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      Glucocorticoid receptor expression on circulating leukocytes in healthy and asthmatic adolescents in response to exercise

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          Abstract

          Background

          Poor aerobic fitness is associated with worsening of asthma symptoms and fitness training may improve asthma control. The mechanism linking fitness with asthma is not known. We hypothesized that repeated bouts of exercise would lead to a downregulation of glucocorticoid receptor (GR) expression on circulating leukocytes reflecting a reduced responsiveness to stress.

          Methods

          In a prospective exercise training intervention of healthy and asthmatic adolescents, GR expression in leukocytes was measured using flow cytometry in response to a brief exercise challenge before and after the training intervention. PBMC gene expression of GR, GRβ, HSP70, and TGFβ1, 2 were determined using RT-PCR.

          Results

          Peak V̇O 2 increased by 14.6 ± 2.3% indicating an effective training (p<0.01). There was a significant difference in GR expression among leukocyte subtypes, with highest expression in eosinophils. Following the training intervention, there was a significant decrease in baseline GR expression (p<0.05) in leukocyte and monocyte subtypes in both healthy and asthmatic adolescents.

          Conclusions

          This is the first study in adolescents to show that exercise training reduces GR expression on circulating leukocytes. We speculate that exercise training downregulates the stress response in general, manifested by decreased GR expression, and may explain why improving fitness improves asthma health.

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          Most cited references40

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          Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk.

          We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.
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            An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction.

            Exercise-induced bronchoconstriction (EIB) describes acute airway narrowing that occurs as a result of exercise. EIB occurs in a substantial proportion of patients with asthma, but may also occur in individuals without known asthma. To provide clinicians with practical guidance, a multidisciplinary panel of stakeholders was convened to review the pathogenesis of EIB and to develop evidence-based guidelines for the diagnosis and treatment of EIB. The evidence was appraised and recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Recommendations for the treatment of EIB were developed. The quality of evidence supporting the recommendations was variable, ranging from low to high. A strong recommendation was made for using a short-acting β(2)-agonist before exercise in all patients with EIB. For patients who continue to have symptoms of EIB despite the administration of a short-acting β(2)-agonist before exercise, strong recommendations were made for a daily inhaled corticosteroid, a daily leukotriene receptor antagonist, or a mast cell stabilizing agent before exercise. The recommendations in this Guideline reflect the currently available evidence. New clinical research data will necessitate a revision and update in the future.
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              Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles.

              The glucocorticoid receptor (GR), like many signaling proteins, depends on the Hsp90 molecular chaperone for in vivo function. Although Hsp90 is required for ligand binding in vivo, purified apo GR is capable of binding ligand with no enhancement from Hsp90. We reveal that Hsp70, known to facilitate client delivery to Hsp90, inactivates GR through partial unfolding, whereas Hsp90 reverses this inactivation. Full recovery of ligand binding requires ATP hydrolysis on Hsp90 and the Hop and p23 cochaperones. Surprisingly, Hsp90 ATP hydrolysis appears to regulate client transfer from Hsp70, likely through a coupling of the two chaperone's ATP cycles. Such coupling is embodied in contacts between Hsp90 and Hsp70 in the GR:Hsp70:Hsp90:Hop complex imaged by cryoelectron microscopy. Whereas GR released from Hsp70 is aggregation prone, release from Hsp90 protects GR from aggregation and enhances its ligand affinity. Together, this illustrates how coordinated chaperone interactions can enhance stability, function, and regulation. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                0100714
                6400
                Pediatr Res
                Pediatr. Res.
                Pediatric research
                0031-3998
                1530-0447
                17 March 2017
                21 June 2017
                August 2017
                29 January 2018
                : 82
                : 2
                : 261-271
                Affiliations
                [1 ]Pediatric Exercise and Genomics Research Center (PERC), Department of Pediatrics, University of California Irvine School of Medicine, Irvine, California
                [2 ]University of Arizona Health Sciences Center, Department of Medicine, Tucson, Arizona
                Author notes
                Corresponding author: Kim D. Lu, 101 Academy Drive, Suite 150, Irvine, CA 92617, Phone: (949) 824-3201, Fax: (949) 824-4149, kdlu@ 123456uci.edu
                Article
                NIHMS858660
                10.1038/pr.2017.66
                5788180
                28796240
                56e4eca3-d8b8-47c1-8780-3ad2eac86956

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                Pediatrics
                Pediatrics

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