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Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis

Kentaro Takahashi, Stelios Pavlidis, Francois Ng Kee Kwong, Uruj Hoda, Christos Rossios, Kai Sun, Matthew Loza, Fred Baribaud, Pascal Chanez, Steve J. Fowler, Ildiko Horvath, Paolo Montuschi, Florian Singer, Jacek Musial, Barbro Dahlen, Sven-Eric Dahlen, Norbert Krug, Thomas Sandstrom, Dominic E. Shaw, Rene Lutter, Per Bakke, Louise J. Fleming, Peter H. Howarth, Massimo Caruso, Ana R. Sousa, Julie Corfield, Charles Auffray, Bertrand De Meulder, Diane Lefaudeux, Ratko Djukanovic, Peter J. Sterk, Yike Guo, Ian M. Adcock, Kian Fan Chung , on behalf of the U-BIOPRED study group
European Respiratory Journal 2018 51: 1702173; DOI: 10.1183/13993003.02173-2017
Kentaro Takahashi
1National Heart and Lung Institute, Imperial College London, and Biomedical Research Unit, Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK
2Research Centre for Allergy and Clinical Immunology, Asahi General Hospital, Matsudo, Japan
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Stelios Pavlidis
3Dept of Computing and Data Science Institute, Imperial College London, London, UK
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Francois Ng Kee Kwong
1National Heart and Lung Institute, Imperial College London, and Biomedical Research Unit, Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK
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Uruj Hoda
1National Heart and Lung Institute, Imperial College London, and Biomedical Research Unit, Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK
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Christos Rossios
1National Heart and Lung Institute, Imperial College London, and Biomedical Research Unit, Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK
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Kai Sun
3Dept of Computing and Data Science Institute, Imperial College London, London, UK
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Matthew Loza
4Janssen Research and Development, High Wycombe, UK
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Fred Baribaud
4Janssen Research and Development, High Wycombe, UK
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Pascal Chanez
5Assistance Publique des Hôpitaux de Marseille, Clinique des Bronches, Allergies et Sommeil, Aix Marseille Université, Marseille, France
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Steve J. Fowler
6Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
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Ildiko Horvath
7Semmelweis University, Budapest, Hungary
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Paolo Montuschi
8Università Cattolica del Sacro Cuore, Milan, Italy
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Florian Singer
9Bern University Hospital, University of Bern, Bern, Switzerland
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Jacek Musial
10Dept of Medicine, Jagiellonian University Medical College, Krakow, Poland
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Barbro Dahlen
11Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden
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Sven-Eric Dahlen
11Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden
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Norbert Krug
12Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
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Thomas Sandstrom
13Dept of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
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Dominic E. Shaw
14Respiratory Research Unit, University of Nottingham, Nottingham, UK
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Rene Lutter
15Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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Per Bakke
16Dept of Clinical Science, University of Bergen, Bergen, Norway
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Louise J. Fleming
1National Heart and Lung Institute, Imperial College London, and Biomedical Research Unit, Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK
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Peter H. Howarth
17NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, UK
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Massimo Caruso
18Dept Clinical and Experimental Medicine, University of Catania, Catania, Italy
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Ana R. Sousa
19Respiratory Therapeutic Unit, GSK, Stockley Park, UK
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Julie Corfield
20AstraZeneca R&D, Molndal, Sweden
21Areteva R&D, Nottingham, UK
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Charles Auffray
22European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France
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Bertrand De Meulder
22European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France
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Diane Lefaudeux
22European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France
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  • ORCID record for Diane Lefaudeux
Ratko Djukanovic
17NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, UK
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Peter J. Sterk
16Dept of Clinical Science, University of Bergen, Bergen, Norway
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Yike Guo
3Dept of Computing and Data Science Institute, Imperial College London, London, UK
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Ian M. Adcock
1National Heart and Lung Institute, Imperial College London, and Biomedical Research Unit, Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK
3Dept of Computing and Data Science Institute, Imperial College London, London, UK
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Kian Fan Chung
1National Heart and Lung Institute, Imperial College London, and Biomedical Research Unit, Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK
3Dept of Computing and Data Science Institute, Imperial College London, London, UK
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  • FIGURE 1
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    FIGURE 1

    Phenotypic differences among severe asthma current smokers (CSA), severe asthma ex-smokers (ESA) and severe asthma nonsmokers (NSA) were unveiled using the SomaLogic linear model for microarray (limma) analysis of sputum. a–c) Volcano plots showing differentially expressed proteins (DEPs) in limma of sputum SomaLogic in the following comparisons: a) CSA and healthy nonsmokers (NH); b) ESA and NH; and c) NSA and NH. The proteins whose absolute fold change ≥2.0 at false discovery rate (FDR) <0.05 were regarded as DEPs. The number of DEPs of each comparison is shown in the left and right upper areas of each plot. d) Venn diagram showing the numbers and names of DEPs in each comparison.

  • FIGURE 2
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    FIGURE 2

    Differentially expressed proteins in severe asthma sputum according to smoking status. Dot plots with mean±sd showing signal intensity levels of protein expression of a) colony-stimulating factor (CSF)-2, b) anterior gradient protein (AGR)2, c) azurocidin (AZU)1, d) C-X-C motif chemokine ligand (CXCL)8, e) neutrophil elastase (ELANE), f) complement factor properdin (CFP) and g) catalase (CAT) in sputum by SomaLogic (Boulder, CO, USA) analysis in severe asthma current smokers (CSA), severe asthma ex-smokers (ESA), severe asthma nonsmokers (NSA) and healthy nonsmokers (NH). RFU: relative fluorescence units, *: p<0.05; **: p<0.01; ***: p<0.001.

  • FIGURE 3
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    FIGURE 3

    Differentially expressed genes (DEGs) in current smokers (CSA) and nonsmokers (NSA) with severe asthma. Volcano plots showing DEGs between CSA and NSA in a) sputa, b) bronchial biopsies and c) bronchial brushings. The genes whose absolute fold change (FC) ≥1.5 at a false discovery rate (FDR) <0.05 are shown as coloured dots. The number of DEGs in each sample is shown in the left and right upper areas of each plot. d) Hierarchical clustering for DEGs from bronchial brushings in severe asthma patients. ESA: severe asthma ex-smokers.

  • FIGURE 4
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    FIGURE 4

    Differentially expressed genes (DEGs) associated with metabolism of xenobiotics, oxidative stress and endoplasmic reticulum stress in bronchial brushings. Dot plots showing DEGs in bronchial brushings associated with a) xenobiotic metabolism by cytochrome P450 family 1 subfamily B member 1 (CYP1B1), b) aldehyde dehydrogenase 3 family member A1 (ALDH3A1), c) NAD(P)H quinone dehydrogenase 1 (NQO1), d) aldo-keto reductase family 1 member C1 (AKR1C1) and e) heat shock protein family A (Hsp70) member 5 (HSPA5). RFU: relative fluorescence units; CSA: severe asthma current smokers; ESA: severe asthma ex-smokers; NSA: severe asthma nonsmokers; NH: healthy nonsmokers. **: p<0.01; ***: p<0.001.

  • FIGURE 5
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    FIGURE 5

    Gene set variation analysis of selected stress-related pathways in bronchial brushings according to smoking status. Box-and-whisker plots showing pathway enrichment of a) xenobiotic metabolism by CYP450, b) glutathione metabolism, c) response to oxidative stress, d) endoplasmic reticulum stress, e) unfolded protein response, f) lysosome and g) glycolysis and gluconeogenesis in bronchial brushings of severe asthma current smokers (CSA), severe asthma ex-smokers (ESA), severe asthma nonsmokers (NSA) and healthy nonsmokers (NH). *: p<0.05; **: p<0.01; ***: p<0.001.

  • FIGURE 6
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    FIGURE 6

    Gene set variation analysis of selected stress-related pathways in bronchial biopsies according to smoking status. Box-and-whisker plots showing pathway enrichment of a) xenobiotic metabolism by CYP450, b) glutathione metabolism, c) response to oxidative stress, d) endoplasmic reticulum stress, e) unfolded protein response, f) lysosome and g) glycolysis and gluconeogenesis in bronchial biopsies of severe asthma current smokers (CSA), severe asthma ex-smokers (ESA), severe asthma nonsmokers (NSA) and healthy nonsmokers (NH). *: p<0.05; **: p<0.01; ***: p<0.001.

  • FIGURE 7
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    FIGURE 7

    Protein interaction analysis in STRING (version 10.0; STRING Consortium 2016, www.string-db.org) using combined differentially expressed genes (DEGs). Combined DEGs in limma from bronchial brushings, biopsies and sputa were used for protein interaction analysis by STRING. The large pink-coloured area is filled with proteins related to xenobiotic metabolism and oxidation–reduction which contains the pentose-phosphate pathway. These proteins function with those in charge of redox and connect with protein production or modification. Some proteins are associated with innate immunity. The other proteins function as lysosomal, membranous, mucus productive, Golgi homeostatic or structural proteins. Overall, this reveals the relationship between oxidative stress, endoplasmic reticulum stress, metabolism of xenobiotics and innate immunity.

Tables

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  • TABLE 1

    Patient characteristics for sputum SomaLogic analyses

    CSAMissing valuesESAMissing valuesNSAMissing valuesHealthy
    nonsmokers
    Missing valuesp-value
    Subjects11223718
    Female5 (45.5)14 (63.6)22 (59.5)6 (33.3)2.01×10−1¶
    Age years50.0±10.655.7±9.752.6±13.339.9±13.8##,¶¶3.95×10−3+
    Onset age of asthma years29.8±19.939.5±19.0¶¶25.0±18.12.45×10−2+
    Age at starting smoking years19.3±4.016.2±2.54.93×10−2§
    Years of smoking cessation13.7±10.5
    Smoking pack-years29.0±18.220.8±16.10±00±01.17×10−1§
    BMI kg·m−227.7±4.731.1±6.727.5±5.725.3±3.2##2.79×10−2+
    Atopic8 (88.9)210 (62.5)628 (84.8)45 (45.5)73.60×10−2¶
    Blood eosinophils cells·μL−1259±173296±246407±3572116±713.31×10−1+,ƒ
    Blood neutrophils ×103 cells·μL−15.10±1.955.84±3.034.97±2.1623.35±1.156.03×10−1+,ƒ
    Sputum eosinophils %7.2±15.214.8±16.818.8±24.60.36±0.572.98×10−1+,ƒ
    Sputum neutrophils %53.9±16.155.2±20.650.8±30.941.0±26.59.28×10−1+,ƒ
    IgE IU·mL−1222±2012313±499305±5103105±1788.84×10−1+,ƒ
    FeNO ppb15.2±16.6##,¶¶40.5±33.9141.2±36.3319.4±9.73 7.55×10−4+,ƒ
    Periostin ng·mL−142.8±9.3253.1±18.9454.9±20.3949.7±5.542.66×10−1+,ƒ
    FEV1 post-bronchodilator# %73.7±18.278.8±21.168.6±21.1105.2±11.51.82×10−1+,ƒ
    FEV1/FVC post-bronchodilator# %61.5±10.163.4±12.260.2±13.979.0±5.96.27×10−1+,ƒ
    Airway reversibility %15.0±9.516.7±12.717.3±20.417.45×10−1+
    Airflow limitation (missing data n=92 overall)7 (63.6)11 (50.0)28 (75.7)1.33×10−1¶
    Average ACQ-72.87±1.3112.67±0.9832.68±1.1948.30×10−1+
    Average AQLQ4.15±1.5714.62±1.0454.35±1.2925.06×10−1+
    Exacerbations in previous year2.6±3.32.1±1.92.4±1.97.47×10−1+
    ER visits due to breathing problems5 (45.5)14 (63.6)25 (62.2)4.41×10−1¶
    Comorbidities
     Allergic rhinitis2 (25.0)38 (40.0)216 (55.2)82.85×10−1¶
     Nasal polyps2 (20.0)17 (33.3)112 (34.3)27.20×10−1¶
     Sinusitis2 (25.0)36 (28.6)19 (28.1)51.00¶
     Chronic bronchitis1 (11.1)12 (9.1)4 (12.1)41.00¶
     Psychiatric disease3 (33.3)23 (14.3)15 (13.9)13.84×10−1¶
     GORD4 (50.0)315 (71.4)¶¶111 (32.4)31.74×10−2¶
    Medications
     Inhaled corticosteroids11 (100.0)22 (100.0)37 (100.0)1.00¶
     Systemic corticosteroids3 (30.0)114 (63.6)16 (45.7)21.93×10−1¶
     Oral corticosteroid dose mg·day−12.50±4.7117.89±8.0134.18±6.6128.53×10−2+
     Anti-IgE therapy0 (0.0)12 (4.0)20 (0.0)21.13×10−1¶
     Long-acting β-agonists11 (100.0)21 (95.5)37 (100.0)4.71×10−1¶
     Leukotriene modifiers4 (36.4)11 (52.4)119 (51.4)6.80×10−1¶
     Tiotropium3 (30.0)14 (22.2)212 (34.3)25.61×10−1¶
     Macrolide2 (18.2)3 (13.6)4 (10.8)7.96×10−1¶

    Data are presented as n, n (%) or mean±sd, unless otherwise stated. Bold type represents statistical significance (p<0.05). CSA: severe asthma current smokers; ESA: severe asthma ex-smokers; NSA: severe asthma nonsmokers; BMI: body mass index; Ig: immunoglobulin; FeNO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; ACQ: asthma control questionnaire; AQLQ: asthma quality of life questionnaire; ER: emergency room; GORD: gastro-oesophageal reflux disease. #: spirometry data without bronchodilator were used for healthy subjects; statistical analysis was performed using ¶: Fisher's exact test, +: Kruskal–Wallis test; or §: Mann–Whitney U-test; ƒ: healthy subjects were excluded from statistical analyses of several items; ##: p<0.05 versus ESA; ¶¶: p<0.052 versus NSA.

    • TABLE 2

      Differentially expressed proteins between severe asthma current smokers (CSA) and healthy nonsmokers (NH) and severe asthma nonsmokers (NSA) and NH by sputum assay

      Probe IDProtein targetGene symbolGene nameFunction
      CSA-NH    
       SL001726CSF2CSF2 (or GM-CSF)Colony-stimulating factor 2Granulocyte, monocyte, macrophage expansion
       SL004925AGR2AGR2Anterior gradient protein 2Mucin (MUC5AC and MUC5B) overproduction in asthma
      Localised in endoplasmic reticulum of bronchial epithelial cells
       SL000039IL-8CXCL8 (=IL8)C-X-C motif chemokine ligand 8Acts as one of the major mediators of the inflammatory response by recruiting neutrophils
      NSA-NH    
       SL000342CatalaseCATCatalaseA key antioxidant enzyme in the body's defence against oxidative stress
       SL000051CRPCRPC-reactive proteinHost defence based on its ability to recognise foreign pathogens and damaged cells of the host and to initiate their elimination by interacting with humoral and cellular effector systems in the blood
       SL004153M-CSF RCSF1RColony-stimulating factor 1 receptorThe receptor for CSF-1, a cytokine which controls the production, differentiation and function of macrophages
       SL004853B7-H2ICOSLGInducible T-cell costimulatory ligandThis protein acts as a costimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation into plasma cells
       SL006108CD5LCD5LCD5 molecule likeThis secreted protein is mainly expressed by macrophages in lymphoid and inflamed tissues and regulates mechanisms in inflammatory responses. Regulation of intracellular lipids mediated by this protein has a direct effect on transcription regulation mediated by nuclear receptors ROR-γ (RORC)
       SL004068GZMBGZMBGranzyme BTargets cell lysis in cell-mediated immune responses. Processes cytokines and degrades extracellular matrix proteins; these roles are implicated in chronic inflammation and wound healing
      CSA-NH and NSA-NH
       SL017613FCG2A/BFCGR2AFc fragment of immunoglobulin-γ receptor IIaThe protein is a cell surface receptor found on phagocytic cells such as macrophages and neutrophils, and is involved in the process of phagocytosis and clearing of immune complexes
       SL003524Protein disulfide isomerase A3PDIA3Protein disulfide isomerase family A member 3Formation of the final antigen conformation, export from the endoplasmic reticulum to the cell surface and adaptation to oxidative damage

      Assay performed by SomaLogic (Boulder, CO, USA). GM-CSF: granulocyte-macrophage colony-stimulating factor; IL: interleukin.

      • TABLE 3

        Differentially expressed key proteins in sputum SomaLogic analysis comparing severe asthma ex-smokers (ESA) and healthy nonsmokers (NH) with severe asthma nonsmokers (NSA) and NH

        Probe IDProtein targetGene symbolGene nameFunction
        ESA-NH    
         SL004589AZU1AZU1Azurocidin 1A pre-proprotein of a mature azurophil granule antibiotic protein with monocyte chemotactic and antimicrobial activity
         SL000401ELANEELANENeutrophil elastaseThis protease hydrolyses proteins within specialised neutrophil lysosomes, called azurophil granules, as well as proteins of the extracellular matrix
         SL003192CFPCFPComplement factor properdinA positive regulator of the alternative pathway of complement system
         SL000039IL-8CXCL8 (=IL-8)C-X-C motif chemokine ligand 8Acts as one of the major mediators of the inflammatory response by recruiting neutrophils
        NSA-NH    
         SL003524Protein disulfide isomerase A3PDIA3Protein disulfide isomerase family A member 3Formation of the final antigen conformation, export from the endoplasmic reticulum to the cell surface and adaptation to oxidative damage
         SL006108CD5LCD5LCD5 molecule likeThis secreted protein is mainly expressed by macrophages in lymphoid and inflamed tissues and regulates mechanisms in inflammatory responses. Regulation of intracellular lipids mediated by this protein has a direct effect on transcription regulation mediated by nuclear receptors ROR-γ (RORC)
         SL004068GZMBGZMBGranzyme BTargets cell lysis in cell-mediated immune responses. This protein also processes cytokines and degrades extracellular matrix proteins, and these roles are implicated in chronic inflammation and wound healing
        ESA-NH and NSA-NH
         SL017613FCG2A/BFCGR2AFc fragment of immunoglobulin-γ receptor IIaCell surface receptor found on phagocytic cells such as macrophages and neutrophils, is involved in the process of phagocytosis and clearing of immune complexes
         SL000342CatalaseCATCatalaseA key antioxidant enzyme in the body's defence against oxidative stress
         SL000051CRPCRPC-reactive proteinHost defence based on its ability to recognise foreign pathogens and damaged cells of the host and to initiate their elimination by interacting with humoral and cellular effector systems in the blood
         SL004153M-CSF RCSF1RColony-stimulating factor 1 receptorThe receptor for CSF1, a cytokine which controls the production, differentiation and function of macrophages
         SL004853B7-H2ICOSLGInducible T-cell costimulatory ligandThis protein acts as a costimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation into plasma cells

        Assay performed by SomaLogic (Boulder, CO, USA). IL: interleukin.

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          Supplementary file 2 ERJ-02173-2017_File_2

          Supplementary file 3 ERJ-02173-2017_File_3

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        Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis
        Kentaro Takahashi, Stelios Pavlidis, Francois Ng Kee Kwong, Uruj Hoda, Christos Rossios, Kai Sun, Matthew Loza, Fred Baribaud, Pascal Chanez, Steve J. Fowler, Ildiko Horvath, Paolo Montuschi, Florian Singer, Jacek Musial, Barbro Dahlen, Sven-Eric Dahlen, Norbert Krug, Thomas Sandstrom, Dominic E. Shaw, Rene Lutter, Per Bakke, Louise J. Fleming, Peter H. Howarth, Massimo Caruso, Ana R. Sousa, Julie Corfield, Charles Auffray, Bertrand De Meulder, Diane Lefaudeux, Ratko Djukanovic, Peter J. Sterk, Yike Guo, Ian M. Adcock, Kian Fan Chung
        European Respiratory Journal May 2018, 51 (5) 1702173; DOI: 10.1183/13993003.02173-2017

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        Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis
        Kentaro Takahashi, Stelios Pavlidis, Francois Ng Kee Kwong, Uruj Hoda, Christos Rossios, Kai Sun, Matthew Loza, Fred Baribaud, Pascal Chanez, Steve J. Fowler, Ildiko Horvath, Paolo Montuschi, Florian Singer, Jacek Musial, Barbro Dahlen, Sven-Eric Dahlen, Norbert Krug, Thomas Sandstrom, Dominic E. Shaw, Rene Lutter, Per Bakke, Louise J. Fleming, Peter H. Howarth, Massimo Caruso, Ana R. Sousa, Julie Corfield, Charles Auffray, Bertrand De Meulder, Diane Lefaudeux, Ratko Djukanovic, Peter J. Sterk, Yike Guo, Ian M. Adcock, Kian Fan Chung
        European Respiratory Journal May 2018, 51 (5) 1702173; DOI: 10.1183/13993003.02173-2017
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