Imperial College London

DrChristosRossios

Faculty of MedicineNational Heart & Lung Institute

Honorary Research Associate
 
 
 
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Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

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62 results found

Martin A, Tempra C, Yu Y, Liekkinen J, Thakker R, Lee H, de Santos Moreno B, Vattulainen I, Rossios C, Javanainen M, Bernardino de la Serna Jet al., 2024, Exposure to Aldehyde Cherry e-Liquid Flavoring and Its Vaping Byproduct Disrupt Pulmonary Surfactant Biophysical Function., Environ Sci Technol, Vol: 58, Pages: 1495-1508

Over the past decade, there has been a significant rise in the use of vaping devices, particularly among adolescents, raising concerns for effects on respiratory health. Pressingly, many recent vaping-related lung injuries are unexplained by current knowledge, and the overall implications of vaping for respiratory health are poorly understood. This study investigates the effect of hydrophobic vaping liquid chemicals on the pulmonary surfactant biophysical function. We focus on the commonly used flavoring benzaldehyde and its vaping byproduct, benzaldehyde propylene glycol acetal. The study involves rigorous testing of the surfactant biophysical function in Langmuir trough and constrained sessile drop surfactometer experiments with both protein-free synthetic surfactant and hydrophobic protein-containing clinical surfactant models. The study reveals that exposure to these vaping chemicals significantly interferes with the synthetic and clinical surfactant biophysical function. Further atomistic simulations reveal preferential interactions with SP-B and SP-C surfactant proteins. Additionally, data show surfactant lipid-vaping chemical interactions and suggest significant transfer of vaping chemicals to the experimental subphase, indicating a toxicological mechanism for the alveolar epithelium. Our study, therefore, reveals novel mechanisms for the inhalational toxicity of vaping. This highlights the need to reassess the safety of vaping liquids for respiratory health, particularly the use of aldehyde chemicals as vaping flavorings.

Journal article

Kemp P, Bashir T, Achison M, Adamson S, Akpan A, Aspray T, Avenell A, Band M, Burton L, Cvoro V, Donnan P, Duncan G, George J, Gordon A, Gregson C, Hapca A, Hume C, Jackson T, Kerr S, Kilgour A, Masud T, McKenzie A, McKenzie E, Patel H, Pilvinyte K, Roberts H, Rossios C, Sayer A, Smith K, Soiza R, Steves C, Struthers A, Tiwari D, Whitney J, Witham Met al., 2023, Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia – analyses from the LACE randomised controlled trial, PLoS One, Vol: 18, ISSN: 1932-6203

BackgroundAgeing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia.MethodsWe compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial.ResultsNeither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone.ConclusionThese data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older in

Journal article

Kemp P, Rossios C, Bashir T, Achison M, Adamson S, Akpan A, Aspray T, Avenell A, Burton L, Cvoror V, Donnan P, Duncan G, Gregson C, Hapca A, Hume C, Jackson T, Kilgour A, Masud T, McKenzie A, McKenzie E, Patel H, Pilvinyte K, Roberts H, Sayer A, Smith K, Soiza R, Steves C, Struthers A, Tiwari D, Whitney J, Witham M, Kemp Pet al., 2023, ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial, PLoS One, Vol: 18, ISSN: 1932-6203

AbstractBackgroundAngiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study.MethodsSarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n=130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months’ treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables.ResultsAllele frequencies for the normal UK population were extracted from 13 previous studies (I=0.473, D=0.527). In the LACE cohort the D allele was over-represented (I=0.412, D=0.588, p=0.046). This over-representation was present in men (I=0.353, D=0.647, p=0.010) but not women (I=0.458, D=0.532, p=0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID= 18.00 kg (14.50, 21.60) vs DD=13.20 kg (10.50, 15.90), p=0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle stren

Journal article

Kole TM, Vanden Berghe E, Kraft M, Vonk JM, Nawijn MC, Siddiqui S, Sun K, Fabbri LM, Rabe KF, Chung KF, Nicolini G, Papi A, Brightling C, Singh D, van der Molen T, Dahlén S-E, Agusti A, Faner R, Wedzicha JA, Donaldson GC, Adcock IM, Lahousse L, Kerstjens HAM, van den Berge M, ATLANTIS, U-BIOPRED, CADSET investigatorset al., 2023, Predictors and associations of the persistent airflow limitation phenotype in asthma: a post-hoc analysis of the ATLANTIS study., The Lancet Respiratory Medicine, Vol: 11, Pages: 55-64, ISSN: 2213-2600

BACKGROUND: Persistent airflow limitation (PAL) occurs in a subset of patients with asthma. Previous studies on PAL in asthma have included relatively small populations, mostly restricted to severe asthma, or have no included longitudinal data. The aim of this post-hoc analysis was to investigate the determinants, clinical implications, and outcome of PAL in patients with asthma who were included in the ATLANTIS study. METHODS: In this post-hoc analysis of the ATLANTIS study, we assessed the prevalence, clinical characteristics, and implications of PAL across the full range of asthma severity. The study population included patients aged 18-65 years who had been diagnosed with asthma at least 6 months before inclusion. We defined PAL as a post-bronchodilator FEV1/forced vital capacity (FVC) of less than the lower limit of normal at recruitment. Asthma severity was defined according to the Global Initiative for Asthma. We used Mann-Whitney U test, t test, or χ2 test to analyse differences in baseline characteristics between patients with and without PAL. Logistic regression was used for multivariable analysis of the associations between PAL and baseline data. Cox regression was used to analyse risk of exacerbation in relation to PAL, and a linear mixed-effects model was used to analyse change in FEV1 over time in patients with versus patients without PAL. Results were validated in the U-BIOPRED cohort. FINDINGS: Between June 30, 2014 and March 3, 2017, 773 patients were enrolled in the ATLANTIS study of whom 760 (98%) had post-bronchodilator FEV1/FVC data available. Of the included patients with available data, mean age was 44 years (SD 13), 441 (58%) of 760 were women, 578 (76%) were never-smokers, and 248 (33%) had PAL. PAL was not only present in patients with severe asthma, but also in 21 (16%) of 133 patients with GINA step 1 and 24 (29%) of 83 patients with GINA step 2. PAL was independently associated with older age at baseline (46 years in PAL group vs 43

Journal article

Witham MD, Adamson S, Avenell A, Band MM, Bashir T, Donnan PT, George J, Hapca A, Hume C, Kemp P, McKenzie E, Pilvinyte K, Rossios C, Smith K, Struthers AD, Sumukadas Det al., 2022, Leucine and perindopril to improve physical performance in people over 70 years with sarcopenia: the LACE factorial RCT, Efficacy and Mechanism Evaluation, Vol: 9, Pages: 1-82, ISSN: 2050-4365

<jats:sec id="abs1-1"> <jats:title>Background</jats:title> <jats:p>Angiotensin-converting enzyme inhibitors and leucine are promising potential treatments for sarcopenia. Neither has yet been tested in adequately powered randomised trials in patients with sarcopenia.</jats:p> </jats:sec> <jats:sec id="abs1-2"> <jats:title>Objectives</jats:title> <jats:p>To determine the efficacy of leucine and perindopril in improving physical function in older people with sarcopenia, to evaluate the effect of leucine and perindopril on muscle mass and to evaluate the predictive biomarkers of sarcopenia.</jats:p> </jats:sec> <jats:sec id="abs1-3"> <jats:title>Design</jats:title> <jats:p>A placebo-controlled, parallel group, double-blind, randomised 2 × 2 factorial trial.</jats:p> </jats:sec> <jats:sec id="abs1-4"> <jats:title>Setting</jats:title> <jats:p>Primary care and geriatric medicine secondary care departments in 14 UK centres.</jats:p> </jats:sec> <jats:sec id="abs1-5"> <jats:title>Participants</jats:title> <jats:p>Adults aged ≥ 70 years with low muscle strength and mass, without contraindications to angiotensin-converting enzyme inhibitors and without known diagnosis-specific skeletal myopathy.</jats:p> </jats:sec> <jats:sec id="abs1-6"> <jats:title>Interventions</jats:title> <jats:p>Eligible participants were randomised 1 : 1 to recei

Journal article

Hoda U, Pavlidis S, Bansal AT, Takahashi K, Hu S, Ng Kee Kwong F, Rossios C, Sun K, Bhavsar P, Loza M, Baribaud F, Chanez P, Fowler SJ, Horvath I, Montuschi P, Singer F, Musial J, Dahlen B, Krug N, Sandstrom T, Shaw DE, Lutter R, Fleming LJ, Howarth PH, Caruso M, Sousa AR, Corfield J, Auffray C, De Meulder B, Lefaudeux D, Dahlen S-E, Djukanovic R, Sterk PJ, Guo Y, Adcock IM, Chung KFet al., 2022, Clinical and transcriptomic features of persistent exacerbation-prone severe asthma in U-BIOPRED cohort, Clinical and Translational Medicine, Vol: 12, ISSN: 2001-1326

Background: Exacerbation-prone asthma is a feature of severe disease. Yet, the basis for its persistency remains unclear. Objectives: To determine the clinical and transcriptomic features of the frequent-exacerbator (FE) and of persistent FEs (PFE) in U-BIOPRED cohort. Methods: We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, <2 exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures.Results: Of 317 patients, 62.4 % were FE of whom 63.6% were PFE, while 37.6% were IE of whom 61.3% were PIE. Using multivariate analysis, FE was associated with short-acting beta-agonist use, sinusitis and daily oral corticosteroid use, while PFE with eczema, short-acting beta-agonist use and asthma control index. CEA Cell Adhesion Molecule 5 (CEACAM5) was the only differentially-expressed transcript in bronchial biopsies between PE and IE. There were no differentially-expressed genes in the other 4 compartments. There were higher expression scores for Type 2 , T-helper type-17 and Type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while higher expression scores of Type 2, Type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE.Conclusion: FE group and its PFE subgroup are associated with poor asthma control while expressing higher Type 1 and Type 2 activation pathways compared to IE and PIE, respectively.

Journal article

Achison M, Adamson S, Akpan A, Aspray T, Avenell A, Band M, Bashir T, Burton L, Cvoro V, Donnan P, Duncan G, George J, Gordon A, Gregson C, Hapca A, Henderson E, Hume C, Jackson T, Kemp P, Kerr S, Kilgour A, Lyell V, Masud T, McKenzie A, McKenzie E, Patel H, Pilvynte K, Roberts H, Rossios C, Sayer A, Smith K, Soiza R, Steves C, Struthers A, Sumukadas D, Tiwari D, Whitney J, Witham Met al., 2022, Effect of Perindopril or Leucine on physical performance in older people with sarcopenia: the LACE randomised controlled trial, Journal of Cachexia, Sarcopenia and Muscle, Vol: 13, Pages: 858-871, ISSN: 2190-6009

Background:This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia.Methods:Placebo-controlled, parallel group, double-blind, randomised two-by-two factorial trial. We recruited adults aged ≥70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4m walk) and/or low handgrip strength (women <20kg, men <30kg) plus low muscle mass (using sex and BMI category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomised to perindopril 4mg or placebo, and to oral leucine powder 2.5g or placebo thrice daily. The primary outcome was the between-group difference in the Short Physical Performance Battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy.Results:We screened 320 people and randomised 145 participants compared to an original target of 440 participants. For perindopril (n=73, mean age 79 [SD 6], female sex 39 [53%], mean SPPB 7.1 [SD 2.3]) vs no perindopril (n=72, mean age 79 [SD 6], female sex 39 [54%], mean SPPB 6.9 [SD 2.4]), medianadherence to perindopril was lower (76% vs 96%; p<0.001). Perindopril did not improve the primary outcome (adjusted treatment effect -0.1 points [95%CI -1.2 to 1.0], p=0.89). No significant treatmentbenefit was seen for any secondary outcome including muscle mass (adjusted treatment effect -0.4kg [95%CI -1.1 to 0.3], p=0.27). More adverse events occurred in the perindopril group (218 vs 165) butfalls rates were similar. For leucine (n=72, mean age 78 [SD 6], female sex 38 [53%], mean SPPB 7.0 [SD 2.1]) vs no leucine (n=72, mean age 79 [SD 6], female sex 40 [55%], mean SPPB 7.0 [SD 2.5]), 5 median adherence was the same in both groups (76% vs 76%; p=0.99). Leucine did not improve the primary outcome (adjusted treatme

Journal article

Tiotiu A, Badi Y, Kermani NZ, Sanak M, Kolmert J, Wheelock CE, Hansbro PM, Dahlen S-E, Sterk PJ, Djukanovic R, Guo Y, Mumby S, Adcock IM, Chung KFet al., 2022, Association of Differential Mast Cell Activation with Granulocytic Inflammation in Severe Asthma, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: 397-+, ISSN: 1073-449X

Journal article

Paschalaki K, Rossios C, Pericleous C, MacLeod M, Rothery S, Donaldson G, Wedzicha J, Gorgoulis V, Randi A, Barnes Pet al., 2022, Inhaled corticosteroids reduce senescence in endothelial progenitor cells from COPD patients, Thorax, Vol: 77, ISSN: 0040-6376

Cellular senescence contributes to the pathophysiology of chronic obstructive pulmonarydisease (COPD) and cardiovascular disease. Using endothelial-colony-forming-cells (ECFC),we have demonstrated accelerated senescence in smokers and COPD patients compared tonon-smokers. Subgroup analysis suggests that ECFC from COPD patients on inhaledcorticosteroids (ICS) (n=14; 8 on ICS) exhibited significantly reduced senescence(Senescence-associated-beta galactosidase activity, p21CIP1), markers of DNA damageresponse (DDR) and IFN-γ-inducible-protein-10 compared to COPD patients not on ICS. Invitro studies using human-umbilical-vein-endothelial-cells showed a protective effect of ICSon the DDR, senescence and apoptosis caused by oxidative-stress, suggesting a protectivemolecular mechanism of action of corticosteroids on endothelium.

Journal article

Paschalaki K, Rossios C, Gorgoulis V, Randi A, Barnes Pet al., 2021, Inhaled corticosteroids reduce senescence in endothelial progenitor cells from COPD patients, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Kermani NZ, Song W-J, Badi Y, Versi A, Guo Y, Sun K, Bhavsar P, Howarth P, Dahlen S-E, Sterk PJ, Djukanovic R, Adcock IM, Chung KF, U-BIOPRED Consortiumet al., 2021, Correction to: Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma., Respiratory Research, Vol: 22, Pages: 1-3, ISSN: 1465-9921

Journal article

Kermani N, Song W-J, Badi Y, Versi A, Guo Y, Sun K, Bhavsar P, Howarth P, Dahlen S-E, Sterk PJ, Djukanovic R, Adcock I, Chung KFet al., 2021, Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma, Respiratory Research, Vol: 22, ISSN: 1465-9921

BackgroundPatients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells.MethodsWe examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels.ResultsACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes.ConclusionLevels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.

Journal article

Adcock I, Alderawi A, Caramori G, Baker E, Hitchings A, Rahman I, Rossios C, Casolari P, Papi A, Ortega V, Curtis J, Dunmore S, Kirkham Pet al., 2020, FN3K expression in COPD: A potential comorbidity factor for cardiovascular disease, BMJ Open Respiratory Research, Vol: 7, ISSN: 2052-4439

Introduction Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels.Methods The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort.Results This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p<0.008–0.02), all failed to reach the threshold (p<0.0028) to be considered highly significant following multi-comparison analysis. Metformin enhanced systemic levels of FN3K in COPD subjects independent of their high-expression or low-expression status.Discussion The data highlight that low and high FN3K expressors exist within our study cohort and metformin induces FN3K levels, highlighting a potential mechanism to reduce the risk of CVD comorbidity and mortality.

Journal article

Östling J, van Geest M, Schofield JPR, Jevnikar Z, Wilson S, Ward J, Lutter R, Shaw DE, Bakke PS, Caruso M, Dahlen S-E, Fowler SJ, Horváth I, Krug N, Montuschi P, Sanak M, Sandström T, Sun K, Pandis I, Auffray C, Sousa AR, Guo Y, Adcock IM, Howarth P, Chung KF, Bigler J, Sterk PJ, Skipp PJ, Djukanović R, Vaarala O, U-BIOPRED Study Groupet al., 2019, IL-17-high asthma with features of a psoriasis immunophenotype, Journal of Allergy and Clinical Immunology, Vol: 144, Pages: 1198-1213, ISSN: 0091-6749

BACKGROUND: The role of interleukin-17 immunity is well established in inflammatory diseases like psoriasis and inflammatory bowel disease but not in asthma where further study is required. OBJECTIVE: To undertake a deep-phenotyping study of asthmatics with up-regulated interleukin-17 immunity. METHODS: Whole genome transcriptomic analysis was performed using epithelial brushings, bronchial biopsies (91 asthmatics patients and 46 healthy controls) and whole blood samples (n=498) from the U-BIOPRED cohort. Gene signatures induced in vitro by interleukin-17 and interleukin-13 in bronchial epithelial cells were used to identify patients with interleukin-17-high and interleukin-13-high phenotypes of asthma. RESULTS: 22 out of 91 patients were identified with interleukin-17 and 9 patients with interleukin-13 gene signatures. The interleukin-17-high asthmatics were characterised by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis, the differentially expressed genes in interleukin-17-high patients were shared with those reported as altered in psoriasis lesions, and included genes regulating epithelial barrier function and defence mechanisms, such as interleukin-1β, interleukin-6, interleukin-8, and beta-defensin. CONCLUSION: The interleukin-17-high asthma phenotype, characterized by bronchial epithelial dysfunction, upregulated anti-microbial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway which should be considered as a biomarker for this phenotype in further studies, including clinical trials targeting interleukin-17.

Journal article

Schofield JPR, Burg D, Nicholas B, Strazzeri F, Brandsma J, Staykova D, Folisi C, Bansal AT, Xian Y, Guo Y, Rowe A, Corfield J, Wilson S, Ward J, Lutter R, Shaw DE, Bakke PS, Caruso M, Dahlen S-E, Fowler SJ, Horváth I, Howarth P, Krug N, Montuschi P, Sanak M, Sandström T, Sun K, Pandis I, Riley J, Auffray C, De Meulder B, Lefaudeux D, Sousa AR, Adcock IM, Chung KF, Sterk PJ, Skipp PJ, Djukanović R, U-BIOPRED Study Groupet al., 2019, Stratification of asthma phenotypes by airway proteomic signatures, Journal of Allergy and Clinical Immunology, Vol: 144, Pages: 70-82, ISSN: 0091-6749

BACKGROUND: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy to predict treatment responses and a need for better understanding of the underlying mechanisms. OBJECTIVE: Identify molecular sub-phenotypes of asthma defined by proteomic signatures for improved stratification. METHODS: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyse the proteomes of sputum supernatants from 246 participants (206 asthmatics) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. RESULTS: Analysis of the sputum proteome resulted in 10 clusters, proteotypes, based on similarity in proteomics features, representing discrete molecular sub-phenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined three of these as highly eosinophilic, three as highly neutrophilic, and two as highly atopic with relatively low granulocytic inflammation. For each of these three phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. CONCLUSION: This study provides further stratification of asthma currently classified by quantifying granulocytic inflammation and gives additional insight into their underlying mechanisms which could become targets for novel therapies.

Journal article

Perotin J-M, Schofield JPR, Wilson SJ, Ward J, Brandsma J, Strazzeri F, Bansal A, Yang X, Rowe A, Corfield J, Lutter R, Shaw DE, Bakke PS, Caruso M, Dahlén B, Fowler SJ, Horváth I, Howarth P, Krug N, Montuschi P, Sanak M, Sandström T, Sun K, Pandis I, Auffray C, De Meulder B, Lefaudeux D, Riley JH, Sousa AR, Dahlen S-E, Adcock IM, Chung KF, Sterk PJ, Skipp PJ, Collins JE, Davies DE, Djukanović R, U-BIOPRED Study Groupet al., 2019, Epithelial dysregulation in obese severe asthmatics with gastro-oesophageal reflux, European Respiratory Journal, Vol: 53, ISSN: 0903-1936

Journal article

De Meulder B, Lefaudeux D, Bansal AT, Mazein A, Chaiboonchoe A, Ahmed H, Balaur I, Saqi M, Pellet J, Ballereau S, Lemonnier N, Sun K, Pandis I, Yang X, Batuwitage M, Kretsos K, van Eyll J, Bedding A, Davison T, Dodson P, Larminie C, Postle A, Corfield J, Djukanovic R, Chung KF, Adcock IM, Guo Y-K, Sterk PJ, Manta A, Rowe A, Baribaud F, Auffray C, U-BIOPRED Study Group and the eTRIKS Consortiumet al., 2018, A computational framework for complex disease stratification from multiple large-scale datasets, BMC Systems Biology, Vol: 12, ISSN: 1752-0509

BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.

Journal article

Takahashi K, Pavlidis S, Ng Kee Kwong F, Hoda U, Rossios C, Sun K, Loza M, Baribaud F, Chanez P, Fowler SJ, Horvath I, Montuschi P, Singer F, Musial J, Dahlen B, Dahlen SE, Krug N, Sandstrom T, Shaw DE, Lutter R, Bakke P, Fleming LJ, Howarth PH, Caruso M, Sousa AR, Corfield J, Auffray C, De Meulder B, Lefaudeux D, Djukanovic R, Sterk PJ, Guo Y, Adcock I, Chung KFet al., 2018, Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis, European Respiratory Journal, Vol: 51, ISSN: 0903-1936

Background: Severe asthma patients with a significant smoking history have airflow obstruction with reported neutrophilia. We hypothesise that multi1omic analysis will enable the definition of smoking and ex1smoking severe asthma molecular phenotypes.Methods The U1BIOPRED severe asthma patients containing current1smokers (CSA), ex1smokers (ESA), non1smokers (NSA) and healthy non1smokers (NH) was examined. Blood and sputum cell counts, fractional exhaled nitric oxide and spirometry were obtained. Exploratory proteomic analysis of sputum supernatants and transcriptomic analysis of bronchial brushings, biopsies and sputum cells was performed. Results Colony stimulating factor (CSF)2 protein levels were increased in CSA sputum supernatants with azurocidin 1, neutrophil elastase and CXCL8 upregulated in ESA. Phagocytosis and innate immune pathways were associated with neutrophilic inflammation in ESA. Gene Set Variation Analysis of bronchial epithelial cell transcriptome from CSA showed enrichment of xenobiotic metabolism, oxidative stress and endoplasmic reticulum stress compared to other groups. CXCL5 and matrix metallopeptidase 12 genes were upregulated in ESA and the epithelial protective genes, mucin 2 and cystatin SN, were downregulated. Conclusion Despite little difference in clinical characteristics, CSA were distinguishable from ESA subjects at the sputum proteomic level with CSA having increased CSF2 expression and ESA patients showed sustained loss of epithelial barrier processes.

Journal article

Rossios C, Pavlidis S, Gibeon D, Horowitz D, Branigan P, Loza M, Baribaud F, Rao N, Chung F, Adcock IMet al., 2017, An Impaired Innate Immune Response In Airway Smooth Muscle Cells From Chronic Cough Patients, International Conference of the American-Thoracic-Society (ATS), Publisher: Portland Press, Biochemical Society, ISSN: 0144-8463

Chronic cough is associated with airway inflammation and remodelling. Abnormal airway smooth muscle cell (ASMC) function may underlie mechanisms of chronic cough. Our objective was to examine the transcriptome and focused secretome of ASMCs from chronic cough patients and healthy non-cough volunteers. ASMC gene expression profiling was performed at baseline and/or after stimulation with polyinosinic:polycytidylic acid (poly(I:C)) to mimic viral infection. Supernatants were collected for multiplex analysis. Our results showed no significant differentially expressed genes (DEGs, false discovery rate (FDR) <0.05) between chronic cough and healthy non-cough ASMCs at baseline. Poly(I:C) stimulation resulted in 212 DEGs (>1.5 fold-change, FDR <0.05) in ASMCs from chronic cough patients compared with 1674 DEGs in healthy non-cough volunteers. The top up-regulated genes included chemokine (C–X–C motif) ligand (CXCL) 11 (CXCL11), CXCL10, chemokine (C–C motif) ligand (CCL) 5 (CCL5) and interferon-induced protein 44 like (IFI44L) corresponding with inflammation and innate immune response pathways. ASMCs from cough subjects had enhanced activation of viral response pathways in response to poly(I:C) compared with healthy non-cough subjects, reduced activation of pathways involved in chronic inflammation and equivalent activation of neuroregulatory genes. The poly(I:C)-induced release of inflammatory mediators, including CXCL8, interleukin (IL)-6 and CXCL1, from ASMCs from cough patients was significantly impaired compared with healthy non-cough subjects. Addition of fluticasone propionate (FP) to poly(I:C)-treated ASMCs resulted in greater gene expression changes in healthy non-cough ASMCs. FP had a differential effect on poly(I:C)-induced mediator release between chronic cough and healthy non-cough volunteers. In conclusion, altered innate immune and inflammatory gene profiles within ASMCs, rather than infiltrating cells or nerves, may drive the cough

Conference paper

Pavlidis S, Guo Y, Sun K, Rossios C, Rowe A, Loza M, Baribaud F, Hoda U, Sousa A, Corfield J, Djukanovic R, Sterk PJ, Adcock I, Chung F, Auffray Cet al., 2017, Molecular evidence of Group 1 innate lymphoid cell activation in the U-BIOPRED cohort, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Rossios C, Pavlidis S, Gibeon D, Mumby S, Durham A, Ojo O, Horowitz D, Loza M, Baribaud F, Rao N, Chung KF, Adcock IM, U-BIOPRED WP6 study groupet al., 2017, Impaired innate immune gene profiling in airway smooth muscle cells from chronic cough patients., Bioscience Reports, ISSN: 0144-8463

Chronic cough is associated with airway inflammation and remodelling. Abnormal airway smooth muscle cell (ASMC) function may underlie mechanisms of chronic cough.  Our objective was to examine the transcriptome and focused secretome of ASMCs from chronic cough patients and healthy non-cough volunteers.  ASMC gene expression profiling was performed at baseline and/or after stimulation with polyinosinic:polycytidylic acid (poly(I:C)) to mimic viral infection.  Supernatants were collected for multiplex analysis.  Our results showed no significant differentially expressed genes (DEGs, false discovery rate: FDR<0.05) between chronic cough and healthy non-cough ASMCs at baseline.  Poly(I:C) stimulation resulted in 212 DEGs (>1.5 fold change, FDR <0.05) in ASMCs from chronic cough patients compared with 1674 DEGs in healthy non-cough volunteers.  The top up-regulated genes included CXCL11 , CXCL10 , CCL5 and IFI44L corresponding with inflammation and innate immune response pathways.  ASMCs from cough subjects had enhanced activation of viral response pathways in response to poly(I:C) compared to healthy non-cough subjects, reduced activation of pathways involved in chronic inflammation and equivalent activation of neuroregulatory genes.  The poly(I:C)-induced release of inflammatory mediators, including CXCL8, IL-6 and CXCL1, from ASMCs from cough patients was significantly impaired compared to healthy non-cough subjects.  Addition of fluticasone propionate (FP) to poly(I:C)-treated ASMCs resulted in greater gene expression changes in healthy non-cough ASMCs.  FP had a differential effect on poly(I:C)-induced mediator release between chronic cough and healthy non-cough volunteers.  In conclusion, altered innate immune and inflammatory gene profiles within ASMCs, rather than infiltrating cells or nerves, may drive the cough response following respiratory viral infection.

Journal article

Papaioannou AI, Spathis A, Kostikas K, Karakitsos P, Papiris S, Rossios Cet al., 2017, The role of endosomal toll-like receptors in asthma, EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 808, Pages: 14-20, ISSN: 0014-2999

Journal article

Pavlidis S, Guo Y, Sun K, Rossios C, Rowe A, Loza M, Baribaud F, Hoda U, Sousa A, Corfield J, Djukanovic R, Sterk PJ, Adcock I, Chung KFet al., 2017, Comparison between bronchial and nasal brushings gene expression in the u-biopred cohort, International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X

Conference paper

Rossios C, Pavlidis S, Hoda U, Kuo CH, Wiegman C, Russell K, Sun K, Loza MJ, Baribaud F, Durham AL, Ojo O, Lutter R, Rowe A, Bansal A, Auffray C, Sousa A, Corfield J, Djukanovic R, Guo Y, Sterk PJ, Chung KF, Adcock IM, Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes U-BIOPRED Consortia Project Teamet al., 2017, Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 560-570, ISSN: 1097-6825

BACKGROUND: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1β protein levels, whereas eosinophilic asthma was associated with an IL-13-induced TH2 signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammati

Journal article

Chung KF, Seiffert J, Chen S, Theodorou IG, Goode AE, Leo BF, McGilvery CM, Hussain F, Wiegman C, Rossios C, Zhu J, Gong J, Tariq F, Yufit V, Monteith AJ, Hashimoto T, Skepper JN, Ryan MP, Zhang J, Tetley TD, Porter AEet al., 2017, Inactivation, clearance, and functional effects of lung-instilled short and long silver nanowires in rats, ACS Nano, Vol: 11, Pages: 2652-2664, ISSN: 1936-086X

There is a potential for silver nanowires (AgNWs) to be inhaled, but there is little information on their health effects and their chemical transformation inside the lungs in vivo. We studied the effects of short (S-AgNWs; 1.5 μm) and long (L-AgNWs; 10 μm) nanowires instilled into the lungs of Sprague–Dawley rats. S- and L-AgNWs were phagocytosed and degraded by macrophages; there was no frustrated phagocytosis. Interestingly, both AgNWs were internalized in alveolar epithelial cells, with precipitation of Ag2S on their surface as secondary Ag2S nanoparticles. Quantitative serial block face three-dimensional scanning electron microscopy showed a small, but significant, reduction of NW lengths inside alveolar epithelial cells. AgNWs were also present in the lung subpleural space where L-AgNWs exposure resulted in more Ag+ve macrophages situated within the pleura and subpleural alveoli, compared with the S-AgNWs exposure. For both AgNWs, there was lung inflammation at day 1, disappearing by day 21, but in bronchoalveolar lavage fluid (BALF), L-AgNWs caused a delayed neutrophilic and macrophagic inflammation, while S-AgNWs caused only acute transient neutrophilia. Surfactant protein D (SP-D) levels in BALF increased after S- and L-AgNWs exposure at day 7. L-AgNWs induced MIP-1α and S-AgNWs induced IL-18 at day 1. Large airway bronchial responsiveness to acetylcholine increased following L-AgNWs, but not S-AgNWs, exposure. The attenuated response to AgNW instillation may be due to silver inactivation after precipitation of Ag2S with limited dissolution. Our findings have important consequences for the safety of silver-based technologies to human health.

Journal article

Kuo CS, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I, Hoda U, Rossios C, Sousa A, Wilson SJ, Howarth P, Dahlen B, Dahlen SE, Chanez P, Shaw D, Krug N, Sandström T, De Meulder B, Lefaudeux D, Fowler S, Fleming L, Corfield J, Auffray C, Sterk PJ, Djukanovic R, Guo Y, Adcock IM, Chung KF, U-BIOPRED Project Teamet al., 2017, A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 443-455, ISSN: 1535-4970

RATIONALE AND OBJECTIVES: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. We used transcriptomic profiling of airway tissues to help define asthma phenotypes. METHODS: The transcriptome from bronchial biopsies and epithelial brushings of 107 moderate-to-severe asthmatics were annotated by gene-set variation analysis (GSVA) using 42 gene-signatures relevant to asthma, inflammation and immune function. Topological data analysis (TDA) of clinical and histological data was used to derive clusters and the nearest shrunken centroid algorithm used for signature refinement. RESULTS: 9 GSVA signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper type 2 (Th-2) cytokines and lack of corticosteroid response (Group 1 and Group 3). Group 1 had the highest submucosal eosinophils, high exhaled nitric oxide (FeNO) levels, exacerbation rates and oral corticosteroid (OCS) use whilst Group 3 patients showed the highest levels of sputum eosinophils and had a high BMI. In contrast, Group 2 and Group 4 patients had an 86% and 64% probability of having non-eosinophilic inflammation. Using machine-learning tools, we describe an inference scheme using the currently-available inflammatory biomarkers sputum eosinophilia and exhaled nitric oxide levels along with OCS use that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity. CONCLUSION: This analysis demonstrates the usefulness of a transcriptomic-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target Th2-mediated inflammation and/or corticosteroid insensitivity.

Journal article

Loza MJ, Djukanovic R, Chung KF, Horowitz D, Ma K, Branigan P, Barnathan ES, Susulic VS, Silkoff PE, Sterk PJ, Baribaud Fet al., 2016, Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study, RESPIRATORY RESEARCH, Vol: 17, ISSN: 1465-993X

Journal article

Lefaudeux D, De Meulder B, Loza MJ, Peffer N, Rowe A, Baribaud F, Bansal AT, Lutter R, Sousa AR, Corfield J, Pandis I, Bakke PS, Caruso M, Chanez P, Dahlen S-E, Fleming LJ, Fowler SJ, Horvath I, Krug N, Montuschi P, Sanak M, Sandstrom T, Shaw DE, Singer F, Sterk PJ, Roberts G, Adcock IM, Djukanovic R, Auffray C, Chung KF, U-BIOPRED Study Groupet al., 2016, U-BIOPRED clinical adult asthma clusters linked to a subset of sputum -omics, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 1797-1807, ISSN: 1097-6825

Journal article

Pavlidis S, Adcock I, Chung F, Rowe A, Rossios C, Pandis I, Djukanovich R, Sterk P, Guo Y, Wiegman Cet al., 2016, Enrichment of the Janus kinase (JAK) activation signature in severe asthma sputum: Correlation with IL-13 expression, European Respiratory Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Hogema F, Dai R, Li X, Rossios C, Chung F, Adcock I, Wiegman Cet al., 2016, High-fat diet in mice leads to amplified ozone-induced airway hyperresponsiveness (AHR), mitochondrial dysfunction and insulin resistance, European Respitory Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

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