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1.
Sci Rep ; 12(1): 5610, 2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379844

RESUMO

Smoking is a leading cause of chronic obstructive pulmonary disease (COPD). It is known to have a significant impact on gene expression and (inflammatory) cell populations in the airways involved in COPD pathogenesis. In this study, we investigated the impact of smoking on the expression of miRNAs in healthy and COPD individuals. We aimed to elucidate the overall smoking-induced miRNA changes and those specific to COPD. In addition, we investigated the downstream effects on regulatory gene expression and the correlation to cellular composition. We performed a genome-wide miRNA expression analysis on a dataset of 40 current- and 22 ex-smoking COPD patients and a dataset of 35 current- and 38 non-smoking respiratory healthy controls and validated the results in an independent dataset. miRNA expression was then correlated with mRNA expression in the same patients to assess potential regulatory effects of the miRNAs. Finally, cellular deconvolution analysis was used to relate miRNAs changes to specific cell populations. Current smoking was associated with increased expression of three miRNAs in the COPD patients and 18 miRNAs in the asymptomatic smokers compared to respiratory healthy controls. In comparison, four miRNAs were lower expressed with current smoking in asymptomatic controls. Two of the three smoking-related miRNAs in COPD, miR-203a-3p and miR-375, were also higher expressed with current smoking in COPD patients and the asymptomatic controls. The other smoking-related miRNA in COPD patients, i.e. miR-31-3p, was not present in the respiratory healthy control dataset. miRNA-mRNA correlations demonstrated that miR-203a-3p, miR-375 and also miR-31-3p expression were negatively associated with genes involved in pro-inflammatory pathways and positively associated with genes involved in the xenobiotic pathway. Cellular deconvolution showed that higher levels of miR-203a-3p were associated with higher proportions of proliferating-basal cells and secretory (club and goblet) cells and lower levels of fibroblasts, luminal macrophages, endothelial cells, B-cells, amongst other cell types. MiR-375 expression was associated with lower levels of secretory cells, ionocytes and submucosal cells, but higher levels of endothelial cells, smooth muscle cells, and mast cells, amongst other cell types. In conclusion, we identified two smoking-induced miRNAs (miR-375 and miR-203a-3p) that play a role in regulating inflammation and detoxification pathways, regardless of the presence or absence of COPD. Additionally, in patients with COPD, we identified miR-31-3p as a miRNA induced by smoking. Our identified miRNAs should be studied further to unravel which smoking-induced inflammatory mechanisms are reactive and which are involved in COPD pathogenesis.


Assuntos
MicroRNAs , Doença Pulmonar Obstrutiva Crônica , Células Endoteliais/metabolismo , Humanos , Pulmão/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumantes
2.
Lancet Respir Med ; 2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35247313

RESUMO

BACKGROUND: Although small airway disease is a feature of asthma, its association with relevant asthma outcomes remains unclear. The ATLANTIS study was designed to identify the combination of physiological and imaging variables that best measure the presence and extent of small airway disease in asthma, both cross-sectionally and longitudinally. In this longitudinal analysis, we evaluated which small airway parameters studied were most strongly associated with asthma control, exacerbations, and quality of life. METHODS: In this observational cohort study, participants with mild, moderate, or severe stable asthma were recruited between June 30, 2014, and March 3, 2017, via medical databases and advertisements in nine countries worldwide. Eligible participants were aged 18-65 years with a clinical asthma diagnosis for at least 6 months. Participants were followed up for 1 year, with visits at baseline, 6 months, and 12 months. Physiological tests included spirometry, lung volumes, impulse oscillometry, multiple breath nitrogen washout (MBNW), and percentage decrease in forced vital capacity during methacholine challenge. CT densitometry was performed to evaluate small airway disease. We examined the associations between these measurements and asthma exacerbations, asthma control, and quality of life using univariate and multivariate analyses. A composite ordinal score comprising percent predicted R5-20 (resistance of small-to-mid-sized airways), AX (area of reactance), and X5 (reactance of more central, conducting small airways at 5 Hz) was constructed. FINDINGS: 773 participants (median age 46 years [IQR 34-54]; 450 [58%] female) were included in this longitudinal study. Univariate analyses showed that components of impulse oscillometry, lung volumes, MBNW, and forced expiratory flow at 25-75% of FVC were significantly correlated with asthma control and exacerbations (Spearman correlations 0·20-0·25, p<0·0001 after Bonferroni correction). As a composite of impulse oscillometry, the ordinal score independently predicted asthma control and exacerbations in a multivariate analysis with known exacerbation predictors. CT parameters were not significantly correlated with asthma control, exacerbation, or quality of life. INTERPRETATION: Small airway disease, as measured by physiological tests, is longitudinally associated with clinically important asthma outcomes, such as asthma control and exacerbations. FUNDING: Chiesi Farmaceutici.

3.
Cells ; 11(3)2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35159335

RESUMO

We recently identified microRNAs (miRNAs) associated with chronic mucus hypersecretion (CMH) in chronic obstructive pulmonary disease (COPD), which were expressed in both airway epithelial cells and fibroblasts. We hypothesized that these miRNAs are involved in communication between fibroblasts and epithelium, contributing to airway remodeling and CMH in COPD. Primary bronchial epithelial cells (PBECs) differentiated at the air-liquid interface, and airway fibroblasts (PAFs) from severe COPD patients with CMH were cultured alone or together. RNA was isolated and miRNA expression assessed. miRNAs differentially expressed after co-culturing were studied functionally using overexpression with mimics in mucus-expressing human lung A549 epithelial cells or normal human lung fibroblasts. In PBECs, we observed higher miR-708-5pexpression upon co-culture with fibroblasts, and miR-708-5p expression decreased upon mucociliary differentiation. In PAFs, let-7a-5p, miR-31-5p and miR-146a-5p expression was significantly increased upon co-culture. miR-708-5p overexpression suppressed mucin 5AC (MUC5AC) secretion in A549, while let-7a-5poverexpression suppressed its target gene COL4A1 in lung fibroblasts. Our findings suggest that let-7a-5p, miR-31-5p and miR-146a-5p may be involved in CMH via fibroblasts-epithelium crosstalk, including extracellular matrix gene regulation, while airway epithelial expression of miR-708-5p may be involved directly, regulating mucin production. These findings shed light on miRNA-mediated mechanisms underlying CMH, an important symptom in COPD.


Assuntos
MicroRNAs , Doença Pulmonar Obstrutiva Crônica , Epitélio/metabolismo , Fibroblastos/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Muco/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo
4.
Chest ; 161(5): 1155-1166, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35104449

RESUMO

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.


Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Asma/diagnóstico , Estudo de Associação Genômica Ampla , Humanos , Pulmão , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética
5.
Allergy ; 2022 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-35113452

RESUMO

Currently available European Alpine Altitude Climate Treatment (AACT) programs combine the physical characteristics of altitude with the avoidance of environmental triggers in the alpine climate and a personalized multidisciplinary pulmonary rehabilitation approach. The reduced barometric pressure, oxygen pressure, and air density, the relatively low temperature and humidity, and the increased UV radiation at moderate altitude induce several physiological and immunological adaptation responses. The environmental characteristics of the alpine climate include reduced aeroallergens such as house dust mites (HDM), pollen, fungi, and less air pollution. These combined factors seem to have immunomodulatory effects controlling pathogenic inflammatory responses and favoring less neuro-immune stress in patients with different asthma phenotypes. The extensive multidisciplinary treatment program may further contribute to the observed clinical improvement by AACT in asthma control and quality of life, fewer exacerbations and hospitalizations, reduced need for oral corticosteroids (OCS), improved lung function, decreased airway hyperresponsiveness (AHR), improved exercise tolerance, and improved sinonasal outcomes. Based on observational studies and expert opinion, AACT represents a valuable therapy for those patients irrespective of their asthma phenotype, who cannot achieve optimal control of their complex condition despite all the advances in medical science and treatment according to guidelines, and therefore run the risk of falling into a downward spiral of loss of physical and mental health. In the light of the observed rapid decrease in inflammation and immunomodulatory effects, AACT can be considered as a natural treatment that targets biological pathways.

6.
Ned Tijdschr Geneeskd ; 1662022 01 12.
Artigo em Holandês | MEDLINE | ID: mdl-35129901

RESUMO

BACKGROUND: When suspected of difficult-to-treat asthma, it is important to detect causal factors. Central airway malignancy should also be excluded in this group. CASE DESCRIPTION: We describe the case of a 23-year-old woman who came to the emergency room for shortness of breath and was subsequently admitted to the intensive care unit for respiratory failure, indicated by an asthma exacerbation. At an outpatient visit for dyspnea complaints, now with a stridor on physical examination, a chest CT was performed, which showed an occlusive lesion. Bronchoscopy turned out to be an endobronchial tumor. PA showed that it was a primary pulmonary myxoid sarcoma. CONCLUSION: The case above shows why it is important to consider rare pathologies, such as a central airway tumor, in asthma that is difficult to treat. A thorough history and physical examination is an important first step, especially the presence of a stridor.


Assuntos
Asma , Asma/complicações , Asma/diagnóstico , Broncoscopia , Diagnóstico Diferencial , Dispneia/diagnóstico , Dispneia/etiologia , Feminino , Humanos , Sons Respiratórios/etiologia , Adulto Jovem
7.
Eur Radiol ; 2022 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-35192013

RESUMO

OBJECTIVE: Research on computed tomography (CT) bronchial parameter measurements shows that there are conflicting results on the values for bronchial parameters in the never-smoking, smoking, asthma, and chronic obstructive pulmonary disease (COPD) populations. This review assesses the current CT methods for obtaining bronchial wall parameters and their comparison between populations. METHODS: A systematic review of MEDLINE and Embase was conducted following PRISMA guidelines (last search date 25th October 2021). Methodology data was collected and summarised. Values of percentage wall area (WA%), wall thickness (WT), summary airway measure (Pi10), and luminal area (Ai) were pooled and compared between populations. RESULTS: A total of 169 articles were included for methodologic review; 66 of these were included for meta-analysis. Most measurements were obtained from multiplanar reconstructions of segmented airways (93 of 169 articles), using various tools and algorithms; third generation airways in the upper and lower lobes were most frequently studied. COPD (12,746) and smoking (15,092) populations were largest across studies and mostly consisted of men (median 64.4%, IQR 61.5 - 66.1%). There were significant differences between populations; the largest WA% was found in COPD (mean SD 62.93 ± 7.41%, n = 6,045), and the asthma population had the largest Pi10 (4.03 ± 0.27 mm, n = 442). Ai normalised to body surface area (Ai/BSA) (12.46 ± 4 mm2, n = 134) was largest in the never-smoking population. CONCLUSIONS: Studies on CT-derived bronchial parameter measurements are heterogenous in methodology and population, resulting in challenges to compare outcomes between studies. Significant differences between populations exist for several parameters, most notably in the wall area percentage; however, there is a large overlap in their ranges. KEY POINTS: • Diverse methodology in measuring airways contributes to overlap in ranges of bronchial parameters among the never-smoking, smoking, COPD, and asthma populations. • The combined number of never-smoking participants in studies is low, limiting insight into this population and the impact of participant characteristics on bronchial parameters. • Wall area percent of the right upper lobe apical segment is the most studied (87 articles) and differentiates all except smoking vs asthma populations.

8.
Eur Respir Rev ; 31(163)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35140105

RESUMO

Recently, "Technical standards for respiratory oscillometry" was published, which reviewed the physiological basis of oscillometric measures and detailed the technical factors related to equipment and test performance, quality assurance and reporting of results. Here we present a review of the clinical significance and applications of oscillometry. We briefly review the physiological principles of oscillometry and the basics of oscillometry interpretation, and then describe what is currently known about oscillometry in its role as a sensitive measure of airway resistance, bronchodilator responsiveness and bronchial challenge testing, and response to medical therapy, particularly in asthma and COPD. The technique may have unique advantages in situations where spirometry and other lung function tests are not suitable, such as in infants, neuromuscular disease, sleep apnoea and critical care. Other potential applications include detection of bronchiolitis obliterans, vocal cord dysfunction and the effects of environmental exposures. However, despite great promise as a useful clinical tool, we identify a number of areas in which more evidence of clinical utility is needed before oscillometry becomes routinely used for diagnosing or monitoring respiratory disease.


Assuntos
Resistência das Vias Respiratórias , Asma , Humanos , Oscilometria , Testes de Função Respiratória , Espirometria
9.
Eur Respir J ; 2022 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-35086829

RESUMO

The Human Cell Atlas (HCA) consortium aims to establish an atlas of all organs in the healthy human body at single-cell resolution to increase our understanding of basic biological processes that govern development, physiology and anatomy, and to accelerate diagnosis and treatment of disease. The lung biological network of the HCA aims to generate the Human Lung Cell Atlas as a reference for the cellular repertoire, molecular cell states and phenotypes, and the cell-cell interactions that characterise normal lung homeostasis in healthy lung tissue. Such a reference atlas of the healthy human lung will facilitate mapping the changes in the cellular landscape in disease. The discovAIR project is one of six pilot actions for the HCA funded by the European Commission in the context of the H2020 framework program. DiscovAIR aims to establish the first draft of an integrated Human Lung Cell Atlas, combining single-cell transcriptional and epigenetic profiling with spatially resolving techniques on matched tissue samples, as well as including a number of chronic and infectious diseases of the lung. The integrated Lung Cell Atlas will be available as a resource for the wider respiratory community, including basic and translational scientists, clinical medicine, and the private sector, as well as for patients with lung disease and the interested lay public. We anticipate that the Lung Cell Atlas will be the founding stone for a more detailed understanding of the pathogenesis of lung diseases, guiding the design of novel diagnostics and preventive or curative interventions.

10.
Ann Allergy Asthma Immunol ; 128(4): 352-360, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35074516

RESUMO

OBJECTIVE: Long-acting muscarinic antagonists (LAMAs) have been used in the treatment of obstructive pulmonary diseases for years. Long-acting muscarinic antagonists were previously mainly used as bronchodilators in chronic obstructive pulmonary disease, but the use of LAMAs in the treatment of asthma has gained great interest. There is now ample evidence of the efficacy and safety of LAMAs as add-on therapy to inhaled corticosteroid (ICS) plus long-acting ß2-agonist (LABA) combinations in patients with moderate to severe uncontrolled asthma. Long-acting muscarinic antagonists have subsequently been included in asthma guidelines. This review summarizes the scientific evidence on the use of LAMAs in asthma and aims to provide a better understanding of the role of LAMAs in the asthma treatment care algorithm and the current gaps in our knowledge. DATA SOURCES: PubMed review using the following words: long-acting muscarinic antagonists, asthma, muscarinic receptors, tiotropium, glycopyrronium, umeclidinium. STUDY SELECTIONS: This review focused on the key trials that led to the inclusion of LAMAs in asthma guidelines. In addition, we highlighted a number of studies with other study designs and populations. RESULTS: We identified 6 major studies that led to inclusion in asthma guidelines and 3 studies with other study designs and populations. CONCLUSION: Long-acting muscarinic antagonists add-on therapy to ICS-LABA improves lung function, reduces exacerbations, and modestly improves asthma control in patients with moderate to severe asthma who are uncontrolled despite the use of ICS-LABA. Long-acting muscarinic antagonists are effective in all asthma phenotypes and endotypes.


Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Asma/tratamento farmacológico , Quimioterapia Combinada , Humanos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/uso terapêutico
12.
Antimicrob Agents Chemother ; 66(1): e0154321, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34633839

RESUMO

Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 µM. These limited in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. However, in April 2021, the World Health Organization stated the following: "The current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive." It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to-head comparison of the antiviral activity of ivermectin and the structurally related, but metabolically more stable moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that these compounds predominantly act on the steps following virus cell entry. Surprisingly, however, in human-airway-derived cell models, both moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at concentrations of 10 µM. These disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on their activity in Vero cells. Altogether, these findings suggest that even using a high-dose regimen of ivermectin, or switching to another drug in the same class, is unlikely to be useful for treatment of SARS-CoV-2 in humans.


Assuntos
COVID-19 , Ivermectina , Animais , Antivirais/farmacologia , Chlorocebus aethiops , Células Epiteliais , Humanos , Ivermectina/farmacologia , Macrolídeos , SARS-CoV-2 , Células Vero , Replicação Viral
13.
Lancet Respir Med ; 10(1): 83-94, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34619103

RESUMO

BACKGROUND: During the past century, socioeconomic and scientific advances have resulted in changes in the health and physique of European populations. Accompanying improvements in lung function, if unrecognised, could result in the misclassification of lung function measurements and misdiagnosis of lung diseases. We therefore investigated changes in population lung function with birth year across the past century, accounting for increasing population height, and examined how such changes might influence the interpretation of lung function measurements. METHODS: In our analyses of cross-sectional data from ten European population-based studies, we included individuals aged 20-94 years who were born between 1884 and 1996, regardless of previous respiratory diagnoses or symptoms. FEV1, forced vital capacity (FVC), height, weight, and smoking behaviour were measured between 1965 and 2016. We used meta-regression to investigate how FEV1 and FVC (adjusting for age, study, height, sex, smoking status, smoking pack-years, and weight) and the FEV1/FVC ratio (adjusting for age, study, sex, and smoking status) changed with birth year. Using estimates from these models, we graphically explored how mean lung function values would be expected to progressively deviate from predicted values. To substantiate our findings, we used linear regression to investigate how the FEV1 and FVC values predicted by 32 reference equations published between 1961 and 2015 changed with estimated birth year. FINDINGS: Across the ten included studies, we included 243 465 European participants (mean age 51·4 years, 95% CI 51·4-51·5) in our analysis, of whom 136 275 (56·0%) were female and 107 190 (44·0%) were male. After full adjustment, FEV1 increased by 4·8 mL/birth year (95% CI 2·6-7·0; p<0·0001) and FVC increased by 8·8 mL/birth year (5·7-12·0; p<0·0001). Birth year-related increases in the FEV1 and FVC values predicted by published reference equations corroborated these findings. This height-independent increase in FEV1 and FVC across the last century will have caused mean population values to progressively exceed previously predicted values. However, the population mean adjusted FEV1/FVC ratio decreased by 0·11 per 100 birth years (95% CI 0·09-0·14; p<0·0001). INTERPRETATION: If current diagnostic criteria remain unchanged, the identified shifts in European values will allow the easier fulfilment of diagnostic criteria for lung diseases such as chronic obstructive pulmonary disease, but the systematic underestimation of lung disease severity. FUNDING: The European Respiratory Society, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Menarini, and Sanofi-Genzyme.


Assuntos
Pneumopatias , Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Espirometria , Capacidade Vital , Adulto Jovem
15.
Thorax ; 77(1): 31-39, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33972452

RESUMO

BACKGROUND: COPD is characterised by progressive lung function decline. Leveraging prior work demonstrating bronchial airway COPD-associated gene expression alterations, we sought to determine if there are alterations associated with differences in the rate of FEV1 decline. METHODS: We examined gene expression among ever smokers with and without COPD who at baseline had bronchial brushings profiled by Affymetrix microarrays and had longitudinal lung function measurements (n=134; mean follow-up=6.38±2.48 years). Gene expression profiles associated with the rate of FEV1 decline were identified by linear modelling. RESULTS: Expression differences in 171 genes were associated with rate of FEV1 decline (false discovery rate <0.05). The FEV1 decline signature was replicated in an independent dataset of bronchial biopsies from patients with COPD (n=46; p=0.018; mean follow-up=6.76±1.32 years). Genes elevated in individuals with more rapid FEV1 decline are significantly enriched among the genes altered by modulation of XBP1 in two independent datasets (Gene Set Enrichment Analysis (GSEA) p<0.05) and are enriched in mucin-related genes (GSEA p<0.05). CONCLUSION: We have identified and replicated an airway gene expression signature associated with the rate of FEV1 decline. Aspects of this signature are related to increased expression of XBP1-regulated genes, a transcription factor involved in the unfolded protein response, and genes related to mucin production. Collectively, these data suggest that molecular processes related to the rate of FEV1 decline can be detected in airway epithelium, identify a possible indicator of FEV1 decline and make it possible to detect, in an early phase, ever smokers with and without COPD most at risk of rapid FEV1 decline.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Transcriptoma , Brônquios , Volume Expiratório Forçado , Humanos , Doença Pulmonar Obstrutiva Crônica/genética , Testes de Função Respiratória , Fumar/efeitos adversos
16.
Eur Respir J ; 59(3)2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34446467

RESUMO

BACKGROUND: Changes in microRNA (miRNA) expression can contribute to the pathogenesis of many diseases, including asthma. We aimed to identify miRNAs that are differentially expressed between asthma patients and healthy controls, and explore their association with clinical and inflammatory parameters of asthma. METHODS: Differentially expressed miRNAs were determined by small RNA sequencing on bronchial biopsies of 79 asthma patients and 82 healthy controls using linear regression models. Differentially expressed miRNAs were associated with clinical and inflammatory asthma features. Potential miRNA-mRNA interactions were analysed using mRNA data available from the same bronchial biopsies, and enrichment of pathways was identified with Enrichr and g:Profiler. RESULTS: In total, 78 differentially expressed miRNAs were identified in bronchial biopsies of asthma patients compared with controls, of which 60 remained differentially expressed after controlling for smoking and inhaled corticosteroid treatment. We identified several asthma-associated miRNAs, including miR-125b-5p and miR-223-3p, based on a significant association with multiple clinical and inflammatory asthma features and their negative correlation with genes associated with the presence of asthma. The most enriched biological pathway(s) affected by miR-125b-5p and miR-223-3p were inflammatory response and cilium assembly/organisation. Of interest, we identified that lower expression of miR-26a-5p was linked to more severe eosinophilic inflammation as measured in blood, sputum as well as bronchial biopsies. CONCLUSION: Collectively, we identified miR-125b-5p, miR-223-3p and miR-26a-5p as potential regulators that could contribute to the pathogenesis of asthma.


Assuntos
Asma , Eosinofilia , MicroRNAs , Asma/metabolismo , Biópsia , Eosinofilia/metabolismo , Perfilação da Expressão Gênica , Humanos , MicroRNAs/genética , Escarro/metabolismo
17.
ERJ Open Res ; 7(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34881328

RESUMO

BACKGROUND: The prevalences of obstructive and restrictive spirometric phenotypes, and their relation to early-life risk factors from childhood to young adulthood remain poorly understood. The aim was to explore these phenotypes and associations with well-known respiratory risk factors across ages and populations in European cohorts. METHODS: We studied 49 334 participants from 14 population-based cohorts in different age groups (≤10, >10-15, >15-20, >20-25 years, and overall, 5-25 years). The obstructive phenotype was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) z-score less than the lower limit of normal (LLN), whereas the restrictive phenotype was defined as FEV1/FVC z-score ≥LLN, and FVC z-score

20.
Am J Physiol Lung Cell Mol Physiol ; 321(6): L1091-L1104, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34668437

RESUMO

Since microRNA (miR)-223-3p modulates inflammatory responses and chronic obstructive pulmonary disease (COPD) is associated with amplified pulmonary inflammation, we hypothesized that miR-223-3p plays a role in COPD pathogenesis. Expression of miR-223-3p was measured in lung tissue of two independent cohorts with patients with GOLD stage II-IV COPD, never smokers, and smokers without COPD. The functional role of miR-223-3p was studied in deficient mice and on overexpression in airway epithelial cells from COPD and controls. We observed higher miR-223-3p levels in patients with COPD stage II-IV compared with (non)-smoking controls, and levels were associated with higher neutrophil numbers in bronchial biopsies of patients with COPD. MiR-223-3p expression was also increased in lungs and bronchoalveolar lavage of cigarette smoke (CS)-exposed mice. CS-induced neutrophil and monocyte lung infiltration was stronger in miR-223-deficient mice on acute (5 days) exposure, but attenuated on subchronic (4 wk) exposure. Additionally, miR-223 deficiency attenuated acute and subchronic CS-induced lung infiltration of dendritic cells and T lymphocytes. Finally, in vitro overexpression of miR-223-3p in non-COPD airway epithelial cells suppressed C-X-C motif chemokine ligand 8 (CXCL8) and granulocyte monocyte-colony stimulation factor (GM-CSF) secretion and gene expression of the proinflammatory transcription factor TRAF6. Importantly, this suppressive effect of miR-223-3p was compromised in COPD-derived cultures. In conclusion, we demonstrate that miR-223-3p is increased in lungs of patients with COPD and CS-exposed mice and is associated with neutrophilic inflammation. In vivo data indicate that miR-223 acts as negative regulator of acute CS-induced neutrophilic and monocytic inflammation. In vitro data suggest that miR-223-3p does so by suppressing proinflammatory airway epithelial responses, which is less effective in COPD epithelium.


Assuntos
Fumar Cigarros/efeitos adversos , Pulmão/patologia , MicroRNAs/genética , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Idoso , Animais , Citocinas/metabolismo , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/genética , Pneumonia/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo
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