Obese Asthma Phenotype Is Associated with hsa-miR-26a-1-3p and hsa-miR-376a-3p Modulating the IGF Axis.

Clarifying inflammatory processes and categorising asthma into phenotypes and endotypes improves asthma management. Obesity worsens severe asthma and reduces quality of life, although its specific molecular impact remains unclear. We previously demonstrated that hsa-miR-26a-1-3p and hsa-miR-376a-3p, biomarkers related to an inflammatory profile, discriminate eosinophilic from non-eosinophilic asthmatics. We aimed to study hsa-miR-26a-1-3p, hsa-miR-376a-3p, and their target genes in asthmatic subjects with or without obesity to find biomarkers and comprehend obese asthma mechanisms. Lung tissue samples were obtained from asthmatic patients (n = 16) and healthy subjects (n = 20). We measured miRNA expression using RT-qPCR and protein levels (IGF axis) by ELISA in confirmation samples from eosinophilic (n = 38) and non-eosinophilic (n = 39) obese (n = 26) and non-obese (n = 51) asthma patients. Asthmatic lungs showed higher hsa-miR-26a-1-3p and hsa-miR-376a-3p expression than healthy lungs. A study of seven genes regulated by these miRNAs revealed differential expression of IGFBP3 between asthma patients and healthy individuals. In obese asthma patients, we found higher hsa-miR-26a-1-3p and IGF-1R values and lower values for hsa-miR-376a-3p and IGFBP-3. Hsa-miR-26a-1-3p and IGFBP-3 were directly and inversely correlated with body mass index, respectively. Hsa-miR-26a-1-3p and hsa-miR-376a-3p could be used as biomarkers to phenotype patients with eosinophilic and non-eosinophilic asthma in relation to comorbid obesity.

Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations.

INTRODUCTION AND OBJECTIVES: Asthma is a chronic inflammatory disease of the airways. Asthma patients may experience potentially life-threatening episodic flare-ups, known as exacerbations, which may significantly contribute to the asthma burden. The Pi*S and Pi*Z variants of the SERPINA1 gene, which usually involve alpha-1 antitrypsin (AAT) deficiency, had previously been associated with asthma. The link between AAT deficiency and asthma might be represented by the elastase/antielastase imbalance. However, their role in asthma exacerbations remains unknown. Our objective was to assess whether SERPINA1 genetic variants and reduced AAT protein levels are associated with asthma exacerbations. MATERIALS AND METHODS: In the discovery analysis, SERPINA1 Pi*S and Pi*Z variants and serum AAT levels were analyzed in 369 subjects from La Palma (Canary Islands, Spain). As replication, genomic data from two studies focused on 525 Spaniards and publicly available data from UK Biobank, FinnGen, and GWAS Catalog (Open Targets Genetics) were analyzed. The associations between SERPINA1 Pi*S and Pi*Z variants and AAT deficiency with asthma exacerbations were analyzed with logistic regression models, including age, sex, and genotype principal components as covariates. RESULTS: In the discovery, a significant association with asthma exacerbations was found for both Pi*S (odds ratio [OR]=2.38, 95% confidence interval [CI]= 1.40-4.04, p-value=0.001) and Pi*Z (OR=3.49, 95%CI=1.55-7.85, p-value=0.003)Likewise, AAT deficiency was associated with a higher risk for asthma exacerbations (OR=5.18, 95%CI=1.58-16.92, p-value=0.007) as well as AAT protein levels (OR= 0.72, 95%CI=0.57-0.91, p-value=0.005). The Pi*Z association with exacerbations was replicated in samples from Spaniards with two generations of Canary Islander origin (OR=3.79, p-value=0.028), and a significant association with asthma hospitalizations was found in the Finnish population (OR=1.12, p-value=0.007). CONCLUSIONS: AAT deficiency could be a potential therapeutic target for asthma exacerbations in specific populations.

Analysis of Differentially Expressed MicroRNAs in Serum and Lung Tissues from Individuals with Severe Asthma Treated with Oral Glucocorticoids.

Nowadays, microRNAs (miRNAs) are increasingly used as biomarkers due to their potential contribution to the diagnosis and targeted treatment of a range of diseases. The aim of the study was to analyze the miRNA expression profiles in serum and lung tissue from patients with severe asthma treated with oral corticosteroids (OCS) and those without OCS treatment. For this purpose, serum and lung tissue miRNAs of OCS and non-OCS asthmatic individuals were evaluated by miRNAs-Seq, and subsequently miRNA validation was performed using RT-qPCR. Additionally, pathway enrichment analysis of deregulated miRNAs was conducted. We observed altered expression by the next-generation sequencing (NGS) of 11 miRNAs in serum, of which five (hsa-miR-148b-3p, hsa-miR-221-5p, hsa-miR-618, hsa-miR-941, and hsa-miR-769-5p) were validated by RT-qPCR, and three miRNAs in lung tissue (hsa-miR-144-3p, hsa-miR-144-5p, and hsa-miR-451a). The best multivariate logistic regression model to differentiate individuals with severe asthma, treated and untreated with OCS, was to combine the serum miRNAs hsa-miR-221-5p and hsa-miR-769-5p. Expression of hsa-miR-148b-3p and hsa-miR-221-5p correlated with FEV1/FVC (%) and these altered miRNAs act in key signaling pathways for asthma disease and the regulated expression of some genes (FOXO3, PTEN, and MAPK3) involved in these pathways. In conclusion, there are miRNA profiles differentially expressed in OCS-treated individuals with asthma and could be used as biomarkers of OCS treatment.

Clinical and inflammatory characteristics of patients with asthma in the Spanish MEGA project cohort.

INTRODUCTION: The MEGA (MEchanism underlying the Genesis and evolution of Asthma) project is a multicenter cohort study carried out in eight Spanish hospitals, gathering clinical, physiological, and molecular data from patients with asthma and multimorbidities in order to gain insight into the different physiopathological mechanisms involved in this disorder. MATERIAL AND METHODS: We report the baseline clinical and physiological characteristics and biomarker measures of adult participants in the project with the aim of better understanding the natural history and underlying mechanisms of asthma as well as the associated multimorbidities across different levels of severity. We carried out a detailed clinical examination, pulmonary function testing, measurement of fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick tests, chest computed tomography scan, asthma questionnaires, and multimorbidity assessment in 512 asthmatic patients. RESULTS: When compared to patients with milder disease, severe asthmatic patients showed greater presence of symptoms, more exacerbations, lower asthma control, increased airflow obstruction, and higher frequency of chronic rhinosinusitis with nasal polyps, severe rhinitis, anxiety and depression, gastroesophageal reflux, and bronchiectasis. CONCLUSION: The MEGA project succeeded in recruiting a high number of asthma patients, especially those with severe disease, who showed lower control and higher frequency of multimorbidities.

Is exhaled nitric oxide a useful adjunctive test for assessing asthma?

RATIONALE: To determine the general utility of clinical (Asthma Control Test) and physiologic (forced expiratory volume in the first second of exhalation [FEV(1)] and fractionated exhaled nitric oxide level [FeNO]) parameters for characterizing asthma patients. METHODS: Two cross-sectional independent studies simultaneously enrolled 100 patients in the US and 109 patients in Spain > or = 18 years of age with a physician-diagnosis of asthma and confirmed by a > or = 12% improvement in FEV(1) after bronchodilators or the presence of airway hyperresponsiveness, a central feature of asthma, as measured by methacholine challenge (PC(20) < 10 mg/mL). There was no restriction on asthma severity or treatment. Patients were excluded if they had a diagnosis of chronic obstructive pulmonary disease and/or were current cigarette smokers. Statistical analyses were performed to compare ACT, FeNO, and spirometry within and between sites. RESULTS: Population characteristics revealed significant differences in distributions of age, percent-predicted FEV(1) (%FEV(1)), FeNO, inhaled corticosteroid usage, and atopy between the two populations. The Spain site enrolled younger patients with milder asthma, based on higher %FEV(1) values and less frequent treatment with inhaled corticosteroids. At each site, mean FeNO levels decreased as asthma control categories increased, and means were lower in the US. There was a negative correlation between ACT and FeNO that was statistically significant for Spain patients not treated with inhaled corticosteroids. CONCLUSIONS: The results of this study support the use of FeNO as an adjunctive tool for assessing asthma primarily in mild inhaled corticosteroid (ICS)-naïve asthma patients. The lack of correlation of ACT with FeNO in this and other studies across the entire population appears to reflect the heterogeneity of asthma patients who have an admixture of asthma severity and treatment regimens making it very difficult to appreciate the nuances of sensitive tests like FeNO.

Allergen vaccination with a liposome-encapsulated extract of Dermatophagoides pteronyssinus: a randomized, double-blind, placebo-controlled trial in asthmatic patients.

BACKGROUND: Liposomes are potent immunologic adjuvants and have been proposed as allergen carriers in allergy vaccination. OBJECTIVE: We sought to investigate the efficacy and safety of vaccination with Dermatophagoides pteronyssinus encapsulated in liposomes. METHODS: We conducted a double-blind, placebo-controlled study. Fifty-five asthmatic patients sensitized to mites were randomly assigned vaccination with D pteronyssinus extract encapsulated in liposomes or empty liposomes for a period of 12 months. The principal parameters were symptom and medication-consumption scores. The percentage of healthy days (ie, days without medication and with absent or mild symptoms) was calculated. Immediate and late skin test results, allergen bronchial challenge test results, and allergen-specific serum immunoglobulin levels were evaluated before and after treatment. RESULTS: All clinical scores were markedly lower in the active group than in the placebo group after vaccination. Nearly half (45.8%) of the patients actively treated reduced their symptom and medication scores by at least 60% versus only 12% of patients receiving placebo treatment (P =.0388). The percentage of healthy days in the active group rose from 10.5% before treatment to 64.5% afterward (P =.0008). Reduction in organ sensitivity was demonstrated by skin prick test responses (P <.01), late-phase response after intradermal testing (P =.009), and bronchial challenge test results (P =.026) in the active group. Serum levels of specific IgG increased throughout the treatment, whereas specific IgE levels showed only an initial transient increase. No change in these parameters was observed in the placebo group. Vaccination was well tolerated, and no subcutaneous nodules appeared. CONCLUSION: Vaccination with D pteronyssinus encapsulated in liposomes is an effective and safe treatment for allergy-induced asthma.