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1.
Gene ; 715: 143991, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357023

RESUMO

BACKGROUND: Asthma is a complex disease with worldwide public health relevance, is related to environmental causes and a genetic predisposition. The chromosomal 17q12-21 locus has been consistently demonstrated to be associated with asthma risk. The effects of variants in the 17q12-21 locus on childhood asthma were first identified in a genome wide- association study. Since that time, those findings have been replicated in different populations but not in South American populations. OBJECTIVE: This study aimed to investigate the role of variants in the 17q12-21 locus on asthma in a sample of Brazilian children. METHODS: This was a cross-sectional study conducted on a cohort of 1247 children. These analyses used 50 Single Nucleotide Variants (SNVs) in the 17q12-21 locus were genotyped as part of a genome wide association study (GWAS). RESULTS: Four SNVs (rs4065275, rs12603332, rs73985228 and rs77777702) were associated with childhood asthma. The rs73985228 exhibited the strongest association across the different genetic models (OR, 95%CI 2.8, 1.44-3.21, p < 0.01). In an analysis that was stratified by atopy, two SNVs (rs73985228 and rs2715555) were found to be associated with atopic and non-atopic asthma. For the first time, we observed a significant interaction with seropositivity for the Varicella zoster virus (for rs4065275, p = 0.02, and for rs12603332, p = 0.04); i.e., the association was found in those who were seropositive but not in those who were seronegative for this virus. CONCLUSIONS: We confirmed the associations of variants in the 17q12-21 locus with atopic and non-atopic asthma and identified an interaction with seropositivity for the Varicella zoster virus.


Assuntos
Asma/genética , Cromossomos Humanos Par 17/genética , Predisposição Genética para Doença , Herpesvirus Humano 3 , Polimorfismo de Nucleotídeo Único , Infecção pelo Vírus da Varicela-Zoster/genética , Asma/virologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino
2.
Genet Test Mol Biomarkers ; 23(6): 363-372, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31161819

RESUMO

Background and Aims: The relationship between the promoter polymorphism (-308G/A) of the tumor necrosis factor-alpha (TNF-α) gene and the susceptibility to asthma has been tested in several studies. However, the results have been inconsistent. Therefore, we performed an updated meta-analysis to evaluate the relationship between this promoter polymorphism of the TNF-α gene and the risk of asthma. Methods: Fifty case-control studies were included in this meta-analysis which provided 17,937 controls and 9961 asthma patients. The pooled p-value, odds ratio (OR), and 95% confidence interval (95% CI) were used to investigate the strength of the association of this polymorphism of the TNF-α gene with the risk of asthma. The meta-analysis was carried out by Comprehensive Meta-Analysis software. Results: The results of our meta-analysis revealed that the TNF-α polymorphism (-308, G/A) was strongly associated with the risk of asthma (p < 0.05 in the allelic, dominant, and recessive models, respectively). In further analyses, based on age group and ethnicity, we observed this association for all subpopulations examined (p < 0.05 in allelic, dominant, and recessive models, respectively). Conclusion: This large-scale meta-analysis supports a strong association between the TNF-α gene promoter polymorphism (-308G/A) and the development to asthma in both children and adults.


Assuntos
Asma/genética , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Fatores de Risco , Fator de Necrose Tumoral alfa/metabolismo
3.
Ter Arkh ; 91(3): 27-30, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31094455

RESUMO

AIM: To study the association of mononucleotide polymorphism rs6737848 SOCS5 gene with the risk of development of allergic bronchial asthma. MATERIALS AND METHODS: Totally 59 patients studied (19 males, 40 females) with allergic bronchial asthma and 50 healthy people (29 males, 21 females) of controls. All patients underwent clinical and instrumental and laboratory investigations in KICH №20 (Krasnoyarsk city) and molecular-genetic investigation of DNA in the Russia-Italian laboratory "MAGI" (Krasnoyarsk city) and Institution of Internal and Preventive Medicine (Novosibirsk city). Statistics included standard programs: Statistica for Windows 7.0. RESULTS: The results of the study showed statistical predominance of prevalent genotype СС of SOCS5 gene in allergic bronchial asthma patients, comparing to control group. CONCLUSION: Homozygous genotype of СС gene of SOCS5 is a risk factor for allergic bronchial asthma.


Assuntos
Asma/genética , DNA/genética , Predisposição Genética para Doença , Polimorfismo Genético , Proteínas Supressoras da Sinalização de Citocina/genética , Asma/metabolismo , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Federação Russa , Proteínas Supressoras da Sinalização de Citocina/metabolismo
4.
Life Sci ; 231: 116485, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31116959

RESUMO

Airway mucin overproduction is the hallmark risk factor of asthma, which is associated with the reduction of lung function. An aberrant mucin expression is responsible for airway obstruction due to its high viscous characteristics. Among the mucins discovered, MUC5AC is the prime mucin of airway epithelia. Nowadays, mucins induced asthma and chronic obstructive pulmonary disease (COPD) are a great concern all over the world. This review focuses on the effects of natural compounds that can be beneficial to explore new drugs to halt MUC5AC secretion and production in airway epithelial, and also their underlying molecular mechanisms based on recent studies. Several researchers are seeking natural sources to identify a new potent MUC5AC inhibitory agent for clinical applications, because of countable limitations of existing synthetic drugs. Currently, flavonoids, glycoside and steroids like natural compounds have acquired great attention due to their anti-inflammatory and mucoregulatory effects. Most importantly, many natural compounds have shown their potential effects as the modulator of mucin expression, secretion, and production. Therefore, targeting airway MUC5AC expression and production represents an auspicious area of research for the development of drugs against various respiratory diseases.


Assuntos
Mucina-5AC/antagonistas & inibidores , Mucina-5AC/biossíntese , Animais , Asma/tratamento farmacológico , Asma/genética , Asma/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Mucina-5AC/genética , Mucina-5AC/metabolismo , Mucina-1/genética , Mucina-1/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Sistema Respiratório/efeitos dos fármacos
5.
Clin Biochem ; 68: 30-36, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981701

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are emerging gene expression regulators and their expression has been linked to various biological processes. However, the role of miRNAs in the regulation of allergic inflammatory disease still not clearly understood. AIM: Our study was designed to investigate circulating miR-155 and Let-7a expression levels in the plasma of asthmatic children and healthy controls. Also, to correlate their expression levels to degree of severity of asthma as well as to IL-13 level and lung function parameters. METHOD: Our study included 100 asthmatic children and 100 healthy children as control group. Plasma miR-155 and Let-7a expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: MicroRNA-155 expression was significantly increased in the plasma of asthmatic children than in control children. While, Let-7a expression was significantly lower in asthmatics than in control children. The relative levels of miR-155 and Let-7a were associated with degree of asthma severity. Receiver operating characteristic (ROC) curve analysis demonstrated that the levels of miR-155 and Let-7a were helpful for diagnosis of childhood asthma (AUC were 0.91 and 0.92, respectively), and in prediction of the severity of disease (AUC were 0.83 and 0.80, respectively). Plasma miRNA-155 was correlated positively with Il-13 levels and correlated negatively with FEV1and FVC. While, Let-7a was correlated negatively with Il-13 and correlated positively with FEV1 and FVC. CONCLUSION: MicroRNA-155 and let-7a could be used as serological non-invasive biomarkers for diagnosis of asthma and degree of severity. Our results could be used for exploring the pathogenesis of asthma and help in selecting promising therapeutic modalities.


Assuntos
Asma/genética , MicroRNAs/genética , Biomarcadores/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Curva ROC
6.
Allergol. immunopatol ; 47(2): 159-165, mar.-abr. 2019. tab
Artigo em Inglês | IBECS | ID: ibc-180804

RESUMO

Introduction and Objectives: Asthma is a complex genetic disorder. Several genes have been found associated with asthma. The cystic fibrosis transmembrane conductance regulator (CFTR) gene is one of them. The aim of this study was to perform a comparative analysis of the genotype and allele frequency distributions of the biallelic marker M470V within the CFTR gene on mutant and wide chromosomes. Patients and methods: The molecular approach consists in the genotyping of the M470V marker by the PCR-RFLP technique in 105 asthmatic patients, aged between four months and 17 years, and 105 healthy subjects. Results: We found a significant difference in the genotype frequencies between the two studied groups (chi2 = 9.855, P = 0.007). The V/V genotype was over represented in the asthmatic group as compared to the controls (32.38% vs. 16.19%). Whereas, the M/V genotype is more frequent in healthy subjects (40.95% vs. 28.71%). We also noted a significant difference in allelic distribution of M470V with associated diseases (chi2 = 9.610, P = 0.022). Conclusions: The present study is the first report on the distribution of the M470V polymorphism in asthmatic Tunisian patients. We noticed that the M470V variant could modulate the clinical phenotype of asthmatic patients. This preliminary study will establish the molecular basis of this disease in Tunisia


No disponible


Assuntos
Humanos , Masculino , Lactente , Pré-Escolar , Criança , Adolescente , Asma/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Genótipo , Mutação/genética , Frequência do Gene , Estudos de Associação Genética , Fenótipo
7.
Nat Immunol ; 20(5): 637-651, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962590

RESUMO

Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.


Assuntos
Asma/imunologia , Redes Reguladoras de Genes/imunologia , Transcriptoma/imunologia , Viroses/imunologia , Adolescente , Asma/genética , Asma/virologia , Estudos de Casos e Controles , Criança , Resfriado Comum/genética , Resfriado Comum/imunologia , Resfriado Comum/virologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Viroses/genética , Viroses/virologia
8.
BMC Med Genet ; 20(1): 58, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940096

RESUMO

BACKGROUND: The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes. METHODS: This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters. RESULTS: In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027). CONCLUSIONS: The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.


Assuntos
Idade de Início , Alelos , Asma/genética , Proteína 1 Semelhante à Quitinase-3/genética , Locos de Características Quantitativas , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Estudo de Associação Genômica Ampla , Humanos , Japão , Fenótipo
10.
Biomed Res Int ; 2019: 3805405, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906771

RESUMO

Background: The Myosin Heavy Chain 15 gene (MYH15) is expressed in the airway epithelium and variants in the gene have been associated with airway responsiveness. The aim of this study was to perform the first investigation of MYH15 polymorphisms in relation to asthma susceptibility. Methods: A total of 410 asthma patients and 418 controls from the Chinese Han population were enrolled in the study. Tag-single nucleotide polymorphisms were genotyped and associations between the polymorphisms and asthma risk were analyzed by logistic regression analysis adjusting for confounding factors. Dual-luciferase reporter gene analysis was performed to detect allele-dependent promoter activity of MYH15 variants in HEK293 cells. Results: The A allele of rs9288876 decreased risk of asthma (allelic model: OR=0.808, 95% CI: 0.658-0.993, additive model: OR=0.747, 95% CI: 0.588-0.947, dominant model: OR=0.693, 95% CI: 0.502-0.955). The G alleles of both rs7635009 and rs1454197 were associated with decreased risk of asthma under the additive model (OR=0.779, 95% CI: 0.618-0.981 and OR=0.756, 95% CI: 0.600-0.953, respectively). rs9288876 allele A was associated with higher luciferase activity than allele T (P<0.001). The luciferase activity of rs7635009 allele A was lower than allele G (P=0.001), while rs1454197 allele T had lower luciferase activity than allele G (P<0.001). Conclusion: This is the first study to report the association of MYH15 gene polymorphisms with asthma. Polymorphisms of rs9288876, rs7635009, and rs1454197 altered transcriptional regulation of MYH15 and may be functional variants conferring susceptibility to asthma. Further study with larger sample size in different ethnic populations is needed.


Assuntos
Asma/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Cadeias Pesadas de Miosina/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , Asma/fisiopatologia , Feminino , Genótipo , Células HEK293 , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética
11.
Respir Res ; 20(1): 38, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30791911

RESUMO

BACKGROUND: Asthma is a common complex chronic, inflammatory polygenic disease with heterogeneous manifestations, affecting individuals of all age groups and posing an immense burden on healthcare resources. A number of studies have identified the association between a disintegrin and metalloprotease 33 (ADAM33) polymorphisms and asthma risk, however, the results still remain inconclusive. The objective of the present study was to identify the effect of ADAM33 variants in asthma susceptibility. METHODS: Eligible case-control studies published between January 2000 and June 2018 was searched and retrieved from online electronic databases. The odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate the effect. RESULTS: A total of 63 case-control studies were finally screened out, including 13,280 asthma patients and 13,340 controls. Eleven SNPs of ADAM33 gene were identified. Our results detected a significant association between ADAM33 T2, Q1, F + 1 and AA genotype of T + 1 polymorphisms and asthma risk in total population. Subgroup analysis by ethnicities showed that the alleles and genotypes of T2, Q1 and F + 1 polymorphisms were associated with asthma susceptibility among Asian populations, while V4 polymorphism was associated with asthma among Caucasian populations. Subgroup analysis by ages showed that T2, F + 1 and ST + 4 polymorphisms were associated with childhood asthma, while Q1 and V4 polymorphisms were associated with asthma risk in adults. Subgroup analysis by asthma severity showed that only the G allele of ADAM33 T1 polymorphism was associated with the severity of asthma when compared with the controls. In addition, T2, Q1 and F + 1 polymorphisms of ADAM33 were significantly associated with increased the asthma risk in Chinese asthma patients. CONCLUSIONS: Our results found that T2, Q1 and F + 1 polymorphisms of ADAM33 gene might contribute to asthma risk. Future well-designed case-control studies with large population and more ethnicities are still needed to estimate the association.


Assuntos
Proteínas ADAM/genética , Asma/diagnóstico , Asma/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Asma/epidemiologia , Estudos de Casos e Controles , Predisposição Genética para Doença/epidemiologia , Humanos , Fatores de Risco
12.
Artigo em Inglês | MEDLINE | ID: mdl-30791383

RESUMO

A high body mass (BMI) index has repeatedly been associated with non-atopic asthma, but the biological mechanism linking obesity to asthma is still poorly understood. We aimed to test the hypothesis that inflammation and/or innate immunity plays a role in the obesity-asthma link. DNA methylome was measured in blood samples of 61 non-atopic participants with asthma and 146 non-atopic participants without asthma (non-smokers for at least 10 years) taking part in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) study. Modification by DNA methylation of the association of BMI or BMI change over 10 years with adult-onset asthma was examined at each CpG site and differentially methylated region. Pathway enrichment tests were conducted for genes in a priori curated inflammatory pathways and the NLRP3-IL1B-IL17 axis. The latter was chosen on the basis of previous work in mice. Inflammatory pathways including glucocorticoid/PPAR signaling (p = 0.0023), MAPK signaling (p = 0.013), NF-κB signaling (p = 0.031), and PI3K/AKT signaling (p = 0.031) were enriched for the effect modification of BMI, while NLRP3-IL1B-IL17 axis was enriched for the effect modification of BMI change over 10 years (p = 0.046). DNA methylation measured in peripheral blood is consistent with inflammation as a link between BMI and adult-onset asthma and with the NLRP3-IL1B-IL17 axis as a link between BMI change over 10 years and adult-onset asthma in non-atopic participants.


Assuntos
Asma/genética , Índice de Massa Corporal , Metilação de DNA , Inflamação/metabolismo , Adulto , Animais , Estudos de Coortes , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , NF-kappa B/metabolismo , Obesidade/complicações , PPAR gama/metabolismo
13.
Int J Pediatr Otorhinolaryngol ; 120: 58-63, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30771554

RESUMO

OBJECTIVES: Asthma and allergic rhinitis (AR) frequently occur as comorbid diseases of the upper airways. Single-nucleotide polymorphisms (SNPs) in the FCRL3 and FCRL5 genes have recently been shown to be associated with various immune-related disorders. This study evaluated the association of FCRL3 and FCRL5 polymorphisms with asthma and allergic rhinitis (AR) in a Han Chinese population. METHODS: Seven single nucleotide polymorphisms (SNPs) of the FCRL3 and FCRL5 were genotyped in 300 asthmatic children, and 206 healthy unrelated individuals using PCR-restriction fragment length polymorphism (PCR-RFLP) assay. Genotyping was validated by direct sequencing. RESULTS: Our results showed that the frequencies of the rs6692977 CT genotype and T allele within FCRL5 were significantly higher in asthma with comorbid AR compared to healthy controls (Bonferroni-corrected p (Pc) = 3.75 × 10-6; Pc = 0.006, respectively), whereas these of the CC genotype and C allele were significantly lower (Pc = 4.15 × 10-5; Pc = 0.006, respectively). The frequencies of the rs7528684 A allele (Pc = 1.80 × 10-3) and the rs10489678 G allele (Pc = 0.04) within FCRL3 were higher in asthma with comorbid AR than in controls. However, no differences in the tested genetic polymorphisms were detected between asthma and healthy individuals. CONCLUSION: This study identified novel SNPs in FCRL3 and FCRL5 significantly associated with the risk for asthma with comorbid AR in the Chinese population. The genetic variants may play role in the development of the asthma phenotype in children with asthma.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Asma/genética , Receptores Fc/genética , Receptores Imunológicos/genética , Rinite Alérgica/genética , Adolescente , Alelos , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Fatores de Risco
14.
Int Immunopharmacol ; 69: 159-168, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30716586

RESUMO

With the increasing morbidity and mortality of asthma, asthma aggravated by environmental pollution has drawn more attention. This study investigated the exacerbating effects of trimellitic anhydride (TMA), a typical pollutant, in ovalbumin (OVA)-induced asthmatic mice and the gene and protein expressions of TRPA1, V1, V2 in lung tissue. Female BALB/c mice were respectively administered for 42 days as follow: sensitized and challenged with OVA, sensitized and challenged with TMA, sensitized with OVA and challenged with OVA plus TMA, as well as sensitized and challenged with OVA plus TMA. 24 h after the last challenge, the changes in airway resistance (RI) and lung dynamic compliance (Cdyn) were tested. The levels of the inflammatory cells in blood and bronchoalveolar lavage fluid (BALF) were determined. The gene and protein expressions of TRPA1, V1, V2 in lung tissue were examined, and levels of interleukin (IL)-4, -13, substance P (SP), prostaglandin D2 (PGD2), nerve growth factor (NGF) in BALF and the supernatant of lung homogenate were measured. The results indicated that OVA plus TMA significantly increased the amount of inflammatory cells in blood and BALF, enhanced RI while decreased Cdyn, and aggravated lung injury. Increased gene and protein expressions of TRPA1, V1, V2 in lung tissue, level of IL-4 in the supernatant of lung homogenate, levels of IL-13, SP, PGD2, NGF in BALF and the supernatant of lung homogenate were observed. It was suggested that exacerbating effects of TMA in OVA-induced asthma might be related to the regulation of TRPA1, V1, V2 and relevant neurokines.


Assuntos
Asma/tratamento farmacológico , Canais de Cálcio/metabolismo , Poluentes Ambientais/toxicidade , Pulmão/fisiologia , Anidridos Ftálicos/toxicidade , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Alérgenos/imunologia , Animais , Asma/induzido quimicamente , Asma/genética , Canais de Cálcio/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Camundongos , Ovalbumina/imunologia , Canal de Cátion TRPA1/genética , Canais de Cátion TRPV/genética
15.
Nat Genet ; 51(3): 494-505, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804561

RESUMO

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.


Assuntos
Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Asma/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Fumar/genética
16.
Cell Tissue Res ; 376(3): 425-432, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30710174

RESUMO

The lung tissue contains a heterogeneous milieu of bronchioles, epithelial, airway smooth muscle (ASM), alveolar, and immune cell types. Healthy bronchiole comprises epithelial cells surrounded by ASM cells and helps in normal respiration. In contrast, airway remodeling, or plasticity, increases surrounding of bronchial epithelium during inflammation, especially in asthmatic condition. Given the profound functional difference between ASM, epithelial, and other cell types in the lung, it is imperative to separate and isolate different cell types of lungs for genomics, proteomics, and molecular analysis, which will improve the diagnostic and therapeutic approach to treat cell-specific lung disorders. Laser capture microdissection (LCM) is the technique generally used for the isolation of specific cell populations under direct visual inspection, which plays a crucial role to evaluate cell-specific effect in clinical and preclinical setup. However, maintenance of tissue RNA quality and integrity in LCM studies are very challenging tasks. It is obvious to believe that the major factor affecting the RNA quality is tissue-fixation method. The prime focus of this study was to address the RNA quality factors within the lung tissue using the different solvent system to fix tissue sample to obtain high-quality RNA. Paraformaldehyde and Carnoy's solutions were used for fixing the lung tissue and compared RNA integrity in LCM captured lung tissue samples. To further confirm the quality of RNA, we measured cellular marker genes in collected lung tissue samples from control and mixed allergen (MA)-induced asthmatic mouse model using qRT-PCR technique. RNA integrity number showed a significantly better quality of RNA in lung tissue samples fixed with Carnoy's solution compared to paraformaldehyde solution. Isolated RNA from MA-induced asthmatic murine lung epithelium, smooth muscle, and granulomatous foci using LCM showed a significant increase in remodeling gene expression compared to control which confirm the quality and integrity of isolated RNA. Overall, the study concludes tissue fixation solvent can alter the quality of RNA in the lung and the outcome of the results.


Assuntos
Microdissecção e Captura a Laser/métodos , Pulmão/química , RNA/análise , Ácido Acético/química , Animais , Asma/genética , Asma/patologia , Clorofórmio/química , Modelos Animais de Doenças , Etanol/química , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , RNA/genética
17.
J Evid Based Integr Med ; 24: 2515690X18821906, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30789054

RESUMO

The aim of this study was to investigate the expression patterns of miRNA-let 7a, 7b, and 7c in bronchoalveolar lavage fluid in infants with asthma and airway foreign bodies. Between January 2016 and February 2017, 27 infants were included and divided into observation group (infants with asthma, n = 15) and control group (infants with airway foreign bodies, n = 12). The differential expression profiles of miRNA-let 7a, 7b, and 7c were determined by reverse transcription-polymerase chain reaction in bronchoalveolar lavage fluid (BALF) from infants of the 2 groups. The BALF was collected from infants undergoing flexible bronchoscopy. MiRNA-let 7a, 7b, and 7c increased significantly in infants from observation group as compared with control group (2.72 ± 0.48 vs 1, 8.23 ± 1.64 vs 1, 3.16 ± 0.62 vs 1, respectively). The increased expression of miRNA-let 7a, 7b, and 7c were associated with the asthma of infants.


Assuntos
Asma/genética , Líquido da Lavagem Broncoalveolar/química , Sistema Respiratório/metabolismo , Asma/líquido cefalorraquidiano , Feminino , Humanos , Lactente , Masculino , Sistema Respiratório/química , Transcriptoma
18.
J Environ Pathol Toxicol Oncol ; 38(1): 41-50, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30806289

RESUMO

In this study, we aimed at assessing the therapeutical potential of 6-gingerol ([5S]-5-hydroxy-1-[4-hydroxy- 3-methoxyphenyl]-3-decanone) against ovalbumin-sensitized asthma in rats. The rats were treated intraperitoneally with 6-gingerol (75 mg/kg body weight) for 30 days and a theophylline (200 mg/kg body weight)-treated group as a control. Changes in the levels of T-cell-linked cytokines (interleukin-4 [IL-4], IL-5, IL-13, and interferon-gamma [IFN-?]), total immunoglobulin E (IgE), gene expressions of bitter taste-sensing type 2-receptor 10 (T2R10), inositol 1,4,5-triphosphate receptor 1 (IP3R1), Orai1 and protein expressions of nuclear factor of activated T cells 1 (NFAT1), c-Myc and histopathological changes were observed in rats. 6-Gingerol exerts its beneficial impacts like theophylline in lessening IL-4, IL-5, and IL-13, and IgE and increasing the level of IFN-?. Significant down-regulation of T2R10 gene expression and up-regulation of IP3R1 and Orai1 gene expression were observed in experimental rats and these alterations were normalized after treatment with 6-gingerol or theophylline. The histopathological study revealed that the accumulation of glycoprotein and thickness of alveolar epithelium in asthmatic rats and supplementation with 6-gingerol or theophylline in asthmatic rats restored these changes to normal. In conclusion, 6-gingerol has a protective effect on lungs in ovalbumin-sensitized asthma in rats.


Assuntos
Asma/tratamento farmacológico , Catecóis/uso terapêutico , Álcoois Graxos/uso terapêutico , Animais , Asma/genética , Asma/metabolismo , Catecóis/química , Catecóis/farmacologia , Citocinas/metabolismo , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Genes myc , Masculino , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
19.
Proc Natl Acad Sci U S A ; 116(9): 3443-3448, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808738

RESUMO

Early life exposure to fine particulate matter (PM) in air is associated with infant respiratory disease and childhood asthma, but limited epidemiological data exist concerning the impacts of ultrafine particles (UFPs) on the etiology of childhood respiratory disease. Specifically, the role of UFPs in amplifying Th2- and/or Th17-driven inflammation (asthma promotion) or suppressing effector T cells (increased susceptibility to respiratory infection) remains unclear. Using a mouse model of in utero UFP exposure, we determined early immunological responses to house dust mite (HDM) allergen in offspring challenged from 0 to 4 wk of age. Two mice strains were exposed throughout gestation: C57BL/6 (sensitive to oxidative stress) and BALB/C (sensitive to allergen exposure). Offspring exposed to UFPs in utero exhibited reduced inflammatory response to HDM. Compared with filtered air (FA)-exposed/HDM-challenged mice, UFP-exposed offspring had lower white blood cell counts in bronchoalveolar lavage fluid and less pronounced peribronchiolar inflammation in both strains, albeit more apparent in C57BL/6 mice. In the C57BL/6 strain, offspring exposed in utero to FA and challenged with HDM exhibited a robust response in inflammatory cytokines IL-13 and Il-17. In contrast, this response was lost in offspring exposed in utero to UFPs. Circulating IL-10 was significantly up-regulated in C57BL/6 offspring exposed to UFPs, suggesting increased regulatory T cell expression and suppressed Th2/Th17 response. Our results reveal that in utero UFP exposure at a level close to the WHO recommended PM guideline suppresses an early immune response to HDM allergen, likely predisposing neonates to respiratory infection and altering long-term pulmonary health.


Assuntos
Asma/imunologia , Hipersensibilidade/imunologia , Material Particulado/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Alérgenos/química , Alérgenos/toxicidade , Animais , Asma/induzido quimicamente , Asma/genética , Asma/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Feminino , Hipersensibilidade/genética , Hipersensibilidade/patologia , Imunossupressão , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Pyroglyphidae/química , Células Th17/imunologia , Células Th2/imunologia
20.
Nat Commun ; 10(1): 880, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787307

RESUMO

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.


Assuntos
Afro-Americanos/genética , Asma/genética , Predisposição Genética para Doença/genética , Asma/epidemiologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
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