Impaired Glucocorticoid Receptor Dimerization Aggravates LPS-Induced Circulatory and Pulmonary Dysfunction

Abstract

Background: Sepsis, that can be modeled by LPS injections, as an acute systemic inflammation syndrome is the most common cause for acute lung injury (ALI). ALI induces acute respiratory failure leading to hypoxemia, which is often associated with multiple organ failure (MOF). During systemic inflammation, the hypothalamus-pituitary-adrenal axis (HPA) is activated and anti-inflammatory acting glucocorticoids (GCs) are released to overcome the inflammation. GCs activate the GC receptor (GR), which mediates its effects via a GR monomer or GR dimer. The detailed molecular mechanism of the GR in different inflammatory models and target genes that might be crucial for resolving inflammation is not completely identified. We previously observed that mice with attenuated GR dimerization (GR dim/dim) had a higher mortality in a non-resuscitated lipopolysaccharide (LPS)-and cecal ligation and puncture (CLP)-induced inflammation model and are refractory to exogenous GCs to ameliorate ALI during inflammation. Therefore, we hypothesized that impaired murine GR dimerization (GR dim/dim) would further impair organ function in LPS-induced systemic inflammation under human like intensive care management and investigated genes that are crucial for lung function in this setup. Methods: Anesthetized GR dim/dim and wildtype (GR +/+) mice were challenged with LPS (10 mg•kg −1 , intraperitoneal) and underwent intensive care management ("lung-protective" mechanical ventilation, crystalloids, and norepinephrine) for 6 h. Lung mechanics and gas exchange were assessed together with systemic hemodynamics, acid-base status, and mitochondrial oxygen consumption (JO 2). Western blots, immunohistochemistry, and real time quantitative polymerase chain reaction were performed to analyze lung tissue and inflammatory mediators were analyzed in plasma and lung tissue. Results: When animals were challenged with LPS and subsequently resuscitated under intensive care treatment, GR dim/dim mice had a higher mortality compared to GR +/+ mice, induced by an increased need of norepinephrine to achieve hemodynamic targets. Wepler et al. Endotoxemic GR dim/dim in Intensive-Care Management After challenge with LPS, GR dim/dim mice also displayed an aggravated ALI shown by a more pronounced impairment of gas exchange, lung mechanics and increased osteopontin (Opn) expression in lung tissue. Conclusion: Impairment of GR dimerization aggravates systemic hypotension and impairs lung function during LPS-induced endotoxic shock in mice. We demonstrate that the GR dimer is an important mediator of hemodynamic stability and lung function, possibly through regulation of Opn, during LPS-induced systemic inflammation.

Glucocorticoids in Sepsis: To Be or Not to Be

“…GR dimerization is also required for survival against LPS- and CLP-induced shock via downregulation of Il-1 β ( 41 ) and upregulation of SphK1 ( 40 ) in macrophages. GR dim/dim mice present impaired lung function upon LPS challenge under intensive care treatment, possibly through regulation of Osteopontin (Opn) in lung tissue ( 49 ). So, GR dimers have the potential to control acute inflammation because they induce dimer-dependent genes, the product of which has anti-inflammatory functions (e.g., SPHK1, MKP1) or by repressing pro-inflammatory genes (e.g., Stat1, Il-1 β) in a dimer-dependent way.…”

“…However, the synthetic GC dexamethasone is able to restore this hyporeactivity to noradrenaline injection, probably resulting from rapid non-genomic effects according to the authors as these effects are seen as early as 10 min after dexamethasone administration ( 67 ). On the other hand, this response seems to be dimer dependent, as GR dim/dim mice display an aggravated hemodynamic instability after LPS challenge, reflected by a significantly increased need for norepinephrine to reach hemodynamic stability ( 49 ). GCs also enhance vasoconstrictor response to catecholamines in septic patients, and this effect was stronger in patients with adrenal insufficiency ( 68 ).…”

The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis

“…Glucocorticoid receptor (GR) signaling is important for normal heart function and development (18). Moreover, we have recently demonstrated that impaired GR dimerization aggravated hemodynamic instability and organ dysfunction during LPS-induced circulatory shock (19). Results for GR expression in peripheral blood cells in sepsis are ambivalent (20,21).…”

Mapping the Multi-Organ miRNA-mRNA Regulatory Network in LPS-Mediated Endotoxemic Mice: Exploring the Shared Underlying Key Genes and Mechanisms

“…Each group included six mice. The control group and LPS group were intraperitoneally injected with PBS and LPS (Sigma, 10 mg/Kg), respectively ( Qi et al, 2016 ; Zhai and Guo, 2016 ; Liu et al, 2017 ; Proniewski et al, 2019 ; Wepler et al, 2019 ). Twelve mice were euthanized, and the samples of the heart, lung, liver, and kidney were harvested at 6 h after LPS or PBS treatment.…”