Page 1408 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 102: Critical Illness–Related Corticosteroid Insufficiency 981

the associated genes (see Fig. 102-2). In addition, the cortisol-GR com- effects of cortisol include an increase in blood glucose concentrations
plex may affect cellular function indirectly by binding to and modulat- through the activation of key enzymes involved in hepatic gluconeo-
ing the transcriptional activity of other nuclear transcription factors genesis and inhibition of glucose uptake in peripheral tissues such as
such as nuclear factor κB (NF-κB) and activator protein-1 (AP-1). the skeletal muscles. In addition, in adipose tissue, lipolysis is activated
Overall, glucocorticoids effect the transcription of thousands of genes in resulting in the release of free fatty acids into the circulation. Cortisol
every cell of the body. It has been estimated that glucocorticoids affect also has a permissive effect on other hormones increasing glucose levels,
20% of the genome of mononuclear blood cells. 13 including catecholamines and glucagon. Sustained cortisol hypersecre-
Glucocorticoids play a major role in regulating the activity of NF-κB tion stimulates glucose production at the expense of protein and lipid
which plays a crucial and generalized role in inducing cytokine gene catabolism and insulin resistance.
transcription. 14-16 NF-κB is normally maintained in an inactive form by Cortisol increases blood pressure through several mechanisms
sequestration in the cytoplasm through interaction with inhibitory pro- involving the kidney and vasculature. In vascular smooth muscle,
teins (IκBs). Upon stimulation by lipopolysaccharide, double-stranded cortisol increases sensitivity to vasopressor agents such as catechol-
DNA, physical and chemical stresses, and inflammatory cytokines, the amines and angiotensin II. 19,20 These effects are mediated partly by
latent NF-κB/IκB complex is activated by phosphorylation and proteo- the increased transcription and expression of the receptors for these
lytic degradation of IκB, with exposure of the NF-κB nuclear localization hormones. 19,20 While the effect of glucocorticoids on nitric oxide (NO)
sequence. The liberated NF-κB then translocates to the nucleus and is complex, it appears to increase endothelial nitric oxide synthetase
binds to promoter regions of target genes to initiate the transcription of (eNOS), thereby maintaining microvascular perfusion. 21-24 Cortisol
multiple cytokines including TNF- α, IL-1, and IL-6 and cell adhesion has potent anti-inflammatory actions including the reduction in the
molecules (eg, ICAM-1, E-selectin) and other mediators of inflammation. number and function of various immune cells, such as T and B lympho-
Glucocorticoids inhibit the activity of NF-κB by increasing the transcrip- cytes, monocytes, neutrophils, and eosinophils at sites of inflammation.
tion of IκBs and by directly binding to and inhibiting NF-κB. 15,16 Cortisol decreases the production of cytokines, chemokines, and
Cortisol has several important physiologic actions on metabolism, eicosanoids and enhances the production of macrophage migration
cardiovascular function, and the immune system. 17,18 The metabolic inhibitory factor. 25,26

Cortisol T cell receptor

HSP90
FKBP51
GR Cortisone LCK FYN
FKBP52
Suppressed TCR signalling PKC/MAPK pathways
Type 2 11 hydroxysteroid
dehydrogenase Annexin-1
GR
NF- B
cPLA2
NF- B

CBP
AP-1 and NF- B
PI3K/PKB pathway
trans-activation trans-repression
eNOS

cis-repression

Decreased inflammatory
GRE Negative GRE mediators Non-genomic effects
Annexin-1 POMC Cytokines Annexin 1 externalization
SLPI CRF-1 Chemokines Phosphotyrosine kinases
MKP-1 Osteocalcin Adhesion molecules eNOS
I B- Keratin Inflammatory enzymes TCR signalling
GILZ Inflammatory proteins NF- B
FIGURE 102-2. An overview of the mechanisms of action of glucocorticoids. CBP, cyclic AMP response element binding (CREB) binding protein; cPLA2α, cytosolic phospholipase A2 alfa;
eNOS, endothelial nitric oxide synthetase; FKBP51/52, FK-binding protein 51/52; FYN, FYN oncogene–related kinase; GILZ, glucocorticoid-induced leucine zipper protein; GRα, glucocorticoid
receptor α; Grβ, glucocorticoid receptor β; HSP90, heat shock protein 90; LCK, lymphocyte-specific protein tyrosine kinase; MAPK, mitogen-activated protein kinases; MKP-1, MAPK phospha-
tase 1; NF-κB, nuclear factor kappa B; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; PKC, protein kinase C; POMC, proopiomelanocortin; SLPI, secretory leukoprotease inhibitor.
(Reproduced with permission from Marik PE. Critical illness related corticoseroid insufficiency. Chest. January 2009;135(1):181-193.)

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