Glucocorticoid receptor function is decreased in neutrophils during endotoxic shock

Bergquist, Maria; Jirholt, Pernilla; Nurkkala, Merja; Rylander, Christian; Hedenstierna, Göran; Lindholm, Catharina

doi:10.1016/j.jinf.2014.03.011

Cited by 26 publications

(27 citation statements)

References 41 publications

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“…Most endotoxin-induced and lipopolysaccharide (LPS) injury models have demonstrated decreased ligand affinity and down-regulation of GCR-α expression. [25][26][27][28][29][30][31][32][33][34] There are some animals model of sepsis, however, which have demonstrated down-regulation of GCR-α or decreased ligand affinity and induction of GCR-β expression. 35,36 In the last years, data on GCR expression and critical illness in humans have started evolving and many groups have described glucocorticoid resistance in cohorts of septic patients.…”

Section: Discussionmentioning

confidence: 99%

Decreased glucocorticoid receptor expression during critical illness

Vassiliou

Floros

Jahaj

et al. 2019

Eur J Clin Investigation

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Introduction In critically ill patients, the hypothalamic‐pituitary‐adrenal axis is activated, resulting in increased serum cortisol concentrations. However, in some patients, especially those with sepsis, cortisol levels are relatively low for the degree of illness severity. Therefore, in the present project, we aim to characterize the time course of glucocorticoid receptor (GCR) alpha and beta expression in peripheral polymorphonuclear cells of critically ill septic or nonseptic patients using real‐time PCR. Design A prospective observational study conducted on 32 critically ill adults not receiving steroids, in a university‐affiliated, multidisciplinary intensive care unit (ICU). Blood samples were collected for measurement of glucocorticoid receptor expression within 24‐48 hours of admission to the ICU and at days 4, 8 and 13 after admission, reflecting the acute and chronic phase of the illness. Results During ICU stay, patients expressed over time reduced levels of both GCR‐α and GCR‐β mRNA. More specifically, GCR‐α mRNA expression was decreased fourfold 4 days after admission (P < 0.0001) and remained low up to 2 weeks after admission (P < 0.001). On the other hand, GCR‐β mRNA levels remained stable shortly after admission, but approx. one week after admission, its levels decreased threefold (P < 0.01) and remained reduced up to 2 weeks after admission (P < 0.001). Discussion Our results suggest that critically ill patients have highly variable expression of alpha and beta GCR, and moreover, the levels of both receptors decrease during ICU stay. Taken together, these might explain the differential responsiveness of patients to exogenous steroid administration or to endogenous cortisol secretion.

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Section: Discussionmentioning

confidence: 99%

Decreased glucocorticoid receptor expression during critical illness

Vassiliou

Floros

Jahaj

et al. 2019

Eur J Clin Investigation

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“…For these reasons it is prudent to implement early interventions designed to achieve the following: (i) reinforce innate immunity, (ii) inhibit further systemic tissue damage, (iii) limit the metabolic and bioenergetic cacostatic overload imposed during vital organ support, (iv) accelerate disease resolution, and (v) prevent persistent-chronic low-grade systemic inflammation (285). This approach is supported by experimental (286) and clinical studies in patients with septic shock or ARDS (287)(288)(289)(290).…”

Section: Conclusion and Implications For Glucocorticoid Treatmentmentioning

confidence: 99%

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

Meduri

Chrousos

2020

Front. Endocrinol.

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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.

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“…Liver dysfunction and cell injury induced by neutrophils have been demonstrated in several experimental models including hepatic IR injury[46], endotoxic shock[47], sepsis[48], alcoholic hepatitis[49], obstructive cholestasis[50], LPS injury[51], remote organ trauma[52], and concanavalin A (ConA)-induced liver injury[53]. Neutrophil-mediated injury was also demonstrated in two-hit models of IR injury or drug hepatotoxicity in combination with endotoxemia[54].…”

Section: Mip-2 Mediates Inflammation By Neutrophil Recruitmentmentioning

confidence: 99%

Macrophage inflammatory protein-2 as mediator of inflammation in acute liver injury

Qin

Liu

et al. 2017

WJG

116

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Macrophage inflammatory protein (MIP)-2 is one of the CXC chemokines and is also known as chemokine CXC ligand (CXCL2). MIP-2 affects neutrophil recruitment and activation through the p38 mitogen-activated-protein-kinase-dependent signaling pathway, by binding to its specific receptors, CXCR1 and CXCR2. MIP-2 is produced by a variety of cell types, such as macrophages, monocytes, epithelial cells, and hepatocytes, in response to infection or injury. In liver injury, activated Kupffer cells are known as the major source of MIP-2. MIP-2-recruited and activated neutrophils can accelerate liver inflammation by releasing various inflammatory mediators. Here, we give a brief introduction to the basic molecular and cellular sources of MIP-2, and focus on its physiological and pathological functions in acute liver injury induced by concanavalin A, lipopolysaccharides, irradiation, ischemia/reperfusion, alcohol, and hypoxia, and hepatectomy-induced liver regeneration and tumor colorectal metastasis. Further understanding of the regulatory mechanisms of MIP-2 secretion and activation may be helpful to develop MIP-2-targeted therapeutic strategies to prevent liver inflammation.

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Glucocorticoid receptor function is decreased in neutrophils during endotoxic shock

Cited by 26 publications

References 41 publications

Decreased glucocorticoid receptor expression during critical illness

Decreased glucocorticoid receptor expression during critical illness

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

Macrophage inflammatory protein-2 as mediator of inflammation in acute liver injury

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