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  • 1. Brinkman, Paul
    et al.
    Wagener, Ariane H.
    Hekking, Pieter-Paul
    Bansal, Aruna T.
    Maitland-van der Zee, Anke-Hilse
    Wang, Yuanyue
    Weda, Hans
    Knobel, Hugo H.
    Vink, Teunis J.
    Rattray, Nicholas J.
    D'Amico, Arnaldo
    Pennazza, Giorgio
    Santonico, Marco
    Lefaudeux, Diane
    De Meulder, Bertrand
    Auffray, Charles
    Bakke, Per S.
    Caruso, Massimo
    Chanez, Pascal
    Chung, Kian F.
    Corfield, Julie
    Dahlen, Sven-Erik
    Djukanovic, Ratko
    Geiser, Thomas
    Horvath, Ildiko
    Krug, Nobert
    Musial, Jacek
    Sun, Kai
    Riley, John H.
    Shaw, Dominic E.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sousa, Ana R.
    Montuschi, Paolo
    Fowler, Stephen J.
    Sterk, Peter J.
    Identification and prospective stability of electronic nose (eNose)-derived inflammatory phenotypes in patients with severe asthma2019In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 143, no 5, p. 1811-1820.e7Article in journal (Refereed)
    Abstract [en]

    Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes.

    Objectives: We aimed (1) to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses) and (2) to assess the stability of eNose-derived phenotypes in relation to withinpatient clinical and inflammatory changes.

    Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability.

    Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNosedriven clusters (n = 26/33/19) were revealed, showing differences in circulating eosinophil (P = .045) and neutrophil (P = .017) percentages and ratios of patients using oral corticosteroids (P = .035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P = .045).

    Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.

  • 2. Jevnikar, Zala
    et al.
    Ostling, Jorgen
    Calven, Jenny
    Thorn, Kristofer
    Israelsson, Elisabeth
    Oberg, Lisa
    Singhania, Akul
    Lau, Laurie C. K.
    Wilson, Susan J.
    Ward, Jonathan A.
    Chauhan, Anoop
    Sousa, Ana R.
    De Meulder, Bertrand
    Loza, Matthew J.
    Baribaud, Frederic
    Sterk, Peter J.
    Chung, Kian Fan
    Sun, Kai
    Guo, Yike
    Adcock, Ian M.
    Payne, Debbie
    Dahlen, Barbro
    Chanez, Pascal
    Shaw, Dominick E.
    Krug, Norbert
    Hohlfeld, Jens M.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Djukanovic, Ratko
    James, Anna
    Hinks, Timothy S. C.
    Howarth, Peter H.
    Vaarala, Outi
    van Geest, Marleen
    Olsson, Henric
    Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation2019In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 143, no 2, p. 577-590Article in journal (Refereed)
    Abstract [en]

    Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear.

    Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.

    Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens.

    Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta.

    Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.

  • 3. Kuo, Chih-Hsi S.
    et al.
    Pavlidis, Stelios
    Zhu, Jie
    Loza, Matthew
    Baribaud, Fred
    Rowe, Anthony
    Pandis, Ioannis
    Gibeon, David
    Hoda, Uruj
    Sousa, Ana
    Wilson, Susan J.
    Howarth, Peter
    Shaw, Dominick
    Fowler, Stephen
    Dahlen, Barbro
    Chanez, Pascal
    Krug, Norbert
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Fleming, Louise
    Corfield, Julie
    Auffray, Charles
    Djukanovic, Ratko
    Sterk, Peter J.
    Guo, Yike
    Adcock, Ian M.
    Chung, Kian Fan
    Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP-10 and MET2019In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 74, no 6, p. 1102-1112Article in journal (Refereed)
    Abstract [en]

    Background Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma. Methods We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry. Results Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value < 0.05, log2 fold change > 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression. Conclusion Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.

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