ORCID Profile
0000-0002-5483-6642
Current Organisation
Imperial College London
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Publisher: Rockefeller University Press
Date: 27-12-2005
DOI: 10.1084/JEM.20050466
Abstract: Glucocorticoids are the most effective antiinflammatory agents for the treatment of chronic inflammatory diseases even though some diseases, such as chronic obstructive pulmonary disease (COPD), are relatively glucocorticoid insensitive. However, the molecular mechanism of this glucocorticoid insensitivity remains uncertain. We show that a defect of glucocorticoid receptor (GR) deacetylation caused by impaired histone deacetylase (HDAC) 2 induces glucocorticoid insensitivity toward nuclear factor (NF)-κB–mediated gene expression. Specific knockdown of HDAC2 by RNA interference resulted in reduced sensitivity to dexamethasone suppression of interleukin 1β–induced granulocyte/macrophage colony-stimulating factor production. Loss of HDAC2 did not reduce GR nuclear translocation, GR binding to glucocorticoid response element (GRE) on DNA, or GR-induced DNA or gene induction but inhibited the association between GR and NF-κB. GR becomes acetylated after ligand binding, and HDAC2-mediated GR deacetylation enables GR binding to the NF-κB complex. Site-directed mutagenesis of K494 and K495 reduced GR acetylation, and the ability to repress NF-κB–dependent gene expression becomes insensitive to histone deacetylase inhibition. In conclusion, we show that overexpression of HDAC2 in glucocorticoid-insensitive alveolar macrophages from patients with COPD is able to restore glucocorticoid sensitivity. Thus, reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-κB–mediated, but not GRE-mediated, gene expression.
Publisher: Elsevier BV
Date: 2016
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.JACI.2013.07.038
Abstract: Combination inhaled therapy with long-acting β2 agonists (LABAs) and corticosteroids is beneficial in treating asthma and chronic obstructive pulmonary disease (COPD). In asthma, LABAs enhance glucocorticoid receptor (GR) nuclear translocation in the presence of corticosteroids. Whether this biological mechanism occurs in COPD, a relatively corticosteroid-resistant disease, is uncertain. Eight patients with mild/moderate COPD participated in a double-blind, placebo-controlled, crossover study and inhaled single doses of fluticasone propionate (FP) 100 μg, FP 500 μg, salmeterol xinafoate (SLM) 50 μg, and combination FP 100 μg + SLM 50 μg. One hour postinhalation, sputum was induced, nuclear proteins isolated from purified macrophages, and levels of activated nuclear GR quantified by using a GR-glucocorticoid response element ELISA-based assay. Nuclear GR significantly increased after the inhalation of FP 500 μg (P < .01), but not after the inhalation of FP 100 μg or SLM 50 μg, compared with placebo. Interestingly, SLM in combination with FP 100 μg increased nuclear GR levels equivalent to those of FP 500 μg alone. This was significantly greater than either FP 100 μg (P < .05) or SLM 50 μg (P < .01) alone. In vitro in a human macrophage cell line, SLM (10(-8) mol/L) enhanced FP (10(-9) mol/L)-induced mitogen-activated protein kinase phosphatase-1 mRNA (5.8 ± 0.6 vs 8.4 ± 1.1 × 10(-6) copies, P < .05) and 2 × glucocorticoid response element-luciferase reporter gene activity (250.1 ± 15.6 vs 103.1 ± 23.6-fold induction, P < .001). Addition of SLM (10(-9) mol/L) to FP (10(-11) mol/L) significantly enhanced FP-mediated suppression of IL-1β-induced CXCL8 (P < .05). Addition of SLM 50 μg to FP 100 μg enhanced GR nuclear translocation equivalent to that seen with a 5-fold higher dose of FP in sputum macrophages from patients with COPD. This may account for the superior clinical effects of combination LABA/corticosteroid treatment compared with either as monotherapy observed in COPD.
Publisher: Informa UK Limited
Date: 04-12-2021
DOI: 10.1080/09638288.2019.1697382
Abstract: Being able to access public transport is vital for mobility device users as this is an affordable way of maintaining community connections and participating in activities that promote quality of life. This systematic review investigated literature on public transport access for people using mobility devices, excluding transit restraint and securement literature. A systematic review of the peer-reviewed literature in English from 1995 to 2019, with critical appraisal and narrative synthesis. Twenty-six articles were identified, including 14 studies investigating user experiences, seven examining bus formats and floor layouts, and five focusing on bus r incidents and optimal design. Studies were generally observational and descriptive, with 12 including analysis of video data. This is the first systematic review of literature related to the accessibility of public transport for people using mobility devices. Topics such as r access have been relatively well-researched, as have the experiences of users. However, many gaps remain and there is a need for research to address the barriers identified through user experiences, discern the best access to stations and stops, as well as floor formats for people to ingress, manoeuvre and egress from a variety of transport modes, and promote universal design principles in the transport sector. Rehabilitation professionals can use the findings of this review to advocate for, and support people using mobility devices to successfully negotiate public transport.Implications for RehabilitationAccessible public transport is vital to enable people using mobility devices to remain connected in their communities.Despite increased international awareness and adoption of accessibility features by the public transport sector to improve getting to a stop, ingress, manoeuvrability within and egress from conveyances, access for people using wheeled mobility devices cannot be assumed.When prescribing new wheeled mobility devices with clients, rehabilitation professionals and users need to consider public transport access and the suitability of different devices for this purpose.Rehabilitation professionals can undertake skills training with people using wheeled mobility devices to test out access prior to independent travel on public transport and develop strategies to overcome any barriers.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 07-2007
Abstract: The role of neutrophils in exacerbations of asthma is poorly understood. We examined the effect of withdrawal of inhaled corticosteroids on sputum inflammatory indexes in a double-blind study in patients with moderate, stable asthma. Following a 2-week run in period, 24 subjects were randomized to receive either budesonide (400 microg bid) or placebo, and the study was continued for another 10 weeks. Loss of asthma control developed in 8 of 12 patients over the 10-week period of steroid withdrawal, whereas only 1 of 10 patients with budesonide treatment had exacerbations. Those with an exacerbation had increased sputum interleukin (IL)-8 (p < 0.0001) and increased sputum neutrophil numbers (p < 0.0001) compared to those without an exacerbation. The significant elevation in sputum IL-8 and neutrophil counts initially occurred 2 weeks prior to an exacerbation. Sputum neutrophilia correlated positively with changes in IL-8 levels (r(2) = 0.76, p = 0.01). Rapid withdrawal of inhaled corticosteroids results in an exacerbation of asthma that is preceded by an increase in sputum neutrophils and IL-8 concentrations, in contrast to an increase in eosinophils reported in previous studies in which inhaled steroids are slowly tapered.
Publisher: Elsevier BV
Date: 10-2005
Abstract: Airway neutrophil levels are increased in patients with severe asthma and during asthma exacerbations. Long-acting beta2-agonists (LABAs), such as formoterol, reduce the number of asthma exacerbations. While beta2-agonists may affect neutrophil function in vitro, it is uncertain whether they have effects on neutrophilic inflammation in asthmatic patients in vivo. In a double-blind randomized crossover study, we evaluated the effects of 4 weeks of treatment with formoterol (Turbuhaler), 24 microg bid, compared to placebo on sputum neutrophil numbers and interleukin (IL)-8 levels in asthmatic patients. Therapy with budesonide (administered via Turbuhaler), 400 microg bid for 4 weeks, was added at the end as a "gold standard" antiinflammatory effect comparison. We studied 15 steroid-naïve nonsmoking patients who ranged from 19 to 51 years of age and had mild persistent asthma. Formoterol therapy significantly reduced sputum IL-8 levels and neutrophil numbers compared to placebo. There was a significant correlation between the reduction in sputum IL-8 levels and the number of neutrophils, indicating that formoterol may attenuate neutrophilic airway inflammation by inhibiting IL-8 production. Our data suggest that the LABA formoterol reduces neutrophilic airway inflammation in patients with mild asthma and that this might be beneficial in preventing asthma exacerbations.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Sarah Essilfie-Quaye.