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- Kuo, Chih-Hsi Scott, et al.
(författare)
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A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED
- 2017
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 194:4, s. 443-455
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE AND OBJECTIVES: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. We used transcriptomic profiling of airway tissues to help define asthma phenotypes.METHODS: The transcriptome from bronchial biopsies and epithelial brushings of 107 moderate-to-severe asthmatics were annotated by gene-set variation analysis (GSVA) using 42 gene-signatures relevant to asthma, inflammation and immune function. Topological data analysis (TDA) of clinical and histological data was used to derive clusters and the nearest shrunken centroid algorithm used for signature refinement.RESULTS: 9 GSVA signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper type 2 (Th-2) cytokines and lack of corticosteroid response (Group 1 and Group 3). Group 1 had the highest submucosal eosinophils, high exhaled nitric oxide (FeNO) levels, exacerbation rates and oral corticosteroid (OCS) use whilst Group 3 patients showed the highest levels of sputum eosinophils and had a high BMI. In contrast, Group 2 and Group 4 patients had an 86% and 64% probability of having non-eosinophilic inflammation. Using machine-learning tools, we describe an inference scheme using the currently-available inflammatory biomarkers sputum eosinophilia and exhaled nitric oxide levels along with OCS use that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity.CONCLUSION: This analysis demonstrates the usefulness of a transcriptomic-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target Th2-mediated inflammation and/or corticosteroid insensitivity.
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| 2. |
- Kuo, Chih-Hsi S., et al.
(författare)
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Contribution of airway eosinophils in airway wall remodeling in asthma : Role of MMP-10 and MET
- 2019
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 74:6, s. 1102-1112
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 3. |
- Perotin-Collard, Jeanne-Marie, et al.
(författare)
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Subtypes of eosinophilic asthma with discrete gene pathway phenotypes
- 2019
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Ingår i: European Respiratory Journal. - : European Respiratory Society Journals. - 0903-1936 .- 1399-3003. ; 54
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Blood eosinophil counts ≥0.3x109/L are used to define Type-2, eosinophilic asthma. However, differential responses to T2 biologics of patients with eosinophilic asthma suggests that this may be a heterogeneous phenotype with subsets driven by different molecular mechanisms.Methods: Blood transcriptomic data, acquired from 99 severe asthmatics from the U-BIOPRED study (62% female, mean age 54 yr, 41% on oral steroids), were clustered by topological data analysis and cluster boundaries defined by the MORSE method. Gene pathway signatures were identified by Ingenuity Pathway Analysis.Results: Analysis revealed 3 clusters with different modulated gene pathways, i.e. molecular phenotypes. Subtype 1 had high IFN-γ, low IL5, low IL13 and low IL17 gene expression, with reduced glucocorticoid-induced gene expression. Subtype 2 had low IFNγ, high IL5, high IL13 and low IL17 gene expression. Subtype 3 had low IFNγ, high IL5, high IL13 and high IL17 gene expression. Pathway analysis suggested a strong steroid response in Subtypes 2 and 3. Clinically, the three clusters were not different in respect of age, gender, prevalence of atopy, blood or sputum eosinophil counts. Subtype 3 was characterized by high neutrophil counts in blood and bronchial epithelium, frequent sinus disease and asthma exacerbations, OCS treatment, low allergic sensitisation and low exhaled NO. Subtype 1 was characterized by high exhaled NO and more frequent IgE therapy.Conclusion: This study suggests that eosinophilic severe asthma (≥0.3x109/L) can be stratified further into 3 subtypes with distinct gene expression profiles that could be developed as molecular diagnostic biomarkers to guide treatment and thereby improve patient outcomes.
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| 4. |
- Wilson, Susan J., et al.
(författare)
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Airway Elastin is increased in severe asthma and relates to proximal wall area : histological and computed tomography findings from the U-BIOPRED severe asthma study
- 2021
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Ingår i: Clinical and Experimental Allergy. - : John Wiley & Sons. - 0954-7894 .- 1365-2222. ; 51:2, s. 296-304
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Tidskriftsartikel (refereegranskat)abstract
- Background: Airway remodelling, which may include goblet cell hyperplasia / hypertrophy, changes in epithelial integrity, accumulation of extracellular matrix components, smooth muscle hypertrophy and thickening of the lamina reticularis, is a feature of severe asthma and contributes to the clinical phenotype.Objective: Within the U-BIOPRED severe asthma study, we have assessed histological elements of airway remodelling and their relationship to computed tomography (CT) measures of proximal airway dimensions.Methods: Bronchial biopsies were collected from two severe asthma groups, one non-smoker (SAn, n = 28) and one current/ex-smoker (SAs/ex, n = 13), and a mild-moderate asthma group (MMA, n = 28) classified and treated according to GINA guidelines, plus a healthy control group (HC, n = 33). Movat's pentachrome technique was used to identify mucin, elastin and total collagen in these biopsies. The number of goblet cells (mucin+) was counted as a percentage of the total number of epithelial cells and the percentage mucin epithelial area measured. The percentage area of elastic fibres and total collagen within the submucosa was also measured, and the morphology of the elastic fibres classified. Participants in the asthma groups also had a CT scan to assess large airway morphometry.Results: The submucosal tissue elastin percentage was higher in both severe asthma groups (16.1% SAn, 18.9% SAs/ex) compared with the HC (9.7%) but did not differ between asthma groups. There was a positive relationship between elastin and airway wall area measured by CT (n = 18-20, rho=0.544, p = 0.024), which also related to an increase in elastic fibres with a thickened lamellar morphological appearance. Mucin epithelial area and total collagen were not different between the four groups. Due to small numbers of suitable CT scans, it was not feasible to compare airway morphometry between the asthma groups.Conclusion: These findings identify a link between extent of elastin deposition and airway wall thickening in severe asthma.
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