Heterozygous CARD9 mutation favors the development of allergic bronchopulmonary aspergillosis / 中华医学杂志(英文版)

BACKGROUND@#Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA.@*METHODS@#A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease.@*RESULTS@#The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production.@*CONCLUSION@#Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.

Inhibition of M2 macrophage polarization and reduction of airway inflammation in asthmatic mice with lncRNA MRAK088388 knockout / 细胞与分子免疫学杂志

Objective To investigate the long non-coding RNA(lncRNA) MRAK08838 regulates macrophage function to influence the development of asthmatic airway inflammation. Methods MRAK088388 gene knockout (MRAK088388-/-) mouse model was prepared and allergic asthma was induced by dust mite protein Dermatophagoides farinae 1 (Der f1). The mice were sacrificed after 28 days of modeling, and serum was collected to measure IgE and IgG. The FinePointe RC system was used to measure airway hyperresponsiveness and evaluate lung function in mice. Lung tissue was taken for HE staining, and periodic acid-Schiff (PAS) staining was used to evaluate inflammatory infiltration and mucus secretion in mouse lungs. Fluorescence quantitative PCR was used to detect the expression level of lncRNA MRAK08838 in bronchoalveolar lavage fluid (BALF) cells and lung tissue of asthmatic mice. ELISA was used to detect the levels of inflammatory cytokines IFN-γ, IL-4, IL-5, IL-13, IL-10 and IL-17A. Flow cytometry was used to evaluate the phenotype of macrophages in BALF and lung tissue, as well as the proportion of neutrophils, eosinophils, and alveolar macrophages. The changes of the above indicators were detected in mice by adoptive transfer of bone marrow-derived macrophages (BMDM). Results Under the challengle of Der f1, MRAK088388-/- mice showed reduced allergic airway inflammation, including reduced eosinophils in BALF and reduced production of IgE and IgG1. In addition, Der f1-treated MRAK088388-/- mice had fewer M2 macrophages than wild-type asthmatic mice. Wild-type mouse BMDM (M0) and Der f1-treated MRAK088388-/- mice also showed mild inflammatory response. Conclusion Knockout of MRAK088388 alleviates airway inflammation in asthmatic mice by inhibiting M2 polarization of airway macrophages.

Association of SLC6A4 gene c.*670T>G polymorphism with the risk for asthma and peripheral blood cytological characteristics among ethnic Zhuang Chinese population / 中华医学遗传学杂志

OBJECTIVE@#To assess the association of SLC6A4 gene c.*670T>G polymorphism with the risk for asthma and peripheral blood cytological characteristics among ethnic Zhuang Chinese from Guangxi, China.@*METHODS@#From May 2017 to March 2020, 258 patients diagnosed with asthma and 244 healthy controls were recruited from the Affiliated Hospital of Youjiang Minzhu Medical College and the People's Hospital of Hechi. Genotypes of the c.*670T>G polymorphism were determined by Sanger sequencing. Flow cytometry was used in combination with an electrical impedance method for the counting and classification of peripheral blood cells.@*RESULTS@#Compared with the T allele, the G allele of the c.*670T>G polymorphism was associated with the risk for asthma in the population (OR = 1.54, 95%CI = 1.15-2.06; P = 0.004). Compared with the GT and TT genotypes, homozygous GG genotype also comprised a risk factor (OR = 1.66, 95%CI = 1.16-2.38; P = 0.005). Stratification of the risk factors showed that the homozygous GG genotype has increased the risk of asthma in males and urban residents (P < 0.01). The erythrocyte, hemoglobin and platelet counts of the asthma group were significantly higher than the control group (P < 0.001). The GG, GT and TT genotypes have respectively accounted for 82.35%, 17.65% and 0% of the samples with platelets exceeding the normal value. The overall platelet level of GG genotype was higher than GT+TT genotype (P < 0.05). The significant association was verified by the false positive report probability, and at a prior probability level of 0.1, G vs. T false positive probability was 0.071, and GG vs. GT+TT false positive probability was 0.153.@*CONCLUSION@#The GG genotype of the c.*670T>G polymorphism is associated with the risk for asthma among ethnic Zhuang Chinese from northwest Guangxi. Above finding has also enriched the genotypic data and peripheral blood phenotype for this polymorphism.

Improvement effect of Shegan Mahuang Decoction on rats with cold-induced asthma based on TRPV1/NRF-1/mtTFA pathway / 中国中药杂志

This study investigated the therapeutic effect of Shegan Mahuang Decoction(SGMHD) on cold-induced asthma in rats and explored its underlying mechanism. Seventy-two healthy male SD rats of specific pathogen free(SPF) grade were randomly divided into a blank group, a model group, a positive control group(dexamethasone, 0.4 mg·kg~(-1)), and low-, medium-, and high-dose SGMHD groups(3.2, 6.4, and 12.8 g·kg~(-1)). The blank group received saline, while the other groups were sensitized by intraperitoneal injection of ovalbumin(OVA) solution. Subsequently, the rats were placed in a cold chamber adjustable to 0-2 ℃, and OVA solution was ultrasonically nebulized to induce cold-induced asthma in rats. After three weeks of treatment, the general behaviors of rats were observed. Hematoxylin-eosin(HE) staining was used to evaluate pathological changes in lung tissues, periodic acid-Schiff(PAS) staining assessed mucin changes, and Masson staining was performed to examine collagen deposition. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of the inflammatory factors interleukin-4(IL-4) and vascular endothelial growth factor(VEGF) in serum and bronchoalveolar lavage fluid(BALF). Real-time quantitative polymerase chain reaction(RT-PCR) was employed to assess the mRNA expression levels of transient receptor potential vanilloid subfamily member 1(TRPV1), nuclear respiratory factor 1(NRF-1), and mitochondrial transcription factor A(mtTFA) in lung tissues. Western blot was used to measure the protein expression levels of TRPV1, NRF-1, and mtTFA in lung tissues. Compared with the blank group, the model group exhibited signs of rapid respiration, increased frequency of defecation with looser stools, and disheveled and dull fur. Pathological results showed significant infiltration of inflammatory cells in lung tissues, narrowing of bronchial lumens, increased mucin secretion, and enhanced collagen deposition in the model group. Additionally, the levels of IL-4 and VEGF in serum and BALF were significantly elevated, and the mRNA and protein expression levels of TRPV1, NRF-1, and mtTFA in lung tissues were significantly increased. Compared with the model group, SGMHD improved the behaviors of rats, alleviated pathological changes in lung tissues, mucin production, and collagen deposition, significantly decreased the levels of IL-4 and VEGF in serum and BALF, and reduced the mRNA expression levels of TRPV1, NRF-1, and mtTFA in lung tissues, with the medium-dose SGMHD group showing the most significant effect. Moreover, the protein expression levels of TRPV1, NRF-1, and mtTFA in lung tissues were also reduced, with the medium-dose SGMHD group exhibiting the most significant effect. In conclusion, this study demonstrates that SGMHD can alleviate airway inflammation and inhibit airway remodeling in cold-induced asthma rats. These effects may be associated with the modulation of the TRPV1/NRF-1/mtTFA signaling pathway.

Association between beta-2 adrenergic receptor variants and clinical outcomes in children and adolescents with acute asthma

ABSTRACT Objective To investigate whether different genotypes of p.Arg16Gly, p.Gln27Glu, p.Arg19Cys and p.Thr164Ile variants interfere in response to treatment in children and adolescents with moderate to severe acute asthma. Methods This sample comprised patients aged 2 to 17 years with a history of at least two wheezing episodes and current moderate to severe asthma exacerbation. All patients received multiple doses of albuterol and ipratropium bromide delivered via pressurized metered-dose inhaler with holding chamber and systemic corticosteroids. Hospital admission was defined as the primary outcome. Secondary outcomes were changes in forced expiratory volume in the first second after 1 hour of treatment, and for outpatients, length of stay in the emergency room. Variants were genotyped by sequencing. Results A total of 60 patients were evaluated. Hospital admission rates were significantly higher in carriers of the genotype AA relative to those with genotype AG or GG, within the p.Arg16Gly variant (p=0.03, test χ2, alpha=0.05). Secondary outcomes did not differ between genotypes. Conclusion Hospital admission rates were significantly higher among carriers of the genotype AA within the p.Arg16Gly variant. Trial registration: ClinicalTrials.gov: NCT01323010

Association between interleukin-10 polymorphisms and CD4+CD25+FOXP3+ T cells in asthmatic children

Abstract Objective: The aim of this study was to evaluate the association between possible functional interleukin-10 (IL-10) polymorphisms, IL-10 expression and regulatory T cells (Tregs) frequency, and/or asthma severity in a sample of children and adolescents. Methods: This is a nested case-control genetic association study. The study sample consisted of children and adolescents aged 8-14 from public schools. Four polymorphisms of the IL-10 gene (rs1518111, rs3024490, rs3024496, rs3024491) were genotyped in asthmatic subjects and controls using real-time PCR. Tregs cells and IL-10 were analyzed in peripheral blood mononuclear cells by flow cytometry. The severity of asthma was defined according to the Global Initiative for Asthma (GINA) guideline. Results: One hundred twenty-three asthmatic subjects and fifty-eight controls participated in the study. The single nucleotide polymorphism (SNP) rs3024491 (T allele) showed association with asthma severity, presenting a higher frequency in patients in the moderate asthma group. The T allele of variant rs3024491 also showed an association with reduced IL-10 levels (p = 0.01) and with increased Tregs frequency (p = 0.01). The other variants did not present consistent associations. Conclusions: Our results suggest that moderate asthma is associated with a higher frequency of the T allele in the SNP rs3024491. In addition, the variant rs3024491 (TT) was associated with a reduction in IL-10 production and an increased percentage of Tregs cells, suggesting possible mechanisms that influence asthma severity.

IL-4-C-590T locus polymorphism and susceptibility to asthma in children: a meta-analysis

Abstract Objectives The study aimed to evaluate the link between the IL-4-C590T polymorphism and asthma susceptibility in children by meta-analysis. Sources The study collected all the case-control studies found in PubMed, Embase, CNKI, Wanfang, VIP, and other databases until September 2019. Stata v. 15.0 was used to conduct meta-analysis, calculate the combined OR and its 95% CI, and then conduct subgroup analysis. Summary of the findings Seven studies were included in the study, containing 860 cases and 810 controls. Relative to the C allele, the T allele at the IL-4-C590T locus was associated with susceptibility to asthma in children (OR = 1.45, 95% CI: 1.05-2.01). The results of ethnicity subgroup analysis showed that there was statistical significance, with OR = 1.61 (95% CI: 1.01-2.57) in the Asian population. In the dominant and recessive genetic models, the overall test and the Asian population subgroup analysis were statistically significant. In the homozygous model, there was statistical significance, but no statistical significance in heterozygous model. Conclusions The IL-4-C590T polymorphism was associated with asthma susceptibility, and T allele and TT genotype may increase the risk of asthma susceptibility in children, especially in the Asian population.

Association between / 中国当代儿科杂志

OBJECTIVES@#To study the association of β2-drenergic receptor (@*METHODS@#A total of 143 children with asthma who attended the hospital from October 2016 to October 2020 were enrolled as the asthma group, among whom 61 children had mild symptoms (mild group) and 82 children had moderate-to-severe symptoms (moderate-to-severe group). A total of 137 healthy children were enrolled as the control group. Peripheral venous blood samples were collected from the two groups. The SNaPshot SNP technique was used to analyze the SNP and haplotypes of the @*RESULTS@#Polymorphisms were observed in the @*CONCLUSIONS@#SNP/haplotype of the

Research progress of non-coding RNA in regulating the function of T cells in asthma / 生理学报

Bronchial asthma (i.e. asthma) is a chronic inflammatory disease characterized by airway inflammatory response, hyperresponsiveness and airway remodeling, in which T cells play a vital role, especially T helper cells (Th cells). Non-coding RNAs (ncRNAs) are the RNAs that do not encode proteins, mainly including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which are widely found in eukaryotic genomes and participate in the regulation of various biological processes. Previous studies have shown that ncRNAs play an important role in the activation and transformation of T cells and other biological processes in asthma. The specific molecular mechanism and clinical application are worth in-depth discussion. This article reviewed the research progress in regulation of miRNAs, lncRNAs and circRNAs on T cells in asthma in recent years.

Association between MCP-1 -2518A>G polymorphism and asthma susceptibility: a meta-analysis

The published data on the association between MCP-1 -2518A>G polymorphism and asthma susceptibility are inconclusive. Therefore, we performed a meta-analysis to estimate the impact of MCP-1 -2518A>G polymorphism on asthma susceptibility. PubMed, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were used to identify eligible studies. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to calculate the strength of association. Sensitivity analysis was performed to evaluate the influence of individual studies on the estimates of overall effect, and funnel plots and Egger's test were used to assess publication bias. Eight publications with 1562 asthma patients and 1574 controls were finally identified. Overall, we found no significant association between MCP-1 -2518A>G polymorphism and asthma susceptibility in any of the genetic model comparisons. After stratified analysis by ethnicity, the results showed that a significant association with asthma risk was found in Caucasians in all the genetic models. However, a protective association was found in Africans under the dominant model. The present meta-analysis suggested that the MCP-1 -2518 A>G polymorphism is a risk factor for asthma in the Caucasian population, nevertheless it has a protective effect in the African population.

Polymorphisms in chronic rhinosinusitis with nasal polyps - a systematic review / Polimorfismos na rinossinusite crônica com pólipos nasais - uma revisão sistemática

Abstract Introduction: Chronic rhinosinusitis with nasal polyps is a multifactorial disease with a complex pathophysiology involving multiple genetic and environmental factors. Objective: The purpose of this work review is to focus on the importance of genetic studies in chronic rhinosinusitis with nasal polyps besides the several barriers that exists for its understanding. Methods: A systematic review on studies of association between single nucleotide polymorphisms and chronic rhinosinusitis with nasal polyps based on a PubMed/Medline and Periódicos CAPES search of all articles published between January 2005 and January 2015 was made. The search was guided on studies containing the terms polymorphisms, rhinosinusitis, and polyps. Results: Two studies found an association of MMP-9 and MMP-2 polymorphisms and chronic rhinosinusitis with nasal polyps, but not in patients with recurrent nasal polyps. Other studies found an association of nasal polyps with MMP-9 polymorphisms, but not with MMP-2 ones. There is evidence of an association of LTC4S, NOS2A, PTGDR, MET, COX-2, OSF-2, and LF polymorphisms and the risk of developing nasal polyps, especially when combined with chronic allergic rhinitis and asthma. Conclusion: Genetic studies on chronic rhinosinusitis with nasal polyps are promising and may offer insights into its pathophysiology, which is likely affected by multiple genetic factors.

Resumo Introdução: A rinossinusite crônica com pólipos nasais é uma doença multifatorial com uma fisiopatologia complexa envolvendo múltiplos fatores genéticos e ambientais. Objetivo: O objetivo deste trabalho é enfatizar a importância dos estudos genéticos na rinossinusite crônica com pólipos nasais, além das diversas barreiras existentes para sua compreensão. Método: Realizou-se uma revisão sistemática de estudos de associação entre polimorfismos de nucleotídeo único e rinossinusite crônica com pólipos nasais com base em uma busca feita nos bancos de dados PubMed/Medline e Periódicos CAPES de todos os artigos publicados entre janeiro de 2005 e janeiro de 2015. A busca foi direcionada à estudos contendo os termos polimorfismos, rinossinusite e pólipos. Resultados: Dois estudos encontraram uma associação entre os polimorfismos MMP-9 e MMP-2 e rinossinusite crônica com pólipos nasais, mas não em pacientes com pólipos nasais recorrentes. Outros estudos encontraram uma associação de pólipos nasais com polimorfismos MMP-9, mas não com MMP-2. Existem evidências de uma associação dos polimorfismos LTC4S, NOS2A, PTGDR, MET, COX-2, OSF-2 e LF e o risco de desenvolver pólipos nasais, especialmente quando combinados com rinite alérgica crônica e asma. Conclusão: Estudos genéticos sobre rinossinusite crônica com pólipos nasais são promissores e podem oferecer conhecimento sobre sua fisiopatologia, que é provavelmente afetada por múltiplos fatores genéticos.

Association between ADAM metallopeptidase domain 33 gene polymorphism and risk of childhood asthma: a meta-analysis

This study aimed to investigate the association between ADAM metallopeptidase domain 33 (ADAM33) gene polymorphisms and the risk of childhood asthma. The relevant studies about the relationship between ADAM33 gene polymorphisms and childhood asthma were searched from electronic databases and the deadline of retrieval was May 2016. The single nucleotide polymorphisms (SNPs) of ADAM33 (rs511898, rs2280092, rs3918396, rs528557, rs2853209, rs44707, rs2280091 and rs2280089) were analyzed based on several models including the allele, codominant, recessive and dominant models. The results showed that the ADAM33 rs2280091 polymorphism in all four genetic models was associated with an increased risk of childhood asthma. Positive associations were also found between the polymorphisms rs2280090, rs2787094, rs44707 and rs528557 and childhood asthma in some genetic models. This meta-analysis suggested that ADAM33 polymorphisms rs2280091, rs2280090, rs2787094, rs44707 and rs528557 were significantly associated with a high risk of childhood asthma.

Polimorfismos de nucleótidos simples V4 y T1 del gen ADAM33 en pacientes venezolanos con asma o enfermedad pulmonar obstructiva crónica / Single nucleotide polymorphisms V4 and T1 of the ADAM33 gene in Venezuelan patients with asthma or chronic obstructive pulmonary disease

ADAM33 es una metaloproteinasa de la matriz extracelular involucrada en la remodelación tisular y, por ello, en el asma y la enfermedad pulmonar obstructiva crónica (EPOC). Se han reportado varios polimorfismos del gen de ADAM33 asociados a la actividad enzimática. Los polimorfismos más estudiados son el V4, citosina por una guanina en la región 3’ UTR, y el T1, adenina por una guanina en el exón 19 del gen. El objetivo del presente trabajo fue determinar la posible asociación de los polimorfismos de nucleótido simple de ADAM33, V4 y T1, con la presencia de asma o EPOC en pacientes venezolanos. Los polimorfismos V4 y T1 fueron analizados en 303 individuos (103 asmáticos, 100 EPOC, y 100 controles) mediante PCR-RFLP (reacción en cadena de la polimerasa y análisis de polimorfismos por longitud de fragmentos de restricción enzimática). La frecuencia genotípica del polimorfismo V4 fue significativamente mayor (p<0,05) en ambos grupos de pacientes, asmáticos y EPOC, con respecto al control. No se encontraron diferencias significativas (P=0,4) en el polimorfismo T1. Sin embargo, se evidenció una diferencia significativa (p<0,05) cuando los haplotipos y diplotipos de ADAM33 V4/T1 se compararon entre los tres grupos. Se concluye que el polimorfismo ADAM33 V4 está asociado con la presencia de asma o EPOC en pacientes venezolanos.

ADAM33 is a metalloproteinase important in the extracellular matrix for tissue remodeling, and, consequently, in asthma and chronic obstructive pulmonary disease (COPD). Several polymorphisms of the ADAM33 gene have been associated with enzyme activity. One of the most studied polymorphisms is V4, cytosine for guanine in the 3’UTR region, and T1, adenine for guanine in the exon 19 of the gen. The aim of this study was to ascertain the possible association among single polymorphisms of ADAM33, V4 and T1, in Venezuelan patients with asthma or COPD. The polymorphisms V4 and T1 were analyzed in 303 individuals (103 asthmatic, 100 COPD and 100 controls) by PCR-RFLP (polymerase chain reaction and restriction fragment length polymorphisms). There was a significant difference (P<0.05) in the frequency of ADAM33 V4 polymorphism in both, asthmatic and COPD patients groups, as compared to controls. No significant differences (P=0.4) were found for T1 polymorphism. However, there were significant differences (P<0.05) when haplotypes and diplotypes of ADAM33 V4/T1 were compared in all three groups. It can be concluded that the polymorphism V4 of ADAM33 is associated with asthma or COPD in Venezuelan patients.

Epigenética en enfermedades alérgicas y asma / Epigenetics in allergic diseases and asthma

Las enfermedades alérgicas y el asma son el resultado de complejas interacciones entre la predisposición genética y factores ambientales. El asma es una de las enfermedades crónicas más prevalentes en niños. En este artículo se revisan algunos factores ambientales como la exposición a alérgenos, tabaco, bacterias, componentes microbianos, dieta, obesidad y estrés, que intervienen durante la vida intrauterina y la infancia en la regulación epigenética de las enfermedades alérgicas y el asma. La revisión se realiza en tres tipos de modelos: in-vitro, animales y humanos.

Allergic diseases and asthma are the result of complex interactions between genetic predisposition and environmental factors. Asthma is one of the most prevalent chronic disease among children. In this article we review some environmental factors like: allergen exposition, tobacco, bacteria, microbial components, diet, obesity and stress, which influences during intrauterine and infancy life in the epigenetic regulation of asthma and allergic diseases. The review has been done in three models: in-vitro, animal and human.

Asma ocupacional / Occupational asthma

El asma ocupacional (AO) es la enfermedad laboral más frecuente en los países industrializados y se estima que aproximadamente un 15% del asma del adulto puede ser de origen ocupacional. En los Estados Unidos se estima que el 5-15% de los casos de asma pueden tener un origen relacionado con el trabajo. Según lo evaluado en diferentes estudios, la proporción de casos nuevos de asma en el adulto que se deben a la exposición ocupacional se desconoce por la ausencia de programas efectivos de vigilancia epidemiológica de las enfermedades de trabajo. Las diferencias en el diseño de los estudios epidemiológicos, la definición de AO, el tipo de población y el país donde se realiza el estudio son algunas de las razones de estas discrepancias y de la dificultad de realizar comparaciones. El AO puede desarrollarse tanto por un mecanismo inmunológico como no inmunológico. En su desarrollo influyen el tipo de agente al que está expuesto el individuo, el nivel y modo de exposición y factores genéticos de susceptibilidad. Dado que el tratamiento de elección en el AO es retirar al paciente de la exposición a su ambiente laboral, el número de personas que puede requerir un cambio de trabajo y las consecuencias económicas para la sociedad son considerables así como el impacto social y económico por la incapacidad laboral tanto temporal como permanente que produce. Por dicho motivo, una historia clínica detallada y personalizada de asma en el individuo juega un papel relevante, aportando conocimientos sobre los posibles desencadenantes (aeroalérgenos, irritantes ambientales), visualizando al trabajador in situ o inmerso en su lugar de trabajo y permitiendo comprender las diferentes situaciones suscitadas. Casi todos los agentes que llevan a otras enfermedades ocupacionales respiratorias también pueden causar asma laboral. Por consiguiente, son menos prevalentes los trabajos sin exposición de riesgo, y considerando que se trata de una patología muy frecuente y en incremento en países industrializados, deberían tomarse medidas preventivas eficaces.(AU)

Occupational asthma (OA) is the most common occupational disease in industrialized countries and it is estimated that approximately 15% of adult asthma may be of occupational origin. In the United States, it is estimated that 5-15% of asthma cases can have a work-related origin.As evaluated in different studies, the proportion of new cases of asthma in adults that are due to occupational exposure is unknown by the absence of effective epidemiological surveillance programs of occupational diseases.The differences in the design of epidemiological studies, the definition of OA, the type of population and the country where the study is conducted are some of the reasons for these discrepancies and the difficulty of making comparisons. The OA can be developed by an immune mechanism so as not immune. In its development influence the type of agent that is exposed individual, level and mode of exposure and genetic susceptibility factors. Since the treatment of choice in the OA is to remove the patient from exposure to their work environment, the number of people who may require a change of job and economic consequences for society are significant and the social and economic impact of both permanent and temporary incapacity produced.For this reason, a detailed and personalized medical history of asthma in the individual plays an important role, providing insights into possible triggers (airborne allergens, environmental irritants), visualizing the worker in situ or immersed in his workplace and allowing understand the different situations arising.Almost all the agents that lead to other occupational respiratory diseases can also cause occupational asthma. Therefore, works without risk exposure are less prevalent, and considering that this is a very common disease andis increasing in industrialized countries, effective preventive measures should be taken.(AU)

Beta 2-adrenergic receptor gene association with overweight and asthma in children and adolescents and its relationship with physical fitness / Associação do gene ADRB2 com sobrepeso e asma em crianças e adolescentes e sua relação com a aptidão física

Objective: To investigate the association of Arg16Gly and Gln27Glu polymorphisms of β2-adrenergic receptor gene (ADRB2) with the occurrence of asthma and overweight and the gene's influence on anthropometric, clinic, biochemical and physical fitness variables in children and adolescents. Methods: Subjects were evaluated for allelic frequencies of the β2-adrenergic receptor gene, height, weight, body mass index (BMI), BMI Z-score, waist circumference (WC), pubertal stage, resting heart rate (HRres), blood pressure (BP), total cholesterol (TC), glucose, insulin, high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), triglyceride (TG), Homeostasis Metabolic Assessment (HOMA2-IR), Quantitative Insulin Sensitivity Check Index (QUICKI) and maximal oxygen uptake (VO2max). The participants were divided in four groups: overweight asthmatic (n=39), overweight non-asthmatic (n=115), normal weight asthmatic (n=12), and normal weight non-asthmatic (n=40). Results: Regarding the Gln27Glu polymorphism, higher total cholesterol was observed in usual genotype individuals than in genetic variant carriers (p=0.04). No evidence was found that the evaluated polymorphisms are influencing the physical fitness. The Arg16 allele was found more frequently among the normal weight asthmatic group when compared to the normal weight non-asthmatic group (p=0.02), and the Glu27 allele was more frequently found in the overweight asthmatics group when compared to the normal weight non-asthmatic group (p=0.03). Conclusions: The association of Arg16 allele with the occurrence of asthma and of the Glu27 allele with overweight asthmatic adolescents evidenced the contribution of the β2-adrenergic receptor gene to the development of obesity and asthma.

Objetivo: Investigar a associação dos polimorfismos Arg16Gly e Gln27Glu do gene receptor β2-adrenérgico (ADRB2) com a ocorrência de asma e sobrepeso, bem como a influência do gene sobre variáveis antropométricas, clínicas, bioquímicas e de aptidão física em crianças e adolescentes. Métodos: Os indivíduos foram avaliados quanto à frequência alélica do gene ADRB2, estatura, peso, índice de massa corporal, IMC-escore Z, circunferência abdominal, estágio puberal, frequência cardíaca de repouso, pressão arterial, colesterol total, glicose, insulina, lipoproteína de alta densidade, lipoproteína de baixa densidade, triglicerídeos, Homeostasis Metabolic Assessment (HOMA2-IR), Quantitative Insulin Sensitivity Check Index (QUICKI) e consumo máximo de oxigênio (VO2max). Os participantes foram divididos em quatro grupos: sobrepeso asmático (n=39), sobrepeso não asmático (n=115), peso normal asmático (n=12) e peso normal não asmático (n=40). Resultados: Com relação ao polimorfismo Gln27Glu, foi observado maior valor de colesterol total nos indivíduos do genótipo usual do que naqueles que carregam a variante (p=0,04). Não foi encontrada evidência de que os polimorfismos avaliados influenciem a aptidão física. O alelo Arg16 foi encontrado em maior frequência no grupo de peso normal asmático comparado com o grupo de peso normal não asmático (p=0,02) e o alelo Glu27 foi mais frequentemente encontrado no grupo de sobrepeso asmático comparado com o grupo de peso normal não asmático (p=0,03). Conclusões: A associação do alelo Arg16 com a ocorrência de asma e a associação do alelo Glu27 com adolescentes com sobrepeso asmáticos evidenciam a contribuição do gene ADBR2 para o desenvolvimento da obesidade e da asma.

Evaluation of multidrug resistance-1 gene C>T polymorphism frequency in patients with asthma

OBJECTIVES:Asthma is a chronic inflammatory lung disease characterized by bronchial hyperresponsiveness and airflow obstruction. Genetic and oxidative stress factors, in addition to pulmonary and systemic inflammatory processes, play a pivotal role in the pathogenesis of asthma. The products of the multidrug resistance-1 gene protect lung tissue from oxidative stress. Here, we aimed to evaluate the association between the multidrug resistance-1 gene C>T polymorphism and asthma with regard to oxidative stress-related parameters of asthmatic patients.METHODS:Forty-five patients with asthma and 27 healthy age-matched controls were included in this study. Blood samples were collected in tubes with ethylenediaminetetraacetic acid. DNA was extracted from the blood samples. The multidrug resistance-1 gene polymorphism was detected by polymerase chain reaction and a subsequent enzyme digestion technique. The serum levels of total oxidant status and total antioxidant status were determined by the colorimetric measurement method.RESULTS:The heterozygous polymorphic genotype was the most frequent in both groups. A significant difference in the multidrug resistance-1 genotype frequencies between groups indicated an association of asthma with the TT genotype. A significant difference between groups was found for wild type homozygous participants and carriers of polymorphic allele participants. The frequency of the T allele was significantly higher in asthmatic patients. The increase in the oxidative stress index parameter was significant in the asthma group compared with the control group.CONCLUSIONS:The multidrug resistance-1 gene C/T polymorphism may be an underlying genetic risk factor for the development of asthma via oxidant-antioxidant imbalance, leading to increased oxidative stress.

PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells

Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.

Asma e DPOC: duas faces de um mesmo dado? / Asthma and COPD: two faces of the same die?

Os imbricados processos patogênicos da asma e da doença pulmonar obstrutiva crônica (DPOC) têm mecanismos comuns que envolvem redes genéticas, subclasses de linfócitos, inúmeras citocinas e quimiocinas e geram comportamento alterado de todas as células estruturais e funcionais do trato respiratório. Parte das centenas de genes que vêm sendo implicados na patogenia da asma e da DPOC são comuns às duas. Aparentemente, eles formam uma grande rede, e sua ação conjunta está associada às alterações presentes nas duas disfunções respiratórias. Dado que parte da base genética de ambas é comum e que muitos processos inflamatórios são comuns às duas, pode-se supor que elas componham uma única entidade que pode se apresentar de diversas formas.

The overlapping pathogenic processes present in asthma and chronic obstructive pulmonary disease (COPD) involve a genetic network, lymphocyte subclasses, numerous cytokines and chemokines which generate altered behavior of all structural and functional cells of the respiratory tract. Part of hundreds of genes implicated in the pathogenesis of asthma and COPD are the same. Apparently, they form a large network and their joint action is associated with several changes present in both respiratory disorders. As part of the genetic basis of both is common and many inflammatory processes are similar in both, one can assume that they form a single entity that can occur in different ways.