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2.
Allergy ; 74(6): 1102-1112, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30667542

RESUMO

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.


Assuntos
Remodelação das Vias Aéreas/genética , Asma/imunologia , Eosinófilos/imunologia , Metaloproteinase 10 da Matriz/genética , Metaloproteinase 10 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Adulto , Asma/patologia , Biópsia , Brônquios/patologia , Estudos de Coortes , Eosinofilia/imunologia , Matriz Extracelular/genética , Feminino , Humanos , Imuno-Histoquímica , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Proteína Proto-Oncogênica c-ets-1/metabolismo , Fatores de Transcrição SOX/metabolismo , Transcriptoma
3.
Eur Respir J ; 53(1)2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578390

RESUMO

Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild-moderate asthma into a T2-high phenotype. We examined whether currently available clinical biomarkers can predict AEC-defined T2-high phenotype within the U-BIOPRED cohort.The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from interleukin (IL)-13-exposed AECs.37% of asthmatics (45% nonsmoking severe asthma, n=49; 33% of smoking or ex-smoking severe asthma, n=18; and 28% mild-moderate asthma, n=36) were T2-high using AEC gene expression. They were more symptomatic with higher exhaled nitric oxide fraction (F eNO) and blood and sputum eosinophils, but not serum IgE or periostin. Sputum eosinophilia correlated best with the T2-high signature. F eNO (≥30 ppb) and blood eosinophils (≥300 cells·µL-1) gave a moderate prediction of T2-high asthma. Sputum IL-4, IL-5 and IL-13 protein levels did not correlate with gene expression.T2-high severe asthma can be predicted to some extent from raised levels of F eNO, blood and sputum eosinophil counts, but serum IgE or serum periostin were poor predictors. Better bedside biomarkers are needed to detect T2-high.


Assuntos
Asma/sangue , Moléculas de Adesão Celular/sangue , Eosinofilia/diagnóstico , Escarro/química , Adulto , Biomarcadores , Testes Respiratórios , Estudos de Casos e Controles , Eosinofilia/sangue , Eosinófilos/citologia , Feminino , Humanos , Imunoglobulina E/sangue , Interleucinas/análise , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/análise , Fenótipo , Estudos Prospectivos , Fumar/efeitos adversos
4.
PLoS One ; 13(9): e0203874, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30240401

RESUMO

Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF2α and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PGF2α; IS-transcriptomics; BB-transcriptomics; BBr-transcriptomics). Urinary 8-iso-PGF2α was quantified using mass spectrometry. Sputum, bronchial biopsy and bronchial brushing were processed for mRNA expression microarray analysis. Urinary 8-iso-PGF2α was increased in SAs/ex, median (IQR) = 31.7 (24.5-44.7) ng/mmol creatinine, compared to SAn, median (IQR) = 26.6 (19.6-36.6) ng/mmol creatinine (p< 0.001), and in CSA, median (IQR) = 34.25 (24.4-47.7), vs. ESA, median (IQR) = 29.4 (22.3-40.5), and NSA, median (IQR) = 26.5 (19.6-16.6) ng/mmol creatinine (p = 0.004). Sputum mRNA expression of NOX2 was increased in SAs/ex compared to SAn (probe sets 203922_PM_s_at fold-change = 1.05 p = 0.006; 203923_PM_s_at fold-change = 1.06, p = 0.003; 233538_PM_s_at fold-change = 1.06, p = 0.014). The mRNA expression of antioxidant enzymes were similar between the two severe asthma cohorts in all airway samples. NOS2 mRNA expression was decreased in bronchial brushing of SAs/ex compared to SAn (fold-change = -1.10; p = 0.029). NOS2 mRNA expression in bronchial brushing correlated with FeNO (Kendal's Tau = 0.535; p< 0.001). From clinical and inflammatory analysis, FeNO was lower in CSA than in ESA in all the analysed subject subsets (p< 0.01) indicating an effect of active smoking. Results about FeNO suggest its clinical limitation, as inflammation biomarker, in severe asthma active smokers. These data provide evidence of greater systemic oxidative stress in severe asthma smokers as reflected by a significant changes of NOX2 mRNA expression in the airways, together with elevated urinary 8-iso-PGF2α in the smokers/ex-smokers group. Trial registration ClinicalTrials.gov-Identifier: NCT01976767.


Assuntos
Asma/metabolismo , Estresse Oxidativo/fisiologia , Fumar Tabaco/efeitos adversos , Adulto , Asma/patologia , Biomarcadores/metabolismo , Broncoscopia , Estudos de Coortes , Feminino , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Fumar/metabolismo , Escarro/metabolismo , Fumar Tabaco/metabolismo
5.
BMC Syst Biol ; 12(1): 60, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29843806

RESUMO

BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.


Assuntos
Doença/genética , Biologia de Sistemas/métodos , Biomarcadores/metabolismo , Análise por Conglomerados , Reações Falso-Positivas , Aprendizado de Máquina , Controle de Qualidade
6.
Eur Respir J ; 51(5)2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29650557

RESUMO

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.


Assuntos
Asma/metabolismo , Ex-Fumantes , Proteômica/métodos , Fumantes , Escarro/metabolismo , Adulto , Idoso , Asma/complicações , Biomarcadores/metabolismo , Brônquios/patologia , Eosinófilos/metabolismo , Expiração , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Fumar/metabolismo , Espirometria
7.
J Allergy Clin Immunol ; 141(2): 560-570, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28528200

RESUMO

BACKGROUND: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1ß protein levels, whereas eosinophilic asthma was associated with an IL-13-induced TH2 signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma. CONCLUSION: IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. TH2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA.


Assuntos
Asma/imunologia , Perfilação da Expressão Gênica , Receptores de Interleucina-1/imunologia , Escarro/imunologia , Regulação para Cima/imunologia , Adulto , Animais , Asma/patologia , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Células Th2/imunologia , Células Th2/patologia
8.
Eur Respir J ; 49(2)2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28179442

RESUMO

Asthma is characterised by heterogeneous clinical phenotypes. Our objective was to determine molecular phenotypes of asthma by analysing sputum cell transcriptomics from 104 moderate-to-severe asthmatic subjects and 16 nonasthmatic subjects.After filtering on the differentially expressed genes between eosinophil- and noneosinophil-associated sputum inflammation, we used unbiased hierarchical clustering on 508 differentially expressed genes and gene set variation analysis of specific gene sets.We defined three transcriptome-associated clusters (TACs): TAC1 (characterised by immune receptors IL33R, CCR3 and TSLPR), TAC2 (characterised by interferon-, tumour necrosis factor-α- and inflammasome-associated genes) and TAC3 (characterised by genes of metabolic pathways, ubiquitination and mitochondrial function). TAC1 showed the highest enrichment of gene signatures for interleukin-13/T-helper cell type 2 (Th2) and innate lymphoid cell type 2. TAC1 had the highest sputum eosinophilia and exhaled nitric oxide fraction, and was restricted to severe asthma with oral corticosteroid dependency, frequent exacerbations and severe airflow obstruction. TAC2 showed the highest sputum neutrophilia, serum C-reactive protein levels and prevalence of eczema. TAC3 had normal to moderately high sputum eosinophils and better preserved forced expiratory volume in 1 s. Gene-protein coexpression networks from TAC1 and TAC2 extended this molecular classification.We defined one Th2-high eosinophilic phenotype TAC1, and two non-Th2 phenotypes TAC2 and TAC3, characterised by inflammasome-associated and metabolic/mitochondrial pathways, respectively.


Assuntos
Asma/genética , Eosinófilos/imunologia , Escarro , Células Th2/imunologia , Transcriptoma , Corticosteroides/uso terapêutico , Adulto , Idoso , Área Sob a Curva , Asma/imunologia , Biomarcadores , Proteína C-Reativa/análise , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Humanos , Interleucina-13/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Fenótipo , Reino Unido
9.
Am J Respir Crit Care Med ; 195(4): 443-455, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-27580351

RESUMO

RATIONALE: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. OBJECTIVES: Using transcriptomic profiling of airway tissues, we sought to define the molecular phenotypes of severe asthma. METHODS: The transcriptome derived from bronchial biopsies and epithelial brushings of 107 subjects with moderate to severe asthma were annotated by gene set variation analysis using 42 gene signatures relevant to asthma, inflammation, and immune function. Topological data analysis of clinical and histologic data was performed to derive clusters, and the nearest shrunken centroid algorithm was used for signature refinement. MEASUREMENTS AND MAIN RESULTS: Nine gene set variation analysis signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper cell type 2 cytokines and lack of corticosteroid response (group 1 and group 3). Group 1 had the highest submucosal eosinophils, as well as high fractional exhaled nitric oxide levels, exacerbation rates, and oral corticosteroid use, whereas group 3 patients showed the highest levels of sputum eosinophils and had a high body mass index. In contrast, group 2 and group 4 patients had an 86% and 64% probability, respectively, of having noneosinophilic inflammation. Using machine learning tools, we describe an inference scheme using the currently available inflammatory biomarkers sputum eosinophilia and fractional exhaled nitric oxide levels, along with oral corticosteroid use, that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity. CONCLUSIONS: This analysis demonstrates the usefulness of a transcriptomics-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target T-helper cell type 2-mediated inflammation and/or corticosteroid insensitivity.


Assuntos
Corticosteroides/imunologia , Asma/genética , Brônquios/patologia , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Adulto , Asma/tratamento farmacológico , Asma/imunologia , Asma/patologia , Biomarcadores/análise , Biópsia , Testes Respiratórios , Broncoscopia/instrumentação , Broncoscopia/métodos , Estudos de Coortes , Resistência a Medicamentos/genética , Resistência a Medicamentos/imunologia , Eosinófilos/citologia , Eosinófilos/imunologia , Feminino , Perfilação da Expressão Gênica/instrumentação , Perfilação da Expressão Gênica/métodos , Humanos , Inflamação , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Índice de Gravidade de Doença , Escarro/citologia , Escarro/imunologia , Células Th2/citologia , Células Th2/imunologia
10.
J Allergy Clin Immunol ; 139(6): 1797-1807, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27773852

RESUMO

BACKGROUND: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalized management approach can be provided. OBJECTIVES: We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum. METHODS: Partition-around-medoids clustering was applied to a training set of 266 asthmatic participants from the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult cohort using 8 prespecified clinic-physiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data. RESULTS: Four reproducible and stable clusters of asthmatic patients were identified. The training set cluster T1 consists of patients with well-controlled moderate-to-severe asthma, whereas cluster T2 is a group of patients with late-onset severe asthma with a history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of nonsmokers. Cluster T4 is predominantly composed of obese female patients with uncontrolled severe asthma with increased exacerbations but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters (T2, T3, and T4) had higher sputum eosinophilia than cluster T1, with no differences in sputum neutrophil counts and exhaled nitric oxide and serum IgE levels. CONCLUSION: Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.


Assuntos
Asma , Escarro , Adulto , Idoso , Algoritmos , Asma/classificação , Asma/genética , Asma/metabolismo , Biomarcadores/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Proteômica , Índice de Gravidade de Doença , Escarro/citologia , Escarro/metabolismo
11.
Am J Respir Crit Care Med ; 195(10): 1311-1320, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27925796

RESUMO

RATIONALE: Stratification of asthma at the molecular level, especially using accessible biospecimens, could greatly enable patient selection for targeted therapy. OBJECTIVES: To determine the value of blood analysis to identify transcriptional differences between clinically defined asthma and nonasthma groups, identify potential patient subgroups based on gene expression, and explore biological pathways associated with identified differences. METHODS: Transcriptomic profiles were generated by microarray analysis of blood from 610 patients with asthma and control participants in the U-BIOPRED (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes) study. Differentially expressed genes (DEGs) were identified by analysis of variance, including covariates for RNA quality, sex, and clinical site, and Ingenuity Pathway Analysis was applied. Patient subgroups based on DEGs were created by hierarchical clustering and topological data analysis. MEASUREMENTS AND MAIN RESULTS: A total of 1,693 genes were differentially expressed between patients with severe asthma and participants without asthma. The differences from participants without asthma in the nonsmoking severe asthma and mild/moderate asthma subgroups were significantly related (r = 0.76), with a larger effect size in the severe asthma group. The majority of, but not all, differences were explained by differences in circulating immune cell populations. Pathway analysis showed an increase in chemotaxis, migration, and myeloid cell trafficking in patients with severe asthma, decreased B-lymphocyte development and hematopoietic progenitor cells, and lymphoid organ hypoplasia. Cluster analysis of DEGs led to the creation of subgroups among the patients with severe asthma who differed in molecular responses to oral corticosteroids. CONCLUSIONS: Blood gene expression differences between clinically defined subgroups of patients with asthma and individuals without asthma, as well as subgroups of patients with severe asthma defined by transcript profiles, show the value of blood analysis in stratifying patients with asthma and identifying molecular pathways for further study. Clinical trial registered with www.clinicaltrials.gov (NCT01982162).


Assuntos
Corticosteroides/uso terapêutico , Asma/sangue , Asma/tratamento farmacológico , Perfilação da Expressão Gênica/métodos , Corticosteroides/sangue , Adulto , Análise por Conglomerados , Estudos de Coortes , Europa (Continente) , Feminino , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Transcriptoma/efeitos dos fármacos
12.
Eur Respir J ; 48(5): 1307-1319, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27799384

RESUMO

The U-BIOPRED study is a multicentre European study aimed at a better understanding of severe asthma. It included three steroid-treated adult asthma groups (severe nonsmokers (SAn group), severe current/ex-smokers (SAs/ex group) and those with mild-moderate disease (MMA group)) and healthy controls (HC group). The aim of this cross-sectional, bronchoscopy substudy was to compare bronchial immunopathology between these groups.In 158 participants, bronchial biopsies and bronchial epithelial brushings were collected for immunopathologic and transcriptomic analysis. Immunohistochemical analysis of glycol methacrylate resin-embedded biopsies showed there were more mast cells in submucosa of the HC group (33.6 mm-2) compared with both severe asthma groups (SAn: 17.4 mm-2, p<0.001; SAs/ex: 22.2 mm-2, p=0.01) and with the MMA group (21.2 mm-2, p=0.01). The number of CD4+ lymphocytes was decreased in the SAs/ex group (4.7 mm-2) compared with the SAn (11.6 mm-2, p=0.002), MMA (10.1 mm-2, p=0.008) and HC (10.6 mm-2, p<0.001) groups. No other differences were observed.Affymetrix microarray analysis identified seven probe sets in the bronchial brushing samples that had a positive relationship with submucosal eosinophils. These mapped to COX-2 (cyclo-oxygenase-2), ADAM-7 (disintegrin and metalloproteinase domain-containing protein 7), SLCO1A2 (solute carrier organic anion transporter family member 1A2), TMEFF2 (transmembrane protein with epidermal growth factor like and two follistatin like domains 2) and TRPM-1 (transient receptor potential cation channel subfamily M member 1); the remaining two are unnamed.We conclude that in nonsmoking and smoking patients on currently recommended therapy, severe asthma exists despite suppressed tissue inflammation within the proximal airway wall.


Assuntos
Asma/fisiopatologia , Asma/terapia , Brônquios/fisiopatologia , Inflamação/tratamento farmacológico , Resinas Acrílicas/química , Adulto , Biópsia , Brônquios/imunologia , Broncoscopia , Linfócitos T CD4-Positivos/citologia , Estudos de Casos e Controles , Estudos Transversais , Europa (Continente) , Feminino , Humanos , Imunoquímica , Masculino , Metacrilatos/química , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fumar , Transcriptoma
13.
Eur Respir J ; 46(5): 1308-21, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26357963

RESUMO

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.


Assuntos
Corticosteroides/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/complicações , Fumar/efeitos adversos , Adulto , Ansiedade/epidemiologia , Asma/tratamento farmacológico , Asma/epidemiologia , Estudos de Casos e Controles , Comorbidade , Estudos Transversais , Depressão/epidemiologia , Europa (Continente) , Feminino , Refluxo Gastroesofágico/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/análise , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Fumar/epidemiologia , Espirometria , Inquéritos e Questionários , Biologia de Sistemas
14.
Eur Respir J ; 46(5): 1322-33, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26405287

RESUMO

U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches. A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study. Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; p<0.001). Exhaled tobacco exposure was common in the severe wheeze cohort. Almost all participants in each cohort were atopic and had a normal body mass index. Asthma-related quality of life, as assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), was worse in the severe cohorts (mean±se school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management.


Assuntos
Corticosteroides/uso terapêutico , Asma/tratamento farmacológico , Asma/epidemiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Adolescente , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Estudos Transversais , Europa (Continente) , Feminino , Humanos , Hipersensibilidade Imediata , Masculino , Pediatria , Estudos Prospectivos , Qualidade de Vida , Sons Respiratórios/diagnóstico , Índice de Gravidade de Doença , Espirometria , Inquéritos e Questionários
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