Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD

Haque, Rubaiyat; Hakim, Amir; Moodley, Thunicia; Torrego, Alfonso; Essilfie-Quaye, Sarah; Jazrawi, Elen; Johnson, Malcolm; Barnes, Peter J.; Adcock, Ian M.; Usmani, Omar

doi:10.1016/j.jaci.2013.07.038

Cited by 47 publications

(33 citation statements)

References 39 publications

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Section: Use Of Icss In Combination With Labasmentioning

confidence: 99%

“…Two-way synergistic activity between ICSs and LABAs has been demonstrated 23,24. One of the cellular actions of ICSs is to translocate glucocorticoid receptors from the cytoplasm to the nucleus 24. This action is enhanced in the presence of β-agonists and causes an anti-inflammatory effect greater than either drug alone, without the need to increase the ICS dosage 23.…”

Section: Use Of Icss In Combination With Labasmentioning

confidence: 99%

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Inhaled corticosteroids for chronic obstructive pulmonary disease: what is their role in therapy?

Tashkin¹,

Strange²

2018

COPD

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Inhaled corticosteroids (ICSs) are a mainstay of COPD treatment for patients with a history of exacerbations. Initial studies evaluating their use as monotherapy failed to show an effect on rate of pulmonary function decline in COPD, despite improvements in symptoms and reductions in exacerbations. Subsequently, ICS use in combination with long-acting β2-agonists (LABAs) was shown to provide improved reductions in exacerbations, lung function, and health status. ICS-LABA combination therapy is currently recommended for patients with a history of exacerbations despite treatment with long-acting bronchodilators alone. The presence of eosinophilic bronchial inflammation, detected by high blood eosinophil levels or a history of asthma or asthma–COPD overlap, may define a population of patients in whom ICSs may be of particular benefit. Prospective clinical studies to determine an appropriate threshold of eosinophil levels for predicting the beneficial effects of ICSs are needed. Further study is also required in COPD patients who continue to smoke to assess the impact of cell- and tissue-specific changes on ICS responsiveness. The safety profile of ICSs in COPD patients is confounded by comorbidities, age, and prior use of systemic corticosteroids. The risk of pneumonia in patients with COPD is increased, particularly with more advanced age and worse disease severity. ICS-containing therapy also has been shown to increase pneumonia risk; however, differences in study design and the definition of pneumonia events have led to substantial variability in risk estimates, and some data indicate that pneumonia risk may differ by the specific ICS used. In summary, treatment with ICSs has a role in dual and triple therapy for COPD to reduce exacerbations and improve symptoms. Careful assessment of COPD phenotypes related to risk factors, triggers, and comorbidities may assist in individualizing treatment while maximizing the benefit-to-risk ratio of ICS-containing COPD treatment.

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Section: Use Of Icss In Combination With Labasmentioning

confidence: 99%

Section: Use Of Icss In Combination With Labasmentioning

confidence: 99%

Inhaled corticosteroids for chronic obstructive pulmonary disease: what is their role in therapy?

Tashkin¹,

Strange²

2018

COPD

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“…Given that GR phosphorylation by JNK and p38 has been shown to result in increased nuclear export of the GR, the authors hypothesized that the decrease in activity of these kinases by formoterol could explain the increased GR nuclear translocation by the LABAs, indicating a possible mechanism of GR activation or priming by the LABAs (Mercado et al, 2011). A more recent study in primary macrophages by Haque et al showed that salmeterol alone had no significant effect on nuclear translocation and binding of the unliganded GR to DNA (Haque et al, 2013). Furthermore, salmeterol did not enhance transactivation of the MKP-1 gene or a GRE-promoter reporter in U937 cells.…”

Section: Glucocorticoid-independent Sensitizing Of Gr Signallingmentioning

confidence: 99%

“…Furthermore, salmeterol did not enhance transactivation of the MKP-1 gene or a GRE-promoter reporter in U937 cells. However, salmeterol significantly increased GC-induced GR nuclear translocation, DNA binding and transactivation of both the MKP-1 gene and the GRE-luc reporter, indicating that salmeterol treatment primes the unliganded GR, rather than activating the unliganded receptor (Haque et al, 2013). It should be mentioned that LABAs have been shown to increase MKP-1 mRNA and protein expression in a manner involving the cAMP-PKA pathway (Kaur et al, 2008; Manetsch et al, 2013).…”

Section: Glucocorticoid-independent Sensitizing Of Gr Signallingmentioning

confidence: 99%

Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy

Hapgood

Avenant

Moliki

2016

Pharmacology & Therapeutics

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Pharmacological doses of glucocorticoids (GCs), acting via the glucocorticoid receptor (GR) to repress inflammation and immune function, remain the most effective therapy in the treatment of inflammatory and immune diseases. Since many patients on GC therapy exhibit GC-resistance and severe side-effects, much research is focussed on developing more selective GCs and combination therapies, with greater anti-inflammatory potency. GCs mediate their classical genomic transcriptional effects by binding to the cytoplasmic GR, followed by nuclear translocation and modulation of transcription of target genes by direct DNA-binding of the GR or its tethering to other transcription factors. Recent evidence suggests, however, that the responses mediated by the GR are much more complex and involve multiple parallel mechanisms integrating simultaneous signals from other receptors, both in the absence and presence of GCs, to shift the sensitivity of a target cell to GCs. The level of cellular stress, immune activation status, or the cell cycle phase may be crucial for determining GC sensitivity and GC responsiveness as well as subcellular localization of the GR and GR levels. Central to the development of new drugs that target GR signalling alone or as add-on therapies, is an in-depth understanding of the molecular mechanisms of GC-independent GR desensitization, priming and activation of the unliganded GR, as well as synergy and cross-talk with other signalling pathways. This review will discuss the information currently available on these topics and their relevance to immunotherapy, as well as identify unanswered questions and future areas of research.

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“…The different actions of ICS and LABA in the treatment of COPD, targeting different receptors suggests potential synergistic interactions, leading to enhanced clinical effects than those achieved with single agent therapy [53].…”

Section: Pharmacology Of Fluticasone Furoate (Ff)mentioning

confidence: 99%

Vilanterol trifenatate for the treatment of COPD

Malerba

Radaeli

Montuschi

et al. 2016

Expert Review of Respiratory Medicine

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Introduction: Currently the treatment of chronic obstructive pulmonary disease (COPD) has limited effectiveness and there is a need to develop new drugs. International guidelines recommend the use of long-acting bronchodilators (β2 agonists and anticholinergics/muscarinics), inhaled steroids and associations between these drugs in the maintenance treatment of moderate-to-severe COPD.Area Covered: Vilanterol trifenate is a new once-daily highly selective β2-agonist available in USA and Europe in association with umeclidinium bromide (a long-acting anti-muscarnic agent) and fluticasone furoate (an inhaled corticosteroid) for the once-daily maintenance treatment of COPD.Vilanterol combined in fixed-dose treatments has been tested in numerous clinical trials involving thousands of patients.Expert Commentary: These new once-daily formulations have the potential to improve compliance to long-term inhaled therapy. This paper will review the clinical and experimental data regarding vilanterol use in the regular treatment of COPD as well as provide a critical discussion of possible future treatment settings.

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Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD

Cited by 47 publications

References 39 publications

Inhaled corticosteroids for chronic obstructive pulmonary disease: what is their role in therapy?

Inhaled corticosteroids for chronic obstructive pulmonary disease: what is their role in therapy?

Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy

Vilanterol trifenatate for the treatment of COPD

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