Reduced glucocorticoid receptor expression and function in airway neutrophils

Plumb, Jonathan; Gaffey, Kate; Kane, Binita; Malia-Milanes, Brendan; Bentley, Andrew; Ray, David; Singh, Dave

doi:10.1016/j.intimp.2011.10.006

Cited by 40 publications

(29 citation statements)

References 35 publications

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“…Our results suggest that neutrophils leaving the bloodstream and entering the lung undergo phenotypic changes, altering the activity of intracellular signalling pathways required for important cell functions. Similarly, we have previously observed normal glucocorticoid receptor expression in blood neutrophils, but depleted glucocorticoid receptor expression in airway neutrophils [35]. These data highlight a potential pitfall of using blood neutrophils as a model for lung neutrophils, as there appear to be differences in the signalling mechanisms responsible for cytokine production.…”

Section: Discussionsupporting

confidence: 79%

“…The lack of activated p38 MAPK observed in lung neutrophils makes it unlikely that p38 MAPK inhibition would have any effect on chemotaxis and superoxide generation in lung neutrophils. The altered phenotype of lung neutrophils, with reduced activation of p38 MAPK and expression of glucocorticoid receptor [35], suggests that specific anti-neutrophil therapies are needed to target this cell type in COPD, rather than broad anti-inflammatory drugs. ) and IL-18 (10 ng?mL -1 ).…”

Section: Discussionmentioning

confidence: 99%

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Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs

et al. 2012

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The p38 mitogen-activated protein kinase (MAPK) pathway is upregulated in chronic obstructive pulmonary disease (COPD). To date, dual labelling to identify cell-type-specific presence of phosphorylated (phospho-)p38 MAPK has not been carried out.Phospho-p38 MAPK was quantified in a variety of cell types in the lung tissue of 20 COPD patients, 12 smokers and 12 nonsmokers using immunohistochemistry. Paired blood and sputum neutrophils (from seven subjects with COPD), and CD8 and epithelial cells (from three subjects with COPD) were cultured with a p38 MAPK inhibitor. Supernatant tumour necrosis factor-a and CXCL8 levels were analysed by ELISA. Sputum and blood neutrophil cytospins were analysed for phospho-p38 MAPK.Phospho-p38 MAPK was increased in bronchial epithelial cells, macrophages and CD20+ and CD8+ lymphocytes in COPD lungs. Sputum and lung tissue neutrophils were devoid of phospho-p38 in all patient groups. The p38 MAPK inhibitor SB100 attenuated pro-inflammatory mediator release in COPD lung CD8 cells and airway epithelia, but there was no effect on COPD sputum neutrophils.Our data indicate cell-specific anti-inflammatory effects of p38 MAPK inhibition in the lung. @ERSpublications p38 MAPK inhibition causes cell-specific anti-inflammatory effects in the lung

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs

et al. 2012

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“…A high amount of glucocorticoid receptors in neutrophils enables them to reduce their apoptosis rate in response to dexamethasone [28]. A reduced glucocorticoid receptor expression may lead to a reduced effect of glucocorticoids on neutrophil CXCL8 production [29]. Increased levels of cortisol may inhibit neutrophil superoxide release [30].…”

Section: Discussionmentioning

confidence: 99%

Low Adiponectin, High Levels of Apoptosis and Increased Peripheral Blood Neutrophil Activity in Healthy Obese Subjects

Trellakis¹,

Rydleuskaya²,

Fischer³

et al. 2012

Obes Facts

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Objective: Growing evidence supports a link between obesity and inflammation. Current research is focused on the role of adipokines such as adiponectin and immune cells, especially macrophages, in adipose tissue. Our aim was to examine the role of inflammation not in tissue but in the peripheral blood of healthy overweight and obese subjects. We especially investigated the role of neutrophils and their possible regulation by adiponectin. Methods: In healthy normal-weight, overweight, and obese human subjects (n = 32) the peripheral blood concentrations of adipokines, satiety hormones, apoptosis markers, and cytokines as well as the blood count were related to inflammation and neutrophils, at 3 independent days of examination. The response of neutrophils to stimulation by adiponectin was also investigated in vitro. Results: In obese and by tendency already in overweight subjects, inflammation was increased showing a higher neutrophil-to-lymphocyte ratio, elevated high-sensitivity C-reactive protein, increased chemokines (CXCL8, CCL3, CCL5), increased apoptosis markers (M30 and M65), and changes in hormone levels in the peripheral blood. LPS- and fMLP-induced production of CXCL8 by neutrophils was elevated in overweight and obese subjects. High plasma levels of adiponectin were associated with reduced CXCL8 production in peripheral blood neutrophils. In vitro, production of CXCL8 by neutrophils was inhibited by adiponectin. Conclusion: Reduced adiponectin and enhanced apoptosis may occur already in the peripheral blood of healthy overweight subjects. This process seems to further enhance neutrophil activity in overweight and obese.

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“…Withdrawal of seretide treatment from subjects with COPD also leads to increased sputum neutrophil counts after 6 weeks (68). Pulmonary neutrophils from COPD patients and controls have reduced expression levels of glucocorticoid receptor, in contrast to peripheral blood neutrophils that display normal glucocorticoid receptor expression levels (69). Th e eff ects of ICS on sputum neutrophils in these studies must therefore be mediated through eff ects on other cell types, such as inhibition of the secretion of neutrophil chemoattractants by epithelial cells and macrophages.…”

Section: Clinical Trialsmentioning

confidence: 89%

Critical assessment of the value of sputum neutrophils

Gupta¹,

Singh²

2013

COPD: Journal of Chronic Obstructive Pulmonary Disease

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Neutrophils are central to the pathogenesis of COPD, releasing a range of pro-inflammatory and tissue destructive mediators. Sputum neutrophil numbers are elevated in COPD patients compared to healthy controls. We critically appraise the potential of sputum neutrophils as a biomarker in COPD. We show that there is insufficient evidence to support the use of this biomarker to define a phenotype of patients with more severe disease characteristics or a different prognosis. However, sputum neutrophil measurements can be used to measure the effects of anti-inflammatory drugs for the treatment of COPD.

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Reduced glucocorticoid receptor expression and function in airway neutrophils

Cited by 40 publications

References 35 publications

Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs

Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs

Low Adiponectin, High Levels of Apoptosis and Increased Peripheral Blood Neutrophil Activity in Healthy Obese Subjects

Critical assessment of the value of sputum neutrophils

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