Glucocorticoid Action Research Articles

Sunk costs under stress: Acute stress reduces the impact of past expenses on risky decisions

Rational choice should be guided solely by the prospects of available options. However, our decisions are often influenced by irrecoverable past costs, even when the current course of action turns out to be unfavorable, reflecting a cognitive bias known as the “sunk-cost effect”. In everyday life, many decisions are made under stress or elicit stress themselves. Whether and how stress impacts the sunk-cost effect, however, is not known. Based on evidence suggesting that the sunk-cost effect critically depends on the dorsolateral prefrontal cortex, which in turn is highly sensitive to stress, we hypothesized that stress may reduce the influence of past expenses on current decisions. Participants underwent a psychosocial stress manipulation or control procedure, before we assessed their sunk-cost tendency in a monetary investment task. Overall, participants showed a pronounced sunk-cost effect, particularly for options with low expected value. Acute stress reduced this tendency to invest in risky options with low probability of success following high prior investments. Moreover, the strength of this reduction of the sunk-cost effect was predicted by individual cortisol reactivity. These findings show that acute stress may reduce the impact of past expenses on current choice and that this effect may be mediated by glucocorticoid action.

Effects of tyrosine kinase inhibitors on androgen, estrogen α, glucocorticoid and thyroid receptors

Modern anticancer therapies favor a targeted approach. Tyrosine kinase inhibitors (TKIs) are drugs that target molecular pathways involved in various types of malignancies. Although TKIs are safe and well tolerated, they remain not completely selective; e.g., endocrine-mediated adverse events have been observed with their use. In the present study, the effects of seven TKIs were determined on the activities of androgen receptor, estrogen receptor α (ERα), glucocorticoid receptor and thyroid receptor in vitro using stably transfected cell lines expressing firefly luciferase reporter gene: AR-EcoScreen, hERα-HeLa9903, MDA-kb2, and GH3.TRE-Luc cells, respectively. Antiandrogenic activity was seen for erlotinib, estrogenic activity for imatinib, antiestrogenic activity for dasatinib, erlotinib, nilotinib, regorafenib and sorafenib, glucocorticoid activity for erlotinib and ibrutinib, antiglucocorticoid activity for regorafenib and sorafenib, and antithyroid activity for ibrutinib. Additionally, synergism was seen for 1–5 μM dasatinib and 500 nM hydrocortisone combination for glucocorticoid activity in MDA-kb2 cells. The estrogenic activity of imatinib was confirmed as mediated through ERα, and interference of the TKIs with the reporter gene assays was ruled out in a cell-lysate-based firefly luciferase enzyme inhibition assay. Imatinib in combination with 4-hydroxytamoxifen showed concentration-dependent effects on the metabolic activity of ERα-expressing AN3CA, MCF-7, and SKOV3 cells, and on cell proliferation and adhesion of MCF-7 cells. These findings contribute to the understanding of the endocrine effects of TKIs, in terms of toxicity and effectiveness, and define the need to further evaluate the endocrine disrupting activities of TKIs to safeguard human and environmental health.

EFFECTS OF LONG-TERM USE OF ETONOGESTREL CONTRACEPTIVE IMPLANT: LITERATURE REVIEW

Implantable contraceptives are a long-term birth control option for women. However, contraceptive implants are not suitable for everyone. One of the contraceptive implants that is often used is etonogestrel. Etonogestrel is a progestin, or synthetic progestogen, and is therefore an agonist of the progesterone receptor, the biological target of progestogens such as progesterone. It works by stopping ovulation, thickening the mucus around the cervical opening, and changing the lining of the uterus. It has very weak androgenic and glucocorticoid activity and no other important hormonal activity. The purpose of this study was to determine the side effects of long-term use of the etonogestrel implant contraceptive through a literature study. The three databases used are Pubmed, ScienceDirect, and Scopus in this study. The literature search was carried out after the PICO was determined and used the keywords “Effect”, “Etonogestrel Contraceptive Implant”, “Long Term”. Based on the analysis of the 11 articles obtained in this study, it can be concluded that the Etonogestrel Implant Contraceptive is a safe and effective contraceptive method for use in women of childbearing age. Even so, etonogestrel has side effects such as menstrual irregularities, breast tenderness, mood swings, acne, headaches, vaginitis

Restrained expression of canine glucocorticoid receptor splice variants \u03b1 and P prognosticates fatal disease outcome in SIRS

Glucocorticoids play a central role in the inflammatory response and alleviate the symptoms in critically ill patients. The glucocorticoid action relies on the glucocorticoid receptor (GR) which translocates into the nucleus upon ligand-binding and regulates transcription of a battery of genes. Although the GR is encoded by a single gene, dozens of its splice variants have been described in diverse species. The GRα isoform encodes the full, functionally active protein that is composed of a transactivation, a DNA-binding, and a C-terminal ligand-binding domain. The second most highly expressed receptor variant, the GR-P, is formed by an intron retention that introduces an early stop codon and results in a probably dysfunctional protein with truncated ligand-binding domain. We described the canine ortholog of GR-P and showed that this splice variant is highly abundant in the peripheral blood of dogs. The level of cGRα and cGR-P transcripts are elevated in patients of SIRS and the survival rate is increased with elevated cGRα and cGR-P expression. The ratio of cGRα and cGR-P mRNA did not differ between the survivor and non-survivor patients; thus, the total GR expression is more pertinent than the relative expression of GR isoforms in assessment of the disease outcome.

Repeated exposure with short-term behavioral stress resolves pre-existing stress-induced depressive-like behavior in mice

Chronic stress induces adaptive changes in the brain via the cumulative action of glucocorticoids, which is associated with mood disorders. Here we show that repeated daily five-minute restraint resolves pre-existing stress-induced depressive-like behavior in mice. Repeated injection of glucocorticoids in low doses mimics the anti-depressive effects of short-term stress. Repeated exposure to short-term stress and injection of glucocorticoids activate neurons in largely overlapping regions of the brain, as shown by c-Fos staining, and reverse distinct stress-induced gene expression profiles. Chemogenetic inhibition of neurons in the prelimbic cortex projecting to the nucleus accumbens, basolateral amygdala, or bed nucleus of the stria terminalis results in anti-depressive effects similarly to short-term stress exposure, while only inhibition of neurons in the prelimbic cortex projecting to the bed nucleus of the stria terminalis rescues defective glucocorticoid release. In summary, we show that short-term stress can reverse adaptively altered stress gains and resolve stress-induced depressive-like behavior.

Modulation by Ozone of Glucocorticoid-Regulating Factors in the Lungs in Relation to Stress Axis Reactivity.

Exposure to air pollutants increases levels of circulating glucocorticoid stress hormones that exert profound effects relevant to health and disease. However, the nature and magnitude of tissue-level effects are modulated by factors that regulate local glucocorticoid activity; accordingly, inter-individual differences could contribute to susceptibility. In the present study, we characterized effects of ozone (O3) inhalation on glucocorticoid-regulating factors in the lungs of rat strains with contrasting hypothalamic–pituitary–adrenal stress axis responses. Hyper-responsive Fischer (F344) and less responsive Lewis (LEW) rats were exposed to air or 0.8 ppm O3 for 4 h by nose-only inhalation. Levels of the high-specificity and -affinity corticosteroid-binding globulin protein increased in the lungs of both strains proportional to the rise in corticosterone levels following O3 exposure. Ozone reduced the ratio of 11β-hydroxysteroid dehydrogenase type 1 (HSDB1)/HSDB2 mRNA in the lungs of F344 but not LEW, indicating strain-specific transcriptional regulation of the major glucocorticoid metabolism factors that control tissue-level action. Intercellular adhesion molecule (ICAM)-1 and total elastase activity were increased by O3 in both strains, consistent with extravasation and tissue remodeling processes following injury. However, mRNA levels of inflammatory markers were significantly higher in the lungs of O3-exposed LEW compared to F344. The data show that strain differences in the glucocorticoid response to O3 are accompanied by corresponding changes in regulatory factors, and that these effects are collectively associated with a differential inflammatory response to O3. Innate differences in glucocorticoid regulatory factors may modulate the pulmonary effects of inhaled pollutants, thereby contributing to differential susceptibility.

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models.

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is, therefore, critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (HSD11B1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive HSD11B1 activity and amplification of local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and ageing-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated mechanisms by which glucocorticoids exert their metabolic effects and have guided us towards more targeted future treatments for metabolic diseases.

Assessment of Plasma-Free Cortisol Concentrations by LC-MS/MS in Patients with Autonomous Cortisol Secretion.

Autonomous cortisol secretion (ACS) of an adrenal incidentaloma (AI) is associated with mild cortisol excess that could result in poor metabolic and cardiovascular outcomes. The biological activity of glucocorticoids depends on the unbound, free fraction. We aimed to evaluate plasma free cortisol (FC) concentrations in patients with ACS in this cross-sectional study. One hundred and ten AI patients in 3 groups; non-functioning (NFA, n=33), possible ACS (n=65), ACS (n=12) were enrolled. Following measurements were conducted: Clinical data and total serum cortisol (TC), plasma corticotrophin (ACTH), serum dehydroepiandrosterone sulfate (DHEA-S), cortisol after 1 mg dexamethasone by both immunoassay and LC-MS/MS (DexF), serum corticosteroid binding globulin (CBG), plasma dexamethasone concentration [DEX] and plasma FC by LC-MS/MS. Patients with ACS featured an unfavorable metabolic profile. Plasma [DEX] and serum CBG levels were similar between groups. Plasma FC was significantly higher in ACS when compared to NFA and possible ACS groups p<0.05 and p<0.01, respectively. In multiple regression analysis DexF (beta=0.402, p<0.001) and CBG (beta=-0.257, p=0.03) remained as the independent predictors of plasma FC while age, sex, BMI, smoking habit, and existing cardiovascular disease did not make a significant contribution to the regression model. In conclusion, the magnitude of cortisol excess in ACS could lead to increased plasma FC concentrations. Further studies in AI patients are needed to demonstrate whether any alterations of cortisol affinity for CBG exist and to establish whether plasma FC concentrations predict the unfavorable metabolic profile in ACS.

Corticosteroid Resistant Pulmonary Fibrosis: Pathophysiology and Management

Pulmonary fibrosis is a disease of the lower respiratory system. It might be as Idiopathic fibrosis which is obscure reason for disease or might be as an optional impact from different causes, for example, the environmental causes, for example, toxins and smoking, some connective tissue illnesses., infection diseases, for example, tuberculosis (TB) and corona virus, a few medications, for example, bleomycin, methotrexate, and radiation treatment. Glucocorticoid are used for treating inflammatory and immune diseases, like asthma, but interstitial lung disease, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) at some stage, may become resistant to corticosteroid treatment. Glucocorticoids inhibit inflammation by many mechanisms. The oxidative stress leads to significantly decrease in activity and expression of Histone deacetylase 2 (HDAC-2) which causes resistant to the action of glucocorticoid. However, the dissociated glucocorticoids have been developed to decrease side effects, the dissociated glucocorticoid receptor agonists (DIGRAs) are a class of experimental drugs designed to share many of the desirable anti-inflammatory, immunosuppressive, or anticancer properties of classical glucocorticoid drugs with fewer side effects, but it is so difficult to dissociate anti-inflammatory effects from adverse effects. Patients with glucocorticoid resistance must use alternative anti-inflammatory treatments as well as drugs that may reverse the molecular mechanism of glucocorticoid resistant. Objective: This paper is to review the corticosteroid resistant pulmonary fibrosis and how overcome this resistance.&#x0D; The data was collected from December 2020 to September 2021.

Disruption of Glucocorticoid Action on CD11c+ Dendritic Cells Favors the Generation of CD4+ Regulatory T Cells and Improves Fetal Development in Mice.

A wealth of innate and adaptive immune cells and hormones are involved in mounting tolerance towards the fetus, a key aspect of successful reproduction. We could recently show that the specific cross talk between the pregnancy hormone progesterone and dendritic cells (DCs) is significantly engaged in the generation of CD4+ FoxP3+ regulatory T (Treg) cells while a disruption led to placental alterations and intra-uterine growth restriction. Apart from progesterone, also glucocorticoids affect immune cell functions. However, their functional relevance in the context of pregnancy still needs clarification. We developed a mouse line with a selective knockout of the glucocorticoid receptor (GR) on DCs, utilizing the cre/flox system. Reproductive outcome and maternal immune and endocrine adaptation of Balb/c-mated C57Bl/6 GRflox/floxCD11ccre/wt (mutant) females was assessed on gestation days (gd) 13.5 and 18.5. Balb/c-mated C57Bl/6 GRwt/wtCD11ccre/wt (wt) females served as controls. The number of implantation and fetal loss rate did not differ between groups. However, we identified a significant increase in fetal weight in fetuses from mutant dams. While the frequencies of CD11c+ cells remained largely similar, a decreased expression of co-stimulatory molecules was observed on DCs of mutant females on gd 13.5, along with higher frequencies of CD4+ and CD8+ Treg cells. Histomorphological and gene expression analysis revealed an increased placental volume and an improved functional placental capacity in mice lacking the GR on CD11c+ DCs. In summary, we here demonstrate that the disrupted communication between GCs and DCs favors a tolerant immune microenvironment and improves placental function and fetal development.

Pituitary-Adrenal Responses and Glucocorticoid Receptor Expression in Critically Ill Patients with COVID-19.

The hypothalamus–pituitary–adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR).

Glucocorticoid Production, Activity Levels, And Personality Traits Of Fennec Foxes (Vulpes zerda) Managed For Different Roles In Zoos

ABSTRACT Fecal glucocorticoid metabolite (FGM) concentrations, activity, and personality were assessed for 35 fennec foxes (Vulpes zerda) to determine whether animals managed as ambassadors differed from exhibit or off-exhibit animals. A FGM assay, pedometer, and personality assessment tool were validated. Then, fecal samples and movement data were collected during winter and summer periods. Handling was recorded, and the personality of each fox was evaluated. Generalized linear mixed models assessed the relationships between FGM concentrations, activity, personality, handling, sex, season, rearing type, and role. FGM concentrations did not differ in relation to role or handling. Foxes were most active at night; the time of peak activity did not vary with role or handling. Foxes were more active in winter; males were more active than females, and ambassador foxes were more active than off-exhibit animals. Hand-reared foxes were more sociable, and, at one institution, ambassador foxes were more sociable than foxes in other roles. These results suggest that management for ambassador programs is not associated with changes in glucocorticoid production or circadian patterns but may increase activity and be associated with greater sociability.

The Impact of Glucocorticoid Therapy on Guideline-Directed Medical Treatment Titration in Patients Hospitalized for Heart Failure with Low Blood Pressure: A Retrospective Study.

BackgroundPositive inotropic and renal protective actions of glucocorticoids have been observed clinically. Therefore, glucocorticoids may be used in patients with heart failure and low blood pressure (HF-LBP).MethodsThe medical records of 144 consecutive patients with HF-LBP who received glucocorticoids as an adjunctive treatment to facilitate the up-titration of β-blocker and angiotensin-converting enzyme inhibitor were reviewed.ResultsAfter four weeks of treatment, the metoprolol and captopril (or equivalent) dosages were progressively and consistently increased from 25 (interquartile range [IQR] = 12.5–75 mg/day) to 100 mg/day (IQR = 50–178.8 mg/day) and from 0 (IQR = 0–25 mg/day) to 12.5 mg/day (IQR = 0–50 mg/day), respectively. There was a remarkable beneficial hemodynamic response to the glucocorticoid treatment signified by an increase in blood pressure and decrease in heart rate. The average heart rate decreased by 6 beat per minute (bpm) (0.5–16 bpm), and the mean arterial blood pressure increased from 74.06 ± 7.81 to 78.85 ± 7.91 mmHg. We also observed an improvement in renal function and an increased diuretic response following glucocorticoid treatment. As a result, the left ventricular ejection fraction increased from 28.92 ± 8.06% to 33.86 ± 8.76%, and the diuretic response increased from 776.7 mL/40 mg furosemide (IQR = 133.8–2000 mL) to 4000 mL/40 mg furosemide on day 28 (IQR = 2200–5925 mL).ConclusionThe use of glucocorticoid treatment to maintain hemodynamic and renal functional targets when titrating guideline-directed medical treatment in patients with HF-LBP may be safe, effective, and feasible.

A RARE BUT WORRYING SIDE EFFECT OF MINERALOCORTICOIDS

TOPIC: Education, Research, and Quality Improvement TYPE: Medical Student/Resident Case Reports INTRODUCTION: Corticosteroids are anti-inflammatory drugs that are known to have multiple side effects. Fludrocortisone, a synthetic mineralocorticoid that lacks glucocorticoid effect, is used in the treatment of hypoaldosteronism but like other corticosteroids is not known to have significant catabolic activity. CASE PRESENTATION: A 58 year old male with hypertension, chronic kidney disease (stage 4) and seizure disorder was admitted for management of persistent hyperkalemia. Initially, serum potassium was 6.2 with BUN of 58 and creatinine of 4.3. Physical exam was negative for orthostatic hypotension. Transtubular potassium gradient (TTKG) during hyperkalemia was calculated to be 3 which pointed to the diagnosis of hypoaldosteronism. Fludrocortisone (FD) was initiated, and potassium level was noted to be trending down and renal function improved to baseline. In the following days, serum chemistry revealed a normal potassium level but a significant rise in BUN, reported to be as high as 102mg/dl. During this period estimated glomerular filtration rate (eGFR) continued to be at baseline, between 20 and 22. Other factors that can cause uremia were ruled out and it was decided to discontinue FD. A significant drop in BUN level was observed, reaching as low as 60. After FD was stopped, a subsequent rise in potassium level was seen which resolved with dietary modifications. DISCUSSION: Fludrocortisone (FD) is a potent mineralocorticoid but has a weak glucocorticoid activity, hence is not known to cause uremia. It is known for treating chronic hyperkalemia in patients with hypoaldosteronism and interdialytic hyperkalemia in ESRD patients. According to a study by Norcliffe-Kaufmann et al., it was reported that patients with FD were found to have higher BUN levels compared to control subjects. For our patient`s persistent hyperkalemia due to hypoaldosteronism, FD was started but subsequently a significant rise in BUN, without changes in renal function, was observed. Uremia can cause debilitating symptoms like extreme fatigue, loss of appetite, headache, nausea and vomiting. In our case, after FD was discontinued a marked drop in BUN and a concomitant increase in potassium were seen. Patient was counseled for strict adherence to low potassium diet which resolved his problem. CONCLUSIONS: In conclusion, since FD has concerning side effects, it should be prescribed with caution in patients with CKD and serial serum chemistry should be followed for abnormalities. Patients, who are taking FD, presenting with uremia and stable renal function should have FD use investigated as one of the underlying cause. For persistent hyperkalemia, other interventions like dietary modification and/or potassium binder can be considered since FD can cause other abnormalities. REFERENCE #1: Dobbin, S., Petrie, J. R., Lean, M., & McKay, G. A. (2017). Fludrocortisone therapy for persistent hyperkalaemia. Diabetic medicine : a journal of the British Diabetic Association, 34(7), 1005–1008. https://doi.org/10.1111/dme.13359 REFERENCE #2: Disorders of Potassium Metabolism. (2011, January 1). ScienceDirect. https://linkinghub.elsevier.com/retrieve/pii/B9781416066408000075 REFERENCE #3: Norcliffe-Kaufmann, L., Axelrod, F. & Kaufmann, H. Developmental abnormalities, blood pressure variability and renal disease in Riley Day syndrome. J Hum Hypertens 27, 51–55 (2013). https://doi.org/10.1038/jhh.2011.107 DISCLOSURES: no disclosure on file for Kisra Anis; no disclosure on file for Zinobia Khan; No relevant relationships by Dileep Kumar, source=Web Response No relevant relationships by Shahzad Shallwani, source=Web Response

Glucocorticoids regulate mitochondrial fatty acid oxidation in fetal cardiomyocytes

The late gestational rise in glucocorticoids contributes to the structural and functional maturation of the perinatal heart. Here, we hypothesized that glucocorticoid action contributes to the metabolic switch in perinatal cardiomyocytes from carbohydrate to fatty acid oxidation. In primary mouse fetal cardiomyocytes, dexamethasone treatment induced expression of genes involved in fatty acid oxidation and increased mitochondrial oxidation of palmitate, dependent upon a glucocorticoid receptor (GR). Dexamethasone did not, however, induce mitophagy or alter the morphology of the mitochondrial network. In vivo, in neonatal mice, dexamethasone treatment induced cardiac expression of fatty acid oxidation genes. However, dexamethasone treatment of pregnant C57Bl/6 mice at embryonic day (E)13.5 or E16.5 failed to induce fatty acid oxidation genes in fetal hearts assessed 24h later. Instead, at E17.5, fatty acid oxidation genes were downregulated by dexamethasone, as was GR itself. PGC-1α, required for glucocorticoid-induced maturation of primary mouse fetal cardiomyocytes in vitro, was also downregulated in fetal hearts at E17.5, 24h after dexamethasone administration. Similarly, following a course of antenatal corticosteroids in a translational sheep model of preterm birth, both GR and PGC-1α were downregulated in heart. These data suggest that endogenous glucocorticoids support the perinatal switch to fatty acid oxidation in cardiomyocytes through changes in gene expression rather than gross changes in mitochondrial volume or mitochondrial turnover. Moreover, our data suggest that treatment with exogenous glucocorticoids may interfere with normal fetal heart maturation, possibly by downregulating GR. This has implications for clinical use of antenatal corticosteroids when preterm birth is considered a possibility. KEY POINTS: Glucocorticoids are steroid hormones that play a vital role in late pregnancy in maturing fetal organs, including the heart. In fetal cardiomyocytes in culture, glucocorticoids promote mitochondrial fatty acid oxidation, suggesting they facilitate the perinatal switch from carbohydrates to fatty acids as the predominant energy substrate. Administration of a synthetic glucocorticoid in late pregnancy in mice downregulates the glucocorticoid receptor and interferes with the normal increase in genes involved in fatty acid metabolism in the heart. In a sheep model of preterm birth, antenatal corticosteroids (synthetic glucocorticoid) downregulates the glucocorticoid receptor and the gene encoding PGC-1α, a master regulator of energy metabolism. These experiments suggest that administration of antenatal corticosteroids in anticipation of preterm delivery may interfere with fetal heart maturation by downregulating the ability to respond to glucocorticoids.

Anti-inflammatory activity of lefamulin versus azithromycin and dexamethasone in vivo and in vitro in a lipopolysaccharide-induced lung neutrophilia mouse model.

Several antibiotics demonstrate both antibacterial and anti-inflammatory/immunomodulatory activities and are used to treat inflammatory pulmonary disorders. Lefamulin is a pleuromutilin antibiotic approved to treat community-acquired bacterial pneumonia (CABP). This study evaluated lefamulin anti-inflammatory effects in vivo and in vitro in a lipopolysaccharide-induced lung neutrophilia model in which mouse airways were challenged with intranasal lipopolysaccharide. Lefamulin and comparators azithromycin and dexamethasone were administered 30min before lipopolysaccharide challenge; neutrophil infiltration into BALF and inflammatory mediator induction in lung homogenates were measured 4h postchallenge. Single subcutaneous lefamulin doses (10‒140mg/kg) resulted in dose-dependent reductions of BALF neutrophil cell counts, comparable to or more potent than subcutaneous azithromycin (10‒100mg/kg) and oral/intraperitoneal dexamethasone (0.5/1mg/kg). Lipopolysaccharide-induced pro-inflammatory cytokine (TNF-α, IL-6, IL-1β, and GM-CSF), chemokine (CXCL-1, CXCL-2, and CCL-2), and MMP-9 levels were significantly and dose-dependently reduced in mouse lung tissue with lefamulin; effects were comparable to or more potent than with dexamethasone or azithromycin. Pharmacokinetic analyses confirmed exposure-equivalence of 30mg/kg subcutaneous lefamulin in mice to a single clinical lefamulin dose to treat CABP in humans (150mg intravenous/600mg oral). In vitro, neither lefamulin nor azithromycin had any relevant influence on lipopolysaccharide-induced cytokine/chemokine levels in J774.2 mouse macrophage or human peripheral blood mononuclear cell supernatants, nor were any effects observed on IL-8‒induced human neutrophil chemotaxis. These in vitro results suggest that impediment of neutrophil infiltration by lefamulin in vivo may not occur through direct interaction with macrophages or neutrophilic chemotaxis. This is the first study to demonstrate inhibition of neutrophilic lung infiltration and reduction of pro-inflammatory cytokine/chemokine concentrations by clinically relevant lefamulin doses. This anti-inflammatory activity may be beneficial in patients with acute respiratory distress syndrome, cystic fibrosis, or severe inflammation-mediated lung injury, similar to glucocorticoid (eg, dexamethasone) activity. Future lefamulin anti-inflammatory/immunomodulatory activity studies are warranted to further elucidate mechanism of action and evaluate clinical implications.

Glucocorticoid circadian rhythms in immune function.

Adrenal glucocorticoid (GC) hormones are important regulators of energy metabolism, brain functions, and the immune system. Their release follows robust diurnal rhythms and GCs themselves serve as entrainment signals for circadian clocks in various tissues. In the clinics, synthetic GC analogues are widely used as immunosuppressive drugs. GC inhibitory effects on the immune system are well documented and include suppression of cytokines and increased immune cell death. However, the circadian dynamics of GC action are often neglected. Synthetic GC medications fail to mimic complex GC natural rhythms. Several recent publications have shown that endogenous GCs and their daily concentration rhythms prepare the immune system to face anticipated environmental threats. That includes migration patterns that direct specific cell population to organs and tissues best exemplified by the rhythmic expression of chemoattractants and their receptors. On the other hand, chronotherapeutic approaches may benefit the treatment of immunological diseases such as asthma. In this review, we summarise our current knowledge on the circadian regulation of GCs, their role in innate and adaptive immune functions and the implications for the clinics.

Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways.

Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential.

11βHSD2 Efficacy in Preventing Transcriptional Activation of the Mineralocorticoid Receptor by Corticosterone.

Affinity of the mineralocorticoid receptor (MR) is similar for aldosterone and the glucocorticoids (GC) cortisol and corticosterone, which circulate at concentrations far exceeding those of aldosterone. 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) inactivation of GC within the immediate vicinity of the MR is credited with prereceptor specificity for aldosterone in cells coexpressing MR and 11βHSD2. 11βHSD2 efficacy is also critical to other recently described 11βHSD2 substrates. The aim of this work was to address doubts that low levels of expression of 11βHSD2 in aldosterone target tissues suffice to prevent the initiation of gene transcription by the MR activated by physiological concentrations of corticosterone. Cell models stably expressing an MR/Gaussia luciferase reporter and various levels of constitutive or induced 11βHSD2 at concentrations lower than those in rat kidney homogenates and microsomes were produced. Aldosterone and corticosterone were equipotent transactivators of the MR reporter gene in cells without 11βHSD2. Rate of conversion of tritiated corticosterone to 11-dehydrocorticosterone increased and corticosterone-induced nuclear translocation of MR decreased, as 11βHSD2 expression increased. The 50% maximal MR activation for the reporter gene stimulation by corticosterone rose with increasing 11βHSD2 expression, shifting the steroid dose-response curve for corticosterone-induced MR transactivation to the right. Several stable cell lines expressing an easily and reproducibly measured MR reporter system and consistent incremental amounts of 11βHSD2 protein were produced and used to document that 11βHSD2 within low physiological levels inactivates relevant concentrations of GC and decreases MR transactivation by GC in a dose-dependent fashion, laying to rest doubts of the efficacy of this enzyme.

GLCCI1 Deficiency Induces Glucocorticoid Resistance via the Competitive Binding of IRF1:GRIP1 and IRF3:GRIP1 in Asthma.

GLCCI1 plays a significant role in modulating glucocorticoid (GC) sensitivity in asthma. This project determines the underlying mechanism that GLCCI1 deficiency attenuates GC sensitivity in dexamethasone (Dex)-treated Ovalbumin (OVA)-induced asthma mice and epithelial cells through upregulating binding of IRF1:GRIP1 and IRF3:GRIP1. Dexamethasone treatment led to less reduced inflammation, airway hyperresponsiveness, and activation of the components responsible for GC activity, as determined by decreased GR and glucocorticoid receptor interacting protein 1 (GRIP1) expression but augmented IRF1 and IRF3 expression in GLCCI1−/− asthmatic mice compared with wild type asthmatic mice. Moreover, the recruitment of GRIP1 to GR was downregulated, while the individual recruitment of GRIP1 to IRF1 and IRF3 was upregulated in GLCCI1−/− Dex-treated asthmatic mice compared to wild type Dex-treated asthmatic mice. We also found that GLCCI1 knockdown reduced GR and GRIP1 expression but increased IRF1 and IRF3 expression in Beas2B and A549 cells. Additionally, GLCCI1 silencing increased the interactions between GRIP1 with IRF1 and GRIP1 with IRF3, but decreased the recruitment of GRIP1 to GR. These studies support a critical but previously unrecognized effect of GLCCI1 expression on epithelial cells in asthma GC responses by which GLCCI1 deficiency reduces the GR and GRIP1 interaction but competitively enhances the recruitment of GRIP1 to IRF1 and IRF3.