-treated cells, and GCs promoted survival of an anti-inflammatory monocytic phenotype in inflammatory reactions [113]
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