Publications
62 results found
Kuo CS, Pavlidis S, Loza M, et al., 2016, Sputum transcriptomics identifies co-expressed network signatures associated with Fev1 and sputum neutrophilia in severe asthmatics on oral corticosteroids, International Conference of the American Thoracic Society (ATS), Publisher: American Thoracic Society, ISSN: 1535-4970
Pavlidis S, Rossios C, Loza M, et al., 2016, Macrophage Inflammasome Activation In Sputum From Severe Asthmatics, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Adcock IM, Ngkelo A, Hoffmann RF, et al., 2015, Glycogen synthase kinase-3β modulation of glucocorticoid responsiveness in COPD, American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol: 309, Pages: L1112-L1123, ISSN: 1522-1504
In Chronic Obstructive Pulmonary Disease (COPD), oxidative stress regulates the inflammatory response of bronchial epithelium and monocytes/macrophages through kinase modulation and has been linked to glucocorticoid unresponsiveness. GSK3β inactivation plays a key role in mediating signalling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3β is involved in oxidative stress-induced glucocorticoid insensitivity in COPD. We studied levels of p-GSK3β-ser9, a marker of GSK3β inactivation, in lung sections and cultured monocytes and bronchial epithelial cells of COPD patients, control smokers and non-smokers. We observed increased levels of p-GSK3β-ser9 in monocytes, alveolar macrophages and bronchial epithelial cells from COPD patients and control smokers compared to non-smokers. Pharmacological inactivation of GSK3β did not affect CXCL8 or GM-CSF expression but resulted in glucocorticoid insensitivity in vitro in both inflammatory and structural cells. Further mechanistic studies in monocyte and bronchial epithelial cell lines showed that GSK3β inactivation is a common effector of oxidative stress induced activation of the MEK/ERK-1/2 and PI3K/Akt signalling pathways leading to glucocorticoid unresponsiveness. In primary monocytes, the mechanism involved modulation of histone deacetylase 2 (HDAC2) activity in response to GSK3β inactivation. In conclusion, we demonstrate for the first time that ROS-induced glucocorticoid unresponsiveness in COPD is mediated through GSK3β, acting as a ROS-sensitive hub.
Fleming L, Murray C, Bansal AT, et al., 2015, The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts, European Respiratory Journal, Vol: 46, Pages: 1322-1333, ISSN: 0903-1936
U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches.A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study.Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; p<0.001). Exhaled tobacco exposure was common in the severe wheeze cohort. Almost all participants in each cohort were atopic and had a normal body mass index. Asthma-related quality of life, as assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), was worse in the severe cohorts (mean±se school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar.Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management.
Shaw DE, Sousa AR, Fowler SJ, et al., 2015, Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort, European Respiratory Journal, Vol: 46, Pages: 1308-1321, ISSN: 1399-3003
U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of “omic” datasets that are at the core of this systems medicine approach.
Guney TG, Danahay H, Durham AL, et al., 2015, Characterisation of a novel 3D model of the airways, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Kuo CH, Guo Y, Pandis I, et al., 2015, <i>MMP10</i> and <i>MET</i> as predictive classifiers of bronchial eosinophilic asthma in UBIOPRED, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 2
Ashmore R, Durham A, Michaeloudes C, et al., 2015, Investigating mitochondrial dysfunction in asthma, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Kuo SC-H, Guo Y, Pandis I, et al., 2015, LATE-BREAKING ABSTRACT: Sputum transcriptome analysis yields eosinophilic and non-eosinophilic inflammatory mechanisms in UBIOPRED asthma cohort, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Pavlidis S, Loza M, Baribaud F, et al., 2015, Th2 subsetting of U-BIOPRED asthma subjects based on airway transciptomic profiles, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 4
Rossios C, Loza M, Pavlidis S, et al., 2015, Sputum supernatant profiling reveals inflammasome-associated signatures in severe asthmatics in U-BIOPRED, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Durham AL, Brook P, Heesom K, et al., 2015, Investigating The Effects Of Glucocorticoids In Epithelial Cells Using Stable Isotope Labelling In Cell Culture (silac) Methodology, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wiegman CH, Russell KE, Seiffert J, et al., 2015, The Selective Pan-Janus Kinase (jak) Inhibitor Vr588 Demonstrates Potent Anti-Inflammatory Activity In A Murine Chronic House Dust Mite (hdm) Model Of Asthma, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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- Citations: 6
Kuo C-HS, Pavlidis S, Loza M, et al., 2015, Asthma Phenotypes From Semi-Supervised Machine-Learning Approach Of Bronchial Biopsy And Brush Transcriptomics In U-Biopred, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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- Citations: 1
Saito J, Mackay AJ, Rossios C, et al., 2014, Sputum-to-serum hydrogen sulfide ratio in COPD, THORAX, Vol: 69, Pages: 903-909, ISSN: 0040-6376
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- Citations: 20
Rossios C, Gibeon D, Chung KF, et al., 2014, Corticosteroid insensitivityin airway smooth muscle cells from severe asthma is dependent on stimulus and cytokine product, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Saito J, Mackay A, Rossios C, et al., 2014, Hydrogen sulfide (H<sub>2</sub>S) in sputum and serum as a novel biomarker of COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Saito J, Mackay A, Rossios C, et al., 2014, Hydrogen sulfide (H<sub>2</sub>S) in sputum and serum as a novel biomarker of COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Gibeon D, Zhu J, Sogbesan A, et al., 2014, Lipid-laden bronchoalveolar macrophages in asthma and chronic cough, RESPIRATORY MEDICINE, Vol: 108, Pages: 71-77, ISSN: 0954-6111
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- Citations: 19
Rossios C, Gibeon D, Macedo P, et al., 2013, TLR7 and TLR9-activated inflammation is differentially regulated in asthma, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Kobayashi Y, Wada H, Rossios C, et al., 2013, A novel macrolide/fluoroketolide, solithromycin (CEM-101), reverses corticosteroid insensitivity via phosphoinositide 3-kinase pathway inhibition, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 169, Pages: 1024-1034, ISSN: 0007-1188
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- Citations: 67
Kobayashi Y, Wada H, Rossios C, et al., 2013, A Novel Macrolide Solithromycin Exerts Superior Anti-inflammatory Effect via NF-κB Inhibition, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, Vol: 345, Pages: 76-84, ISSN: 0022-3565
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- Citations: 89
Wheelock CE, Goss VM, Balgoma D, et al., 2013, Application of 'omics technologies to biomarker discovery in inflammatory lung diseases, Eur.Respir.J.
Inflammatory lung diseases are highly complex in respect of pathogenesis and relationships between inflammation, clinical disease and response to treatment. Sophisticated large-scale analytical methods to quantify gene expression (transcriptomics), proteins (proteomics), lipids (lipidomics) and metabolites (metabolomics) in the lungs, blood and urine are now available to identify biomarkers that define disease in terms of combined clinical, physiological and patho-biological abnormalities. The aspiration is that these approaches will improve diagnosis, i.e., define pathological phenotypes, and facilitate the monitoring of disease and therapy and, also, unravel underlying molecular pathways. Biomarker studies can either select pre-defined biomarker(s) measured by specific methods or apply an "unbiased" approach involving detection platforms that are indiscriminate in focus. This article reviews the technologies presently available to study biomarkers of lung disease within the 'omics field. The contributions of the individual 'omics analytical platforms to the field of respiratory diseases are summarised, with the goal of providing background on their respective abilities to contribute to systems medicine-based studies of lung disease
Papaioannou AI, Rossios C, Kostikas K, et al., 2013, Can We Delay the Accelerated Lung Aging in COPD? Anti-Aging Molecules and Interventions, Curr.Drug Targets., Vol: 14, Pages: 149-157
Chronic obstructive pulmonary disease (COPD) has been recently characterized as a disease of accelerated lung aging. The prevalence of COPD is age-dependent suggesting an intimate relationship between the pathogenesis of COPD and aging. Lung function decline, the hallmark feature of COPD evolution, is more prominent with increasing age and this decline is greater in smoking individuals. One of the major goals of COPD pharmacotherapy is the development of drugs that would be able to result in a decrease of the decline in lung function over years. However, till nowadays smoking cessation is the only known intervention which is able to decelerate lung function decline. Several mechanisms of aging, including oxidative stress, inflammation and telomere shortening have been shown to be implicated in COPD. Furthermore, numerous anti-aging molecules, including sirtuins and Nrf-2 are reduced, and pathways such as mTOR and genes such as Klotho have also been shown to be abnormal in the lungs of COPD patients. The above mechanisms have been associated with the accelerated lung aging in COPD patients. Numerous therapeutic interventions have been studied in an attempt to reverse accelerated lung aging, and some of them have already been tested in clinical trials. The aim of the present review is to summarize the mechanisms associated with the accelerated lung aging in COPD and to provide information about the possible therapeutic implications targeting those mechanisms
Durham AL, Rossios C, Gibeon D, et al., 2013, Use Of Stable Isotope Labelling By Amino Acids (silac) To Investigate Differences Between Asthmatic And Normal Epithelial Cells, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 187, ISSN: 1073-449X
Rossios C, Gibeon D, Chung K, et al., 2013, Tlr3 Activation Causes Corticosteroid Insensitivity In Human Bronchial Epithelial Cells, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 187, ISSN: 1073-449X
Rossios C, To Y, Osoata G, et al., 2012, Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 167, Pages: 775-786, ISSN: 0007-1188
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- Citations: 49
Tsitsiou E, Williams AE, Moschos SA, et al., 2012, Transcriptome analysis shows activation of circulating CD8+ T cells in patients with severe asthma, J.Allergy Clin.Immunol., Vol: 129, Pages: 95-103
BACKGROUND: Although previous studies have implicated tissue CD4(+) T cells in the development and maintenance of the inflammatory response in asthmatic patients, little is known about the role of CD8(+) T cells. There is now accumulating evidence that microRNAs and other noncoding RNAs are important regulators of T-cell function. OBJECTIVES: We sought to use transcriptomics to determine the activation state of circulating CD4(+) and CD8(+) T cells in patients with nonsevere and severe asthma. METHODS: mRNA and noncoding RNA expression in circulating T cells was measured by means of microarray, quantitative real-time PCR, or both. RESULTS: Comparison of mRNA expression showed widespread changes in the circulating CD8(+) but not CD4(+) T cells from patients with severe asthma. No changes were observed in the CD4(+) and CD8(+) T cells in patients with nonsevere asthma versus those in healthy control subjects. Bioinformatics analysis showed that the changes in CD8(+) T-cell mRNA expression were associated with multiple pathways involved in T-cell activation. As with mRNAs, we also observed widespread changes in expression of noncoding RNA species, including natural antisense, pseudogenes, intronic long noncoding RNAs (lncRNAs), and intergenic lncRNAs in CD8(+) T cells from patients with severe asthma. Measurement of the microRNA expression profile showed selective downregulation of miR-28-5p in CD8(+) T cells and reduction of miR-146a and miR-146b in both CD4(+) and CD8(+) T cells. CONCLUSIONS: Severe asthma is associated with the activation of circulating CD8(+) T cells but not CD4(+) T cells. This response is correlated with the downregulation of miR-146a/b and miR-28-5p, as well as changes in the expression of multiple species of lncRNA that might regulate CD8(+) T-cell function
Rossios C, To Y, To M, et al., 2011, Long-acting fluticasone furoate has a superior pharmacological profile to fluticasone propionate in human respiratory cells, EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 670, Pages: 244-251, ISSN: 0014-2999
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- Citations: 48
Nakamaru Y, Vuppusetty C, Wada H, et al., 2009, A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9, FASEB JOURNAL, Vol: 23, Pages: 2810-2819, ISSN: 0892-6638
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- Citations: 183
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