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2.
JAMA ; 324(8): 752-760, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32840597

RESUMO

Importance: Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3 supplementation reduces severe childhood asthma exacerbations is unclear. Objective: To determine whether vitamin D3 supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels. Design, Setting, and Participants: The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3 supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019. Interventions: Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 µg/d (6-11 years old), or 220 µg/d (12-16 years old). Main Outcomes and Measures: The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial. Results: Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3 group vs 253 days in the placebo group (mean group difference, -13.1 days [95% CI, -42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85]; P = .63). Vitamin D3 supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group, n = 11; placebo group, n = 9). Conclusions and Relevance: Among children with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3 supplementation to prevent severe asthma exacerbations in this group of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02687815.


Assuntos
Asma/tratamento farmacológico , Colecalciferol/uso terapêutico , Suplementos Nutricionais , Deficiência de Vitamina D/tratamento farmacológico , Vitaminas/uso terapêutico , Adolescente , Corticosteroides/uso terapêutico , Asma/sangue , Asma/complicações , Criança , Colecalciferol/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Exacerbação dos Sintomas , Falha de Tratamento , Vitamina D/sangue , Deficiência de Vitamina D/complicações , Vitaminas/efeitos adversos
3.
Gene ; 763: 145073, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32827684

RESUMO

BACKGROUND: The role of FoxP3, a master regulator of T regulatory cells, in allergic diseases such as asthma is of immense importance yet the effect of its gene variants on the disease predisposition is not fully understood. We studied the association of FoxP3 polymorphisms (-2383C/T and -3279C/A) in allergic asthma patients and their correlation with serum IL-4, IL-13, Total IgE, and Vitamin D levels. METHODS: In this study 350 individuals were enrolled, 150 allergic asthma patients and 200 healthy controls. SNP analyses were performed by RFLP. IL-4, IL-13 vitamin D and Total IgE were measured by ELISA. RESULTS: The AA homozygous mutant of -3279C/A posed a three-fold risk [P < 0.005; OR, 3.52] whereas the -2383C/T variants TT genotype carried a fourfold risk [P = 0.002; OR, 4.04]. Haplotype analysis exhibited predisposition to allergic asthmawith CC/TT [P = 0.01; OR 5.93 (95%CI)], AA/CC [P = 0.01; OR 3.29] and AA/TT haplotypes [P = 0; OR 11.86 (1.31-85.87)]. A negative correlation between IgE and Vitamin D was found [r = -0.30p-value 0.001] but a negative correlation betweenIgE and Vit D was established in the haplotype CC/TT [r = -0.45P = 0.002] and CC/CT [r = -0.52P = 0.04]. In allergic patients, the eosinophils count was high [p = 0.003] and the mean levels of pro-inflammatory cytokines IL-4 and IL-13 were elevated [P < 0.001] as well. CONCLUSIONS: The study suggests SNP -3279 -AA genotype and, -2383-TT genotype in association with certain haplotypes pose a risk for allergy development. There was no correlation between different genotypes and serum levels of various cytokines.


Assuntos
Asma/genética , Fatores de Transcrição Forkhead/genética , Polimorfismo de Nucleotídeo Único , Adulto , Asma/sangue , Eosinofilia/sangue , Eosinofilia/genética , Feminino , Humanos , Imunoglobulina E/sangue , Interleucina-13/sangue , Interleucina-4/sangue , Masculino , Vitamina D/sangue
5.
Braz J Med Biol Res ; 53(7): e9271, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520202

RESUMO

Montelukast sodium is an effective and well-tolerated anti-asthmatic drug. Long non-coding RNAs (lncRNAs) are involved in the treatment of asthma. Therefore, this study aimed to investigate the effect of montelukast sodium on children with cough-variant asthma (CVA) and the role of lncRNA prostate cancer gene expression marker 1 (PCGEM1) in drug efficacy. The efficacy of montelukast sodium was evaluated by assessing the release of inflammatory factors and pulmonary function in CVA children after a 3-month treatment. An ovalbumin (OVA)-sensitized mouse model was developed to simulate asthmatic conditions. PCGEM1 expression in clinical peripheral blood samples and lung tissues of asthmatic mice was determined. Asthmatic mice experienced nasal inhalation of PCGEM1 overexpression with simultaneous montelukast sodium to investigate the roles of PCGEM1 in asthma treatment. The NF-κB axis after PCGEM1 overexpression was detected to explore the underling mechanisms. Consequently, montelukast sodium contributed to reduced levels of pro-inflammatory factors and improved pulmonary function in CVA children. PCGEM1 was poorly expressed in OVA-sensitized asthmatic mice and highly expressed in CVA children with response to the treatment. PCGEM1 overexpression enhanced the anti-inflammatory effects and promoted effects on pulmonary function of montelukast sodium in CVA children and OVA-sensitized asthmatic mice. Furthermore, PCGEM1 inhibited the activation of the NF-κB axis. This study demonstrated the anti-inflammatory and lung-protective effects of montelukast sodium on CVA, which was strengthened by overexpression of PCGEM1. Findings in this study highlighted a potential anti-asthmatic target of montelukast sodium.


Assuntos
Acetatos/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Tosse/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Quinolinas/uso terapêutico , RNA Longo não Codificante/metabolismo , Animais , Asma/sangue , Criança , Pré-Escolar , Tosse/sangue , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C
6.
Am J Respir Crit Care Med ; 202(7): 973-982, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32479111

RESUMO

Rationale: Cross-sectional studies suggest an exacerbation-prone asthma (EPA) phenotype and the utility of blood eosinophils and plasma IL-6 as predictive biomarkers.Objectives: To prospectively test for EPA phenotype and utility of baseline blood measures of eosinophils and IL-6 as predictive biomarkers.Methods: Three-year asthma exacerbation data were analyzed in 406 adults in the Severe Asthma Research Program-3. Transition models were used to assess uninformed and informed probabilities of exacerbation in year 3. Binomial regression models were used to assess eosinophils and IL-6 as predictive biomarkers.Measurements and Main Results: Eighty-three participants (21%) had ≥1 exacerbation in each year (EPA) and 168 participants (41%) had no exacerbation in any year (exacerbation-resistant asthma). The uninformed probability of an exacerbation in Year 3 was 40%, but the informed probability increased to 63% with an exacerbation in Year 2 and 82% with an exacerbation in Years 1 and 2. The probability of a Year 3 exacerbation with no Year 1 or 2 exacerbations was 13%. Compared with exacerbation-resistant asthma, EPA was characterized by lower FEV1 and a higher prevalence of obesity, hypertension, and diabetes. High-plasma IL-6 occurred in EPA, and the incident rate ratio for exacerbation increased 10% for each 1-pg/µl increase in baseline IL-6 level. Although high blood eosinophils did not occur in EPA, the incident rate ratio for exacerbations increased 9% for each 100-cell/µl increase in baseline eosinophil number.Conclusions: Longitudinal analysis confirms an EPA phenotype characterized by features of metabolic dysfunction. Blood measures of IL-6, but not eosinophils, were significantly associated with EPA, and IL-6 and eosinophils predicted exacerbations in the sample as a whole.


Assuntos
Asma/sangue , Eosinófilos , Interleucina-6/sangue , Adulto , Asma/epidemiologia , Asma/fisiopatologia , Biomarcadores , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Volume Expiratório Forçado , Humanos , Hipertensão/epidemiologia , Inflamação/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Fenótipo , Exacerbação dos Sintomas
7.
J Steroid Biochem Mol Biol ; 201: 105687, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32360596

RESUMO

The increasing use of vitamin D supplements has stimulated interest in identifying factors that may modify the effect of supplementation on circulating 25-hydroxyvitamin D (25(OH)D) concentrations. Such information is of potential interest to researchers, clinicians and patients when deciding on bolus dose of vitamin D supplementation. We carried out a large randomized controlled trial of 5110 adults aged 50-84 years, of European/Other (84%), Polynesian (11%) and Asian (5%) ethnicity, to whom we gave a standard dose of vitamin D3 supplements (200,000 IU initially, then 100,000 IU monthly) which was taken with high adherence. All participants provided a baseline blood sample, and follow-up blood samples were collected at 6 months and annually for 3 years in a random sample of 441 participants, and also at 2 years in 413 participants enrolled in a bone density sub-study. Serum 25(OH)D was measured by LC/MSMS. Mixed model analyses were carried out on all 854 participants providing follow-up blood samples in multivariable models that included age, sex, ethnicity, body mass index (kg/m2), tobacco smoking, alcohol intake, physical activity, sun exposure, season, medical prescription of high-dose vitamin D3 (Cal.D.Forte tablets), asthma/COPD and the study treatment (vitamin D or placebo). The adjusted mean difference in 25(OH)D in the follow-up points between vitamin D supplementation and placebo groups was inversely related (all p for interaction <0.05) to baseline 25(OH)D, BMI, and hours of sun exposure, and higher in females, elders, and those with high frequency of alcohol, medical prescription of vitamin D, and asthma/COPD. The mean difference was not significantly related to ethnicity (p = 0.12), tobacco (p = 0.34), and vigorous activity (p = 0.33). In summary, these data show that vitamin D status, BMI, sun exposure hours, sex and asthma/COPD modify the 25(OH)D response to vitamin D supplementation. By contrast, ethnicity, tobacco smoking, and vigorous activity do not.


Assuntos
Suplementos Nutricionais , Vitamina D/análogos & derivados , Vitaminas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Asma/sangue , Índice de Massa Corporal , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/sangue , Caracteres Sexuais , Luz Solar , Vitamina D/administração & dosagem , Vitamina D/sangue , Vitaminas/sangue
8.
Am J Respir Crit Care Med ; 202(1): 65-72, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32272022

RESUMO

Rationale: Inhaled corticosteroids (ICS) are key treatments for controlling asthma and preventing asthma attacks. However, the responsiveness to ICS varies among individuals. MicroRNAs (miRNAs) have been lauded for their prognostic utility.Objectives: We hypothesized that circulating miRNAs obtained at baseline/prerandomization in the Childhood Asthma Management Program (CAMP) could serve as biomarkers and biologic mediators of ICS clinical response over the 4-year clinical trial period.Methods: We selected baseline serum samples from 462 CAMP subjects subsequently randomized to either ICS (budesonide) or placebo. Samples underwent small RNA sequencing, and read counts were normalized and filtered by depth and coverage. Linear regression was used to associate miRNAs with change in FEV1% (prebronchodilator FEV1 as a percent predicted) over the 4-year treatment period in both main effects and interaction models. We validated the function of the top associated miRNAs by luciferase reporter assays of glucocorticoid-mediated transrepression and predicted response to ICS through logistic regression models.Measurements and Main Results: We identified 7 miRNAs significantly associated with FEV1% change (P ≤ 0.05) and 15 miRNAs with significant interaction (P ≤ 0.05) to ICS versus placebo treatments. We selected three miRNAs for functional validation, of which hsa-miR-155-5p and hsa-miR-532-5p were significantly associated with changes in dexamethasone-induced transrepression of NF-κB. Combined, these two miRNAs were predictive of ICS response over the course of the clinical trial, with an area under the receiver operating characteristic curve of 0.86.Conclusions: We identified two functional circulating miRNAs predictive of asthma ICS treatment response over time.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Budesonida/uso terapêutico , MicroRNA Circulante/sangue , Administração por Inalação , Asma/sangue , Asma/diagnóstico , Biomarcadores/sangue , Criança , Feminino , Seguimentos , Volume Expiratório Forçado , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Resultado do Tratamento
9.
PLoS One ; 15(4): e0231816, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32330171

RESUMO

INTRODUCTION: Existing evidence on the relationship between childhood lower respiratory tract infections (LRTI) and the subsequent atopy development is controversial. We aimed to investigate an association between viral LRTI at <5 years and the development of atopy at > 2 years. METHODS: We conducted a search at Embase, Pubmed, Web of Science, and Global Index Medicus. We collected data from the included articles. We estimated the odds ratio and the 95% confidence intervals with a random effect model. We determined factors associated with atopy development after childhood LRTI using univariate and multivariate meta-regression analyses. We recorded this systematic review at PROSPERO with the number CRD42018116955. RESULTS: We included 24 studies. There was no relationship between viral LRTI at <5 years and skin prick test-diagnosed-atopy (OR = 1.2, [95% CI = 0.7-2.0]), unknown diagnosed-atopy (OR = 0.7, [95% CI = 0.4-1.3]), atopic dermatitis (OR = 1.2, [95% CI = 0.9-1.6]), hyperreactivity to pollen (OR = 0.8, [95% CI = 0.3-2.7]), food (OR = 0.8, [95% CI = 0.3-2.5]), or house dust mite (OR = 1.1, [95% CI = 0.6-2.2]). Although not confirmed in all studies with a symmetric distribution of the 23 confounding factors investigated, the overall analyses showed that there was a relationship between childhood viral LRTI at < 5 years and serum test diagnosed-atopy (OR = 2.0, [95% CI = 1.0-4.1]), allergic rhinoconjunctivitis (OR = 1.7, [95% CI = 1.1-2.9]), hyperreactivity diagnosed by serum tests with food (OR = 5.3, [1.7-16.7]) or inhaled allergens (OR = 4.2, [95% CI = 2.1-8.5]), or furred animals (OR = 0.6, [95% CI = 0.5-0.9]). CONCLUSION: These results suggest that there is no association between viral LRTI at < 5 years and the majority of categories of atopy studied during this work. These results, however, are not confirmed for the remaining categories of atopy and more particularly those diagnosed by serum tests. There is a real need to develop more accurate atopy diagnostic tools.


Assuntos
Asma/epidemiologia , Conjuntivite Alérgica/epidemiologia , Dermatite Atópica/epidemiologia , Infecções Respiratórias/imunologia , Rinite Alérgica/epidemiologia , Alérgenos/efeitos adversos , Animais , Asma/sangue , Asma/diagnóstico , Asma/imunologia , Criança , Conjuntivite Alérgica/sangue , Conjuntivite Alérgica/diagnóstico , Conjuntivite Alérgica/imunologia , Dermatite Atópica/sangue , Dermatite Atópica/diagnóstico , Dermatite Atópica/imunologia , Dermatophagoides pteronyssinus/imunologia , Humanos , Pólen/efeitos adversos , Pólen/imunologia , Infecções Respiratórias/virologia , Rinite Alérgica/sangue , Rinite Alérgica/diagnóstico , Rinite Alérgica/imunologia , Testes Cutâneos , Fatores de Tempo
10.
Artigo em Inglês | MEDLINE | ID: mdl-32143340

RESUMO

Ghrelin is a peptide hormone with direct or indirect effects on obesity and asthma. More data are required to understand the effect of ghrelin on the control and pathogenesis of these diseases. The aim of this study was to evaluate ghrelin levels in selected groups of children to identify the association between serum ghrelin, obesity, and the severity of asthma. The study included 401 school children selected from the Najran area and grouped into non-obese asthmatics, obese asthmatics, obese non-asthmatics and controls (non-obese non-asthmatics). Blood levels of ghrelin, interleukin (IL)-4, IL-5 and IL-21 were determined by ELISA. The mean ghrelin values were insignificantly increased in obese children compared with non-obese children. The highest blood ghrelin values were in the non-obese asthmatic group. Serum ghrelin, IL-4 and IL-21 levels were significantly increased in asthmatic children compared with non-asthmatic children (p < 0.05), and there were significant positive correlations between ghrelin and IL-4, IL-5, and IL-21 in asthmatic children. Furthermore, ghrelin, IL-4, and IL-21 levels were significantly higher in uncontrolled asthmatics compared with controlled-asthmatic children (p < 0.05). Asthma was the only significant risk factor for high ghrelin values. This study provides evidence supporting the anti-inflammatory role of ghrelin in the pathogenesis of asthma. Asthma might be considered as an important determinant of high ghrelin values in children.


Assuntos
Asma , Grelina , Interleucinas , Asma/sangue , Asma/patologia , Criança , Grelina/sangue , Humanos , Inflamação/sangue , Interleucina-4/sangue , Interleucina-5/sangue , Interleucinas/sangue , Obesidade/sangue , Arábia Saudita
11.
Artigo em Inglês | MEDLINE | ID: mdl-32004685

RESUMO

Lysophosphatidic acid (LPA) species are present in almost all organ systems and play diverse roles through its receptors. Asthma is an airway disease characterized by chronic allergic inflammation where various innate and adaptive immune cells participate in establishing Th2 immune response. Here, we will review the contribution of LPA and its receptors to the functions of immune cells that play a key role in establishing allergic airway inflammation and aggravation of allergic asthma.


Assuntos
Asma/imunologia , Lisofosfolipídeos/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/imunologia , Animais , Asma/sangue , Asma/genética , Asma/patologia , Movimento Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Técnicas de Introdução de Genes , Humanos , Pulmão/irrigação sanguínea , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Linfonodos/irrigação sanguínea , Linfonodos/imunologia , Linfonodos/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Knockout , Diester Fosfórico Hidrolases/genética , Receptores de Ácidos Lisofosfatídicos/genética , Células Th2/imunologia , Células Th2/metabolismo
12.
PLoS One ; 15(2): e0226950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32015564

RESUMO

BACKGROUND: An increased prevalence of allergies and an increased incidence of breast cancer have been observed. The hypothesis that atopy may have a protective effect against the risk of different types of breast cancer was evaluated. METHODS: In this study, 11,101 patients (11,101 women with a mean age of 55.2±14.7 years) with different types of breast cancer were tested for allergies. Allergies were confirmed based on the retrospective analysis of allergy diagnostic procedures in patients who had been previously diagnosed with breast cancer. The retrospective prevalence rates of active allergic diseases, including allergic rhinitis, bronchial asthma and atopic dermatitis, were assessed. All patients were also analyzed for bronchial asthma and allergic rhinitis according to the relevant guidelines. A group of healthy control patients was used for the comparisons. RESULTS: The women with breast cancer had a significantly lower incidence of IgE-mediated allergic diseases than the controls. The odds ratios (ORs) for allergic rhinitis, atopic dermatitis, and bronchial asthma were 0.61 (95% CI: 0.57-0.73), 0.17 (95% CI: 0.11-0.44), and 0.73 (95% CI: 0.65-0.83), respectively. The mean serum concentrations of total IgE were significantly lower in the study population of women with breast cancer than in the patients of the control group (39.2 ± 26.2 kU/L vs. 108.5 ± 38.5 kU/L; p = 0.002). CONCLUSION: Our results suggest that the overall incidence of allergies, especially allergic rhinitis, is lower in patients with certain types of cancer than in individuals who did not have cancer. Further studies are needed to confirm our findings.


Assuntos
Alérgenos/sangue , Neoplasias da Mama/epidemiologia , Hipersensibilidade/epidemiologia , Imunoglobulina E/sangue , Idoso , Asma/sangue , Asma/complicações , Asma/epidemiologia , Neoplasias da Mama/sangue , Dermatite Atópica/sangue , Dermatite Atópica/complicações , Dermatite Atópica/epidemiologia , Feminino , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/complicações , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Rinite Alérgica Sazonal/sangue , Rinite Alérgica Sazonal/complicações , Rinite Alérgica Sazonal/epidemiologia
13.
Sci Rep ; 10(1): 1962, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029879

RESUMO

Mechanisms mediating the protective effects of molecular hydrogen (H2) are not well understood. This study explored the possibility that H2 exerts its anti-inflammatory effect by modulating energy metabolic pathway switch. Activities of glycolytic and mitochondrial oxidative phosphorylation systems were assessed in asthmatic patients and in mouse model of allergic airway inflammation. The effects of hydrogen treatment on airway inflammation and on changes in activities of these two pathways were evaluated. Monocytes from asthmatic patients and lungs from ovalbumin-sensitized and challenged mice had increased lactate production and glycolytic enzyme activities (enhanced glycolysis), accompanied by decreased ATP production and mitochondrial respiratory chain complex I and III activities (suppressed mitochondrial oxidative phosphorylation), indicating an energy metabolic pathway switch. Treatment of ovalbumin-sensitized and challenged mice with hydrogen reversed the energy metabolic pathway switch, and mitigated airway inflammation. Hydrogen abrogated ovalbumin sensitization and challenge-induced upregulation of glycolytic enzymes and hypoxia-inducible factor-1α, and downregulation of mitochondrial respiratory chain complexes and peroxisome proliferator activated receptor-γ coactivator-1α. Hydrogen abrogated ovalbumin sensitization and challenge-induced sirtuins 1, 3, 5 and 6 downregulation. Our data demonstrates that allergic airway inflammation is associated with an energy metabolic pathway switch from oxidative phosphorylation to aerobic glycolysis. Hydrogen inhibits airway inflammation by reversing this switch. Hydrogen regulates energy metabolic reprogramming by acting at multiple levels in the energy metabolism regulation pathways.


Assuntos
Asma/tratamento farmacológico , Glicólise/efeitos dos fármacos , Hidrogênio/administração & dosagem , Leucócitos Mononucleares/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Animais , Asma/sangue , Asma/induzido quimicamente , Asma/imunologia , Broncoconstritores/efeitos adversos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Glicólise/imunologia , Humanos , Ácido Láctico/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Cloreto de Metacolina/efeitos adversos , Camundongos , Pessoa de Meia-Idade , Ovalbumina/imunologia , Cultura Primária de Células
14.
J Clin Invest ; 130(2): 921-926, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31929190

RESUMO

Risk for childhood asthma is conferred by alleles within the 17q21 locus affecting ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) expression. ORMDL3 inhibits sphingolipid de novo synthesis. Although the effects of 17q21 genotypes on sphingolipid synthesis in human asthma remain unclear, both decreased sphingolipid synthesis and ORMDL3 overexpression are linked to airway hyperreactivity. To characterize the relationship of genetic asthma susceptibility with sphingolipid synthesis, we analyzed asthma-associated 17q21 genotypes (rs7216389, rs8076131, rs4065275, rs12603332, and rs8067378) in both children with asthma and those without asthma, quantified plasma and whole-blood sphingolipids, and assessed sphingolipid de novo synthesis in peripheral blood cells by measuring the incorporation of stable isotope-labeled serine (substrate) into sphinganine and sphinganine-1-phosphate. Whole-blood dihydroceramides and ceramides were decreased in subjects with the 17q21 asthma-risk alleles rs7216389 and rs8076131. Children with nonallergic asthma had lower dihydroceramides, ceramides, and sphingomyelins than did controls. Children with allergic asthma had higher dihydroceramides, ceramides, and sphingomyelins compared with children with nonallergic asthma. Additionally, de novo sphingolipid synthesis was lower in children with asthma compared with controls. These findings connect genetic 17q21 variations that are associated with asthma risk and higher ORMDL3 expression to lower sphingolipid synthesis in humans. Altered sphingolipid synthesis may therefore be a critical factor in asthma pathogenesis and may guide the development of future therapeutics.


Assuntos
Asma , Cromossomos Humanos Par 17 , Doenças Genéticas Inatas , Proteínas de Membrana , Esfingolipídeos/biossíntese , Adolescente , Asma/sangue , Asma/genética , Asma/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/metabolismo , Feminino , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Fatores de Risco
15.
Pediatr Pulmonol ; 55(3): 571-579, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31944632

RESUMO

OBJECTIVES: The aim of this study was to investigate airway responsiveness and eosinophil and neutrophil inflammatory markers in clinically confirmed nonasthmatic adolescents with elevated fractional exhaled nitric oxide (FeNO), a marker of type-2 inflammation in the airways. METHODOLOGY: A total of 959 subjects from a general population, aged 12 to 15 years, answered a standardised questionnaire and underwent FeNO measurements at a screening visit at school. Adolescents without asthma, who had elevated FeNO (FeNO100 > 15 ppb) (n = 19), and control subjects, with low FeNO (FeNO100 < 5 ppb) and without reported symptoms of asthma or allergy (n = 28), participated in a follow-up study where FeNO50 , airway responsiveness to methacholine (PD20 ), blood eosinophil counts, and serum neutrophil lipocalin (HNL) and myeloperoxidase (MPO) levels were measured. Questionnaire follow-ups were performed 4 and 16 years later. RESULTS: Airway responsiveness (PD20 : 6.94 [1.87, 11.39] vs 11.42 [6.33, 59.4] µmol; P < .05) and blood eosinophil counts (0.31 [0.20, 0.44] vs 0.13 [0.1, 0.22] 109 /L; P < .001) (geometric mean [95% CI]) were higher among cases than controls. A significant correlation between blood eosinophils and FeNO was found (rho = 0.41; P = .005). In contrast, serum HNL and MPO were lower in cases than controls (P < .05 both), and there was a negative correlation between HNL and FeNO (r = -0.31; P = .04). At both follow-ups, a higher proportion of subjects reported allergic symptoms compared with baseline (P = .02, P = .01). CONCLUSIONS: Elevated FeNO in nonasthmatic adolescents was associated with airway hyperresponsiveness, elevated blood eosinophil counts, and lower systemic activation of neutrophils.


Assuntos
Asma/metabolismo , Asma/fisiopatologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Óxido Nítrico/metabolismo , Sistema Respiratório/fisiopatologia , Adolescente , Adulto , Asma/sangue , Asma/imunologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Hiper-Reatividade Brônquica/sangue , Hiper-Reatividade Brônquica/imunologia , Criança , Eosinófilos , Expiração , Feminino , Seguimentos , Humanos , Contagem de Leucócitos , Lipocalinas/sangue , Masculino , Cloreto de Metacolina/administração & dosagem , Adulto Jovem
16.
PLoS One ; 15(1): e0228045, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995587

RESUMO

BACKGROUND: Most patients with nonallergic asthma have normal serum immunoglobulin E (IgE) levels. Recent reports suggest that total and aeroallergen-specific IgE levels in induced sputum may be higher in nonallergic asthmatics than in healthy controls. Our objective is to compare total and dust-mite specific (Der p 1) IgE levels in induced sputum in allergic and nonallergic asthmatics and healthy controls. METHODS: Total and Der p 1-specific IgE were measured in induced sputum (ImmunoCAP immunoassay) from 56 age- and sex-matched asthmatics (21 allergic, 35 nonallergic) and 9 healthy controls. Allergic asthma was defined as asthma with a positive prick test and/or clinically-significant Der p 1-specific serum IgE levels. RESULTS: Patients with allergic asthma presented significantly higher total and Der p 1-specific serum IgE levels. There were no significant between-group differences in total sputum IgE. However, Der p 1-specific sputum IgE levels were significantly higher (p = 0.000) in the allergic asthmatics, but without differences between the controls and nonallergic asthmatics. Serum and sputum IgE levels were significantly correlated, both for total IgE (rho = 0.498; p = 0.000) and Der p 1-specific IgE (rho, 0.621; p = 0001). CONCLUSIONS: Total IgE levels measured in serum and induced sputum are significantly correlated. No significant differences were found between the differents groups in total sputum IgE. Nevertheless, the levels of Der p 1-specific sputum IgE levels were significantly higher in the allergic asthmatics, but without differences between the controls and nonallergic asthmatics. Probably due to the lack of sensitivity of the test used, but with the growing evidence for local allergic reactions better methods are need to explore its presence. The Clinical Trials Identifier for this project is NCT03640936.


Assuntos
Asma/imunologia , Hipersensibilidade/imunologia , Imunoglobulina E/metabolismo , Escarro/imunologia , Adulto , Asma/sangue , Asma/complicações , Estudos de Casos e Controles , Feminino , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/complicações , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade
17.
Artigo em Inglês | MEDLINE | ID: mdl-31906378

RESUMO

Epidemiological studies have reported the relationship between bisphenol A (BPA) exposure and increased prevalence of asthma, but the mechanisms remain unclear. Here, we investigated whether BPA exposure and DNA methylation related to asthma in children. We collected urinary and blood samples from 228 children (Childhood Environment and Allergic Diseases Study cohort) aged 3 years. Thirty-three candidate genes potentially interacting with BPA exposure were selected from a toxicogenomics database. DNA methylation was measured in 22 blood samples with top-high and bottom-low exposures of BPA. Candidate genes with differential methylation levels were validated by qPCR and promoter associated CpG islands have been investigated. Correlations between the methylation percentage and BPA exposure and asthma were analyzed. According to our findings, MAPK1 showed differential methylation and was further investigated in 228 children. Adjusting for confounders, urinary BPA glucuronide (BPAG) level inversely correlated with MAPK1 promoter methylation (ß = -0.539, p = 0.010). For the logistic regression analysis, MAPK1 methylation status was dichotomized into higher methylated and lower methylated groups with cut off continuous variable of median of promoter methylation percentage (50%) while performing the analysis. MAPK1 methylation was lower in children with asthma than in children without asthma (mean ± SD; 69.82 ± 5.88% vs. 79.82 ± 5.56%) (p = 0.001). Mediation analysis suggested that MAPK1 methylation acts as a mediation variable between BPA exposure and asthma. The mechanism of BPA exposure on childhood asthma might, therefore, be through the alteration of MAPK1 methylation. The mechanism of BPA exposure on childhood asthma might, therefore, be through the alteration of MAPK1 methylation.


Assuntos
Asma , Compostos Benzidrílicos , Metilação de DNA , Fenóis , Asma/sangue , Asma/epidemiologia , Asma/urina , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/urina , Pré-Escolar , Estudos de Coortes , Ilhas de CpG/genética , Feminino , Glucuronídeos/urina , Humanos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fenóis/toxicidade , Fenóis/urina , Regiões Promotoras Genéticas/genética
18.
Sci Rep ; 10(1): 151, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932625

RESUMO

DNA methylation (DNAm) profiles in central airway epithelial cells (AECs) may play a key role in pathological processes in asthma. The goal of the current study is to compare the diagnostic performance of DNAm markers across three tissues: AECs, nasal epithelial cells (NECs), and peripheral blood mononuclear cells (PBMCs). Additionally, we focused on the results using the machine learning algorithm in the context of multi-locus effects to evaluate the diagnostic performance of the optimal subset of CpG sites. We obtained 74 subjects with asthma and 41 controls from AECs, 15 subjects with asthma and 14 controls from NECs, 697 subjects with asthma and 97 controls from PBMCs. Epigenome-wide DNA methylation levels in AECs, NECs and PBMCs were measured using the Infinium Human Methylation 450 K BeadChip. Overlap analysis across the three different sample sources at the locus and pathway levels were studied to investigate shared or unique pathophysiological processes of asthma across tissues. Using the top 100 asthma-associated methylation markers as classifiers from each dataset, we found that both AEC- and NEC-based DNAm signatures exerted a lower classification error than the PBMC-based DNAm markers (p-value = 0.0002). The area-under-the-curve (AUC) analysis based on out-of-bag errors using the random forest classification algorithm revealed that PBMC-, NEC-, and AEC-based methylation data yielded 31 loci (AUC: 0.87), 8 loci (AUC: 0.99), and 4 loci (AUC: 0.97) from each optimal subset of tissue-specific markers, respectively. We also discovered the locus-locus interaction of DNAm levels of the CDH6 gene and RAPGEF3 gene might interact with each other to jointly predict the risk of asthma - which suggests the pivotal role of cell-cell junction in the pathological changes of asthma. Both AECs and NECs might provide better diagnostic accuracy and efficacy levels than PBMCs. Further research is warranted to evaluate how these tissue-specific DNAm markers classify and predict asthma risk.


Assuntos
Asma/genética , Biomarcadores/análise , Metilação de DNA , Epigenômica , Regulação da Expressão Gênica , Leucócitos Mononucleares/metabolismo , Asma/sangue , Asma/diagnóstico , Estudos de Casos e Controles , Criança , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Leucócitos Mononucleares/patologia , Masculino , Prognóstico
19.
J Immunol ; 204(6): 1592-1597, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31988179

RESUMO

IL-33 and its receptor ST2 are contributing factors to airway inflammation and asthma exacerbation. The IL-33/ST2 signaling pathway is involved in both the onset and the acute exacerbations of asthma. In this study, we address the role of endogenous IL-33 and its autoamplification of the IL-33/ST2 pathway in Ag-dependent and Ag-independent asthma-like models. Wild-type, IL-33 knockout, ST2 knockout mice were either intratracheally administrated with 500 ng of rIL-33 per day for four consecutive days or were sensitized and challenged with OVA over 21 d. In wild-type mice, IL-33 or OVA induced similar airway hyperresponsiveness and eosinophilic airway inflammation. IL-33 induced its own mRNA and ST2L mRNA expression in the lung. IL-33 autoamplified itself and ST2 protein expression in airway epithelial cells. OVA also induced IL-33 and ST2 protein expression. In IL-33 knockout mice, the IL-33- and OVA-induced airway hyperresponsiveness and eosinophilic airway inflammation were both significantly attenuated, whereas IL-33-induced ST2L mRNA expression was preserved, although no autoamplification of IL-33/ST2 pathway was observed. In ST2 knockout mice, IL-33 and OVA induced airway hyperresponsiveness and eosinophilic airway inflammation were both completely diminished, and no IL-33/ST2 autoamplification was observed. These results suggest that endogenous IL-33 and its autoamplification of IL-33/ST2 pathway play an important role in the induction of asthma-like phenotype. Thus an intact IL-33/ST2 pathway is necessary for both Ag-dependent and Ag-independent asthma-like mouse models.


Assuntos
Asma/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Mucosa Respiratória/imunologia , Transdução de Sinais/imunologia , Alérgenos/administração & dosagem , Alérgenos/imunologia , Animais , Asma/sangue , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/administração & dosagem , Interleucina-33/genética , Camundongos , Camundongos Knockout , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Transdução de Sinais/genética
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