PT - JOURNAL ARTICLE AU - Kentaro Takahashi AU - Stelios Pavlidis AU - Francois Ng Kee Kwong AU - Uruj Hoda AU - Christos Rossios AU - Kai Sun AU - Matthew Loza AU - Fred Baribaud AU - Pascal Chanez AU - Steve J Fowler AU - Ildiko Horvath AU - Paolo Montuschi AU - Florian Singer AU - Jacek Musial AU - Barbro Dahlen AU - Sven-Eric Dahlen AU - N. Krug AU - Thomas Sandstrom AU - Dominic E. Shaw AU - Rene Lutter AU - Per Bakke AU - Louise J. Fleming AU - Peter H. Howarth AU - Massimo Caruso AU - Ana R Sousa AU - Julie Corfield AU - Charles Auffray AU - Bertrand De Meulder AU - Diane Lefaudeux AU - Ratko Djukanovic AU - Peter J Sterk AU - Yike Guo AU - Ian M. Adcock AU - Kian Fan Chung ED - , TI - Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis AID - 10.1183/13993003.02173-2017 DP - 2018 Jan 01 TA - European Respiratory Journal PG - 1702173 4099 - http://erj.ersjournals.com/content/early/2018/02/15/13993003.02173-2017.short 4100 - http://erj.ersjournals.com/content/early/2018/02/15/13993003.02173-2017.full AB - Background: Severe asthma patients with a significant smoking history have airflow obstruction with reported neutrophilia. We hypothesise that multi-omic analysis will enable the definition of smoking and ex-smoking severe asthma molecular phenotypes.Methods: The U-BIOPRED severe asthma patients containing current-smokers (CSA), ex-smokers (ESA), non-smokers (NSA) and healthy non-smokers (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.Inflammatory, oxidative/ER stress and epithelial barrier pathways are differentially activated in current smoking and ex-smoking severe asthma patientsFootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Takahashi reports personal fees from Asahi General Hospital, during the conduct of the study.Conflict of interest: Dr. Pavlidis has nothing to disclose.Conflict of interest: Dr. Ng Kee Kwong has nothing to disclose.Conflict of interest: Dr. Hoda has nothing to disclose.Conflict of interest: Dr. Rossios has nothing to disclose.Conflict of interest: Dr. Sun has nothing to disclose.Conflict of interest: Dr. Loza reports other from Janssen R& D, outside the submitted work.Conflict of interest: F. Baribaud reports being an employee and share holder of Janssen R& D.Conflict of interest: PC had:Consultancy services for Boehringer Ingelheim, Johnson & Johnson, GlaxoSmithKline, Merck Sharp & Dohme, AstraZeneca, Novartis, Teva, Chiesi, Sanofi and SNCF?Served on advisory boards for Almirall, Boehringer Ingelheim, Johnson & Johnson, GlaxoSmithKline, AstraZeneca, Novartis, Teva, Chiesi, and Sanofi Received lecture fees from Boehringer Ingelheim, Centocor, GlaxoSmithKline, AstraZeneca, Novartis, Teva, Chiesi, Boston Scientific and ALK?Received industry-sponsored grants from Roche, Boston Scientific, Boehringer Ingelheim, Centocor, GlaxoSmithKline, AstraZeneca, ALK, Novartis, Teva, and ChiesiConflict of interest: Dr. Fowler has nothing to disclose.Conflict of interest: Dr. Horvath reports personal fees from Astra Zeneca, personal fees from Boeringher Ingelheim, personal fees from Novartis, personal fees from CSL, personal fees from Chiesi, personal fees from Roche, personal fees from GSK, personal fees from Berlin-Chemie, personal fees from Sandoz, outside the submitted work.Conflict of interest: Dr. Montuschi reports personal fees from Advisory Board meeting with AstraZeneca, outside the submitted work.Dr. Montuschi reports personal fees from Advisory Board membership, outside the submitted work.Conflict of interest: Dr. Singer reports personal fees from Honoraria for speaking engagements for Vertex and Novartis, outside the submitted work.Conflict of interest: Dr. Musial has nothing to disclose.Conflict of interest: Dr. Dahlén reports Research grants from several Swedish funding bodies such as MRC, Heart-Lung-Foundation, the Strategic Research Foundation, during the conduct of the study; personal fees from Advisory Board meetings with pharmaceutical companies GSK, AZ, Novartis, Teva, Regeneron/Sanofi, Merck and RSPR AB, grants on asthma phenotyping from AZ, personal fees from Honoraria for speaking engagements for GSK and Teva, outside the submitted work.Conflict of interest: Dr. Dahlén reports personal fees from Teva (Advisory Board membership), personal fees from AstraZeneca (Payments for lectures), outside the submitted work.Conflict of interest: Dr. Krug reports grants from IMI (U-BIOPRED Consortium IMI n°115010), during the conduct of the study.Conflict of interest: Dr. Sandström reports personal fees from Advisory Board meetings with pharmaceutical companies GSK, A-Z, Novartis, Teva, Boeringher Ingelheim , personal fees from Honoraria for speaking engagements for AZ, Novartis, Boeringher Ingelheim, outside the submitted work.Conflict of interest: Dr. Shaw reports personal fees from advisory boards outside the submitted work.Conflict of interest: Dr. Lutter reports personal fees from Advisory Board meetings with pharmaceutical companies GSK and Boeringher Ingelheim., grants on asthma and COPD from GSK, Lung Foundation, MedImmune, outside the submitted work.Conflict of interest: Dr. Bakke reports personal fees from Advisory Board meetings with pharmaceutical companies GSK, A-Z, Novartis, Teva, personal fees from Honoraria for speaking engagements for AZ and Boehringer-Ingelheim, outside the submitted work.Dr. Bakke reports personal fees from Advisory Board meetings with pharmaceutical companies GSK, A-Z, Novartis, Teva, personal fees from Honoraria for speaking engagements for AZ and Boehringer-Ingelheim, outside the submitted work.Conflict of interest: Dr. Fleming reports personal fees from Advisory Board meetings with pharmaceutical companies Novartis, Vectura and Boeringher Ingelheim, grants from Asthma UK and BLF , personal fees from Honoraria for speaking engagements for Novartis, outside the submitted work.Conflict of interest: Dr. Howarth reports and Part time employment by GSK as Global Medical Expert.Conflict of interest: Dr. Massimo Caruso reports grants for his Institute from Innovative Medicines Initiative (IMI), during the conduct of the study.Conflict of interest: Dr. Sousa has nothing to disclose.Conflict of interest: Julie Corfield has nothing to discloseConflict of interest: Dr. AUFFRAY reports grants from Innovative Medicine Initiative (U-BIOPRED Consortium IMI n°115010), grants from Innovative Medicine Initiative (eTRIKS Consortium IMI n°115446), during the conduct of the study.Conflict of interest: Dr. De Meulder reports grants from Innovative Medicine Initiative, for U-BIOPRED Consortium IMI number 115010 and eTRIKS Consortium IMI number 115446, during the conduct of the study.Conflict of interest: Dr. LEFAUDEUX reports grants from Innovative Medicine Initiative (U-BIOPRED Consortium IMI n°115010), grants from Innovative Medicine Initiative (eTRIKS Consortium IMI n°115446), during the conduct of the study.Conflict of interest: Dr. Djukanovic reports personal fees from TEVA, grants and personal fees from Novartis, and personal fees and other support from Synairgen outside the submitted work.Conflict of interest: Dr. Sterk reports grants from Innovative Medicines Initiative (IMI), during the conduct of the study.Conflict of interest: Dr. Guo has nothing to disclose.Conflict of interest: Dr. Adcock reports personal fees from Advisory Board meetings with pharmaceutical companies GSK, A-Z, Novartis, Boeringher Ingelheim and Vectura, Grants on asthma and COPD from Pfizer, GSK, MRC, EU, BI and IMI, personal fees from Honoraria for speaking engagements for AZ and BI., outside the submitted work.Conflict of interest: Dr. Chung reports personal fees from Advisory Board meetings with pharmaceutical companies GSK, A-Z, Novartis, Teva, Boeringher Ingelheim and J & J., grants on asthma and COPD from Pfizer, GSK, MRC, EU IMI and NIH, personal fees from Honoraria for speaking engagements for AZ and Merck, outside the submitted work; 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