Abstract
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.
The U-BIOPRED cohort of severe asthma patients, containing current-smokers (CSA), ex-smokers (ESA), nonsmokers and healthy nonsmokers 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.
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.
Despite little difference in clinical characteristics, CSA were distinguishable from ESA subjects at the sputum proteomic level, with CSA patients having increased CSF2 expression and ESA patients showing sustained loss of epithelial barrier processes.
Abstract
Inflammatory, oxidative/ER stress and epithelial barrier pathways are differentially activated in current smoking and ex-smoking severe asthma patients http://ow.ly/BVv530j3iP3
Footnotes
The transcriptomic data have been deposited in the Gene Expression Omnibus database, www.ncbi.nlm.nih.gov/geo (accession number GSE76225 for gene expression data of bronchial biopsies).
This article has supplementary material available from erj.ersjournals.com
Author Contributions: K. Takahashi, C. Rossios, M. Loza, F. Ng Kee Kwong, K. Sun and S. Pavlidis performed the analysis; K. Takahashi, K.F. Chung, M. Loza, F. Baribaud, B. de Muelder, C. Auffray, I.M. Adcock and Y. Guo designed the analytical approaches taken and analysed the results; U. Hoda, P. Montuschi, F. Singer, J. Musial, P. Bakke, R. Lutter, P. Chanez, S.J. Fowler, I. Horvath, N. Krug, T. Sandstrom, D.E. Shaw, L.J. Fleming, P.H. Howarth, M. Caruso and B. Dahlen participated in the clinical characterisation of the patients; K. Sun, A.R. Sousa and J. Corfield were part of the data curation team; I.M. Adcock, R. Djukanovic, P.J. Sterk and K.F. Chung conceived of and designed the study; and K. Takahashi, I.M. Adcock and K.F. Chung coordinated the data and drafted the manuscript. All authors read the final version of the manuscript.
Conflict of interest: K. Takahashi received personal fees from Asahi General Hospital, during the conduct of the study.
Conflict of interest: M. Loza is employed by and owns stock in Johnson & Johnson, the parent company of Janssen R&D.
Conflict of interest: F. Baribaud is an employee and shareholder of Janssen R&D.
Conflict of interest: P. Chanez has provided consultancy services for Boehringer Ingelheim, Johnson & Johnson, GlaxoSmithKline, Merck Sharp & Dohme, AstraZeneca, Novartis, Teva, Chiesi, Sanofi and SNCF; has served on advisory boards for Almirall, Boehringer Ingelheim, Johnson & Johnson, GlaxoSmithKline, AstraZeneca, Novartis, Teva, Chiesi and Sanofi; has received lecture fees from Boehringer Ingelheim, Centocor, GlaxoSmithKline, AstraZeneca, Novartis, Teva, Chiesi, Boston Scientific and ALK; and has received industry-sponsored grants from Roche, Boston Scientific, Boehringer Ingelheim, Centocor, GlaxoSmithKline, AstraZeneca, ALK, Novartis, Teva and Chiesi.
Conflict of interest: I. Horvath has received personal fees from Astra Zeneca, Boehringer Ingelheim, Novartis, CSL, Chiesi, Roche, GSK, Berlin-Chemie and Sandoz, outside the submitted work.
Conflict of interest: P. Montuschi reports personal fees from advisory board meetings with AstraZeneca, outside the submitted work.
Conflict of interest: F. Singer has received personal fees and honoraria for speaking engagements from Vertex and Novartis, outside the submitted work.
Conflict of interest: S-E. Dahlén has received research grants from several Swedish funding bodies such as MRC, Heart-Lung-Foundation and the Strategic Research Foundation, during the conduct of the study; and has received personal fees for advisory board meetings from GSK, AZ, Novartis, Teva, Regeneron/Sanofi, Merck and RSPR AB, grants on asthma phenotyping from AZ, and honoraria for speaking engagements from GSK and Teva, outside the submitted work.
Conflict of interest: B. Dahlén has received personal fees from Teva (for advisory board membership) and AstraZeneca (payments for lectures), outside the submitted work.
Conflict of interest: N. Krug reports grants from IMI (U-BIOPRED consortium IMI number 115010), during the conduct of the study.
Conflict of interest: T. Sandström has received personal fees from advisory board meetings with pharmaceutical companies GSK, AZ, Novartis, Teva and Boehringer Ingelheim, and honoraria for speaking engagements for AZ, Novartis, Boehringer Ingelheim, outside the submitted work.
Conflict of interest: D.E. Shaw has received personal fees for advisory board work from GSK, AZ, Teva and Boehringer Ingelheim, outside the submitted work.
Conflict of interest: R. Lutter has received personal fees for advisory board meetings from GSK and Boehringer Ingelheim, and grants on asthma and COPD from GSK, Lung Foundation and MedImmune, outside the submitted work.
Conflict of interest: P. Bakke has received personal fees for advisory board meetings from GSK, AZ, Novartis and Teva, and honoraria for speaking engagements from AZ and Boehringer Ingelheim, outside the submitted work.
Conflict of interest: L.J. Fleming has received personal fees for advisory board meetings from Novartis, Vectura and Boehringer Ingelheim, grants from Asthma UK and BLF, and honoraria for speaking engagements for Novartis, outside the submitted work.
Conflict of interest: P.H. Howarth was employed part time by GSK as Global Medical Expert.
Conflict of interest: M. Caruso received grants (paid to institute) from the Innovative Medicines Initiative (IMI), during the conduct of the study.
Conflict of interest: C. Auffray received grants from the Innovative Medicine Initiative (U-BIOPRED Consortium IMI number 115010 and eTRIKS Consortium IMI number 115446), during the conduct of the study.
Conflict of interest: B. De Meulder received grants from the Innovative Medicine Initiative (U-BIOPRED Consortium IMI number 115010 and eTRIKS Consortium IMI number 115446), during the conduct of the study.
Conflict of interest: D. Lefaudeux received grants from the Innovative Medicine Initiative (U-BIOPRED Consortium IMI number 115010 and eTRIKS Consortium IMI number 115446), during the conduct of the study.
Conflict of interest: R. Djukanovic has received personal fees for lectures at company sponsored symposia and consulting in advisory boards from TEVA, grants (for an investigator led study of mechanisms of action of omalizumab) and personal fees (for lectures at company sponsored symposia and consulting in advisory boards) from Novartis, and is a consultant to, co-founder of, and holds shares in Synairgen, outside the submitted work.
Conflict of interest: P.J. Sterk has received a public-private grant (paid to institute) from Innovative Medicines Initiative (IMI) covered by the European Union (EU) and the European Federation of Pharmaceutical Industries and Associations (EFPIA), during the conduct of the study.
Conflict of interest: I.M. Adcock has received personal fees for advisory board meetings from GSK, AZ, Novartis, Boehringer Ingelheim and Vectura, grants on asthma and COPD from Pfizer, GSK, MRC, EU, BI and IMI, and honoraria for speaking engagements for AZ and BI, outside the submitted work.
Conflict of interest: K.F. Chung has received personal fees for advisory board meetings from GSK, AZ, Novartis, Teva, Boehringer Ingelheim and J&J, grants on asthma and COPD from Pfizer, GSK, MRC, EU IMI and NIH, and honoraria for speaking engagements for AZ and Merck, outside the submitted work.
Support statement: The U-BIOPRED project is supported through an Innovative Medicines Initiative joint undertaking under grant agreement 115010, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions (www.imi.europa.eu). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received December 5, 2017.
- Accepted February 22, 2018.
- Copyright ©ERS 2018
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