Severe asthma exists despite suppressed tissue inflammation: findings of the U-BIOPRED study

Wilson, Susan J.; Ward, Jonathan; Sousa, Ana R.; Corfield, Julie; Bansal, Aruna T.; Meulder, Bertrand De; Lefaudeux, Diane; Auffray, Charles; Loza, Matthew J.; Baribaud, Frédéric; Fitch, Neil; Sterk, Peter J.; Chung, Kian Fan; Gibeon, David; Sun, Kai; Guo, Yike; Adcock, Ian M.; Djukanović, Ratko; Dahlén, Barbro; Chanez, Pascal; Shaw, Dominick; Krug, Norbert; Hohlfeld, Jens M.; Sandström, Thomas; Howarth, Peter H.

doi:10.1183/13993003.01129-2016

Cited by 50 publications

(53 citation statements)

References 40 publications

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“…Thus, in treatment-resistant severe asthma there appears to be an effective steroid response in central airways, which is less evident in peripheral airways where the IL-13 disease signature persists (Fig 5). This would be consistent with recently reported central airway biopsy findings in severe asthma [29]. …”

Section: Discussionsupporting

confidence: 94%

Altered Epithelial Gene Expression in Peripheral Airways of Severe Asthma

et al. 2017

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Management of severe asthma remains a challenge despite treatment with glucocorticosteroid therapy. The majority of studies investigating disease mechanisms in treatment-resistant severe asthma have previously focused on the large central airways, with very few utilizing transcriptomic approaches. The small peripheral airways, which comprise the majority of the airway surface area, remain an unexplored area in severe asthma and were targeted for global epithelial gene expression profiling in this study. Differences between central and peripheral airways were evaluated using transcriptomic analysis (Affymetrix HG U133 plus 2.0 GeneChips) of epithelial brushings obtained from severe asthma patients (N = 17) and healthy volunteers (N = 23). Results were validated in an independent cohort (N = 10) by real-time quantitative PCR. The IL-13 disease signature that is associated with an asthmatic phenotype was upregulated in severe asthmatics compared to healthy controls but was predominantly evident within the peripheral airways, as were genes related to mast cell presence. The gene expression response associated with glucocorticosteroid therapy (i.e. FKBP5) was also upregulated in severe asthmatics compared to healthy controls but, in contrast, was more pronounced in central airways. Moreover, an altered epithelial repair response (e.g. FGFBP1) was evident across both airway sites reflecting a significant aspect of disease in severe asthma unadressed by current therapies. A transcriptomic approach to understand epithelial activation in severe asthma has thus highlighted the need for better-targeted therapy to the peripheral airways in severe asthma, where the IL-13 disease signature persists despite treatment with currently available therapy.

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Section: Discussionsupporting

confidence: 94%

Altered Epithelial Gene Expression in Peripheral Airways of Severe Asthma

et al. 2017

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“…Cell counts were performed in a blinded fashion and expressed as number of positive cells/mm 2 . These results have already been reported …”

Section: Methodssupporting

confidence: 87%

“…Because the comparison of asthmatic to normal controls did not yield any satisfactory clinical profiles, we next focused on the transcriptomic differences in bronchial biopsies between eosinophil‐high and eosinophil‐low patients. To this end, the K‐mean clustering method was applied, which yielded four homogeneous mucosal eosinophil clusters (low, medium‐low, medium‐high, and high; Figure A), as determined by the within‐group sum of squares, using the eosinophil counts in bronchial biopsies that have been previously reported in this cohort (Figure B). The low and medium‐low clusters were further aggregated as the low mucosal eosinophil (LE) group (n = 48), and the medium‐high and high clusters as the high mucosal eosinophil (HE) group (n = 33).…”

Section: Resultsmentioning

confidence: 99%

Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP‐10 and MET

Kuo

Pavlidis

Zhu

et al. 2019

Allergy

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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.

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“…3 This is the biggest study of its kind and revealed unexpected data. There were fewer mast cells in the submucosa of the asthmatics than with the healthy controls.…”

Section: Q: How Can the Definition Of Asthma Phenotypes Help In Diseamentioning

confidence: 99%