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2.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576095

RESUMO

Titanium dioxide nanoparticles (TiO2NPs) are widely used in industrial and medicinal fields and in various consumer products, and their increasing use has led to an increase in the number of toxicity studies; however, studies investigating the underlying toxicity mechanism have been rare. In this study, we evaluated potential toxic effects of TiO2NPs exposure on lungs as well as the development of asthma through the ovalbumin (OVA)-induced mouse model of asthma. Furthermore, we also investigated the associated toxic mechanism. TiO2NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number and level of inflammatory cells and mediators, respectively. OVA-induced asthma exposed mice to TiO2NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with those in non-exposed asthmatic mice. This was also accompanied by increased inflammatory cell infiltration and mucus production in the lung tissues. Additionally, TiO2NPs decreased the expression of B-cell lymphoma 2 (Bcl2) and the expressions of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 were escalated in the lungs of asthmatic mice compared with those in non-exposed asthmatic mice. These responses were consistent with in vitro results obtained using human airway epithelial cells. TiO2NPs treated cells exhibited an increase in the mRNA and protein expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO2NP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiO2NP exposure induced toxicological changes in the respiratory tract and exacerbated the development of asthma via activation of the TXNIP-apoptosis pathway. These results provide insights into the underlying mechanism of TiO2NP-mediated respiratory toxicity.


Assuntos
Asma/patologia , Proteínas de Transporte/genética , Hipersensibilidade/patologia , Inflamação/patologia , Pulmão/patologia , Nanopartículas/toxicidade , Tiorredoxinas/genética , Titânio/toxicidade , Regulação para Cima/genética , Animais , Apoptose , Asma/sangue , Asma/complicações , Asma/genética , Líquido da Lavagem Broncoalveolar , Proteínas de Transporte/metabolismo , Caspase 3/metabolismo , Contagem de Células , Linhagem Celular , Fenômenos Químicos , Citocinas/biossíntese , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/complicações , Hipersensibilidade/genética , Imunoglobulina E/sangue , Inflamação/sangue , Inflamação/genética , Mediadores da Inflamação/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Camundongos , Muco/metabolismo , Nanopartículas/ultraestrutura , Ovalbumina , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Hipersensibilidade Respiratória/complicações , Tiorredoxinas/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
3.
BMC Pulm Med ; 21(1): 268, 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404358

RESUMO

BACKGROUND: Curcumin, a derivative of the spice turmeric, has been adopted by Eastern medicine for centuries as an adjunct to treat several medical conditions (e.g., anorexia and arthritis) because of its well-established anti-inflammatory properties. Studies have shown that the use of curcumin in mice models has led to reduction in several inflammatory markers as well as key inflammatory pathway enzymes. As a result, studies in Western medicine have developed to determine if this recognized benefit can be utilized for patients with inflammatory lung diseases, such as asthma. This study will seek to better understand if curcumin can be used as an adjunctive therapy for improving asthma control of patients with moderate to severe asthma; a finding we hope will allow for a more affordable treatment. METHODS: This study will utilize a randomized, placebo controlled, double blinded pilot superiority phase 2 trial at an outpatient pulmonary clinic in Southern California, USA. Subjects will be receiving Curcumin 1500 mg or matching placebo by mouth twice daily for the study period of 12 weeks. Subjects will be randomized to either a placebo or intervention Curcumin. Subjects will have 6 clinic visits: screening visit, a baseline visit, monthly clinic visits (weeks 4, 8, and 12), at weeks 4, 8, and a follow-up clinic visit or phone-call (week 16). Changes in asthma control test scores, number of days missed from school/work, FEV1 (% predicted), FEV1/FVC ratio, FVC (% predicted), blood eosinophil count, blood total IgE, and FeNO levels will be compared by group over time. DISCUSSION: The therapeutic effects of curcumin have been studied on a limited basis in asthmatics and has shown mixed results thus far. Our study hopes to further establish the benefits of curcumin, however, there are potential issues that may arise from our study design that we will address within this paper. Moreover, the onset of the COVID-19 pandemic has resulted in safety concerns that have delayed initiation of our study. This study will contribute to existing literature on curcumin's role in reducing lung inflammation as it presents in asthmatics as well as patients suffering from COVID-19. TRIAL REGISTRATION: This study protocol has been approved by the Institutional Review Board at Loma Linda University Health, (NCT04353310). IND# 145101 Registered April 20th, 2020. https://clinicaltrials.gov/ct2/show/NCT04353310 .


Assuntos
Asma , COVID-19 , Curcumina , Eosinófilos , Imunoglobulina E/sangue , Administração Oral , Adulto , Assistência Ambulatorial/métodos , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Asma/sangue , Asma/diagnóstico , Asma/tratamento farmacológico , Asma/fisiopatologia , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/fisiopatologia , Ensaios Clínicos Fase II como Assunto , Curcumina/administração & dosagem , Curcumina/efeitos adversos , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Contagem de Leucócitos/métodos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
4.
Ann Clin Lab Sci ; 51(4): 540-545, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452893

RESUMO

OBJECTIVE: Mycoplasma pneumoniae (M. pneumoniae), an extracellular pathogen lacking a cell wall, causes respiratory infection in adults and children and has been implicated in asthma exacerbation; immunoglobulin (Ig) E may be involved in these exacerbations. Specific IgM and IgG immune response to M. pneumoniae has been reported, but less is known about IgE M. pneumoniae antibody (Ab) responses in asthma. Previous studies in our laboratory demonstrated that asthmatic children have increased IgM M. pneumoniae levels, but not IgE. Thus, we sought to investigate whether past M. pneumoniae infection triggers production of M. pneumoniae-specific IgE Abs in adult subjects with/without asthma. METHODS: M. pneumoniae- IgE and -IgM Ab responses were studied in adult asthmatic (N=22) and non-asthmatic (N=22) subjects (ELISA). Data are reported as antibody index. Threshold detection levels: IgE, IgM: 0.2, 0.9, respectively. RESULTS: M. pneumoniae-IgE Ab levels were low and below the threshold of detection in both asthmatic and non-asthmatics (0.002±0.008 vs. 0.02±0.03; P=0.021). However, specific-IgM levels were slightly higher in non-asthmatics compared with asthmatics (0.96±0.37 vs. 0.79±0.31; P=0.054). M. pneumoniae-IgM Ab positivity was similar in both groups (P=1.0). CONCLUSION: IgM M. pneumoniae Abs may play an important role in non-asthma and persist for months after acute infection. IgE M. pneumoniae Abs may play a less important role in both groups.


Assuntos
Anticorpos Antibacterianos/sangue , Asma/imunologia , Imunoglobulina E/imunologia , Imunoglobulina M/sangue , Mycoplasma pneumoniae/imunologia , Pneumonia por Mycoplasma/imunologia , Adulto , Anticorpos Antibacterianos/imunologia , Asma/sangue , Asma/complicações , Asma/epidemiologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , New York/epidemiologia , Pneumonia por Mycoplasma/sangue , Pneumonia por Mycoplasma/epidemiologia , Pneumonia por Mycoplasma/etiologia , Prognóstico
5.
Life Sci ; 282: 119792, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34229006

RESUMO

AIMS: Exercise training increases circulating and tissue levels of angiotensin-(1-7) [Ang-(1-7)], which was shown to attenuate inflammation and fibrosis in different diseases. Here, we evaluated whether Ang-(1-7)/Mas receptor is involved in the beneficial effects of aerobic training in a chronic model of asthma. MATERIAL AND METHODS: BALB/c mice were subjected to a protocol of asthma induced by ovalbumin sensitization (OVA; 4 i.p. injections) and OVA challenge (3 times/week for 4 weeks). Simultaneously to the challenge period, part of the animals was continuously treated with Mas receptor antagonist (A779, 1 µg/h; for 28 days) and trained in a treadmill (TRE; 60% of the maximal capacity, 1 h/day, 5 days/week during 4 weeks). PGC1-α mRNA expression (qRT-PCR), plasma IgE and lung cytokines (ELISA), inflammatory cells infiltration (enzymatic activity assay) and airway remodeling (by histology) were evaluated. KEY FINDINGS: Blocking the Mas receptor with A779 increased IgE and IL-13 levels and prevented the reduction in extracellular matrix deposition in airways in OVA-TRE mice. Mas receptor blockade prevented the reduction of myeloperoxidase activity, as well as, prevented exercise-induced IL-10 increase. These data show that activation of Ang-(1-7)/Mas receptor pathway is involved in the anti-inflammatory and anti-fibrotic effects of aerobic training in an experimental model of chronic asthma. SIGNIFICANCE: Our results support exercise training as a non-pharmacological tool to defeat lung remodeling induced by chronic pulmonary inflammation. Further, our result also supports development of new therapy based on Ang-(1-7) or Mas agonists as important tool for asthma treatment in those patients that cannot perform aerobic training.


Assuntos
Angiotensina I/metabolismo , Asma/terapia , Fragmentos de Peptídeos/metabolismo , Pneumonia/terapia , Angiotensina I/sangue , Animais , Asma/sangue , Asma/metabolismo , Modelos Animais de Doenças , Terapia por Exercício , Masculino , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/sangue , Pneumonia/sangue , Pneumonia/metabolismo
6.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204767

RESUMO

Increased airway wall thickness and remodeling of bronchial mucosa are characteristic of asthma and may arise from altered integrin signaling on airway cells. Here, we analyzed the expression of ß1-subfamily integrins on blood and airway cells (flow cytometry), inflammatory biomarkers in serum and bronchoalveolar lavage, reticular basement membrane (RBM) thickness and collagen deposits in the mucosa (histology), and airway geometry (CT-imaging) in 92 asthma patients (persistent airflow limitation subtype: n = 47) and 36 controls. Persistent airflow limitation was associated with type-2 inflammation, elevated soluble α2 integrin chain, and changes in the bronchial wall geometry. Both subtypes of asthma showed thicker RBM than control, but collagen deposition and epithelial α1 and α2 integrins staining were similar. Type-I collagen accumulation and RBM thickness were inversely related to the epithelial expression of the α2 integrin chain. Expression of α2ß1 integrin on T-cells and eosinophils was not altered in asthma. Collagen I deposits were, however, more abundant in patients with lower α2ß1 integrin on blood and airway CD8+ T-cells. Thicker airway walls in CT were associated with lower α2 integrin chain on blood CD4+ T-cells and airway eosinophils. Our data suggest that α2ß1 integrin on inflammatory and epithelial cells may protect against airway remodeling advancement in asthma.


Assuntos
Asma/metabolismo , Asma/patologia , Progressão da Doença , Integrina alfa2beta1/metabolismo , Pulmão/patologia , Substâncias Protetoras/metabolismo , Adulto , Idoso , Remodelação das Vias Aéreas , Asma/sangue , Asma/imunologia , Membrana Basal/patologia , Brônquios/diagnóstico por imagem , Brônquios/patologia , Brônquios/fisiopatologia , Lavagem Broncoalveolar , Feminino , Humanos , Inflamação/patologia , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/patologia , Subunidades Proteicas/metabolismo , Ventilação Pulmonar , Solubilidade , Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X
7.
Sci Rep ; 11(1): 15373, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321534

RESUMO

Blood eosinophil count is a useful measure in asthma or COPD management. Recent epidemiological studies revealed that body mass index (BMI) is positively associated with eosinophil counts. However, few studies focused on the role of adiposity and fatty acid-related metabolites on eosinophil counts, including the effect of genetic polymorphism. In this community-based study involving 8265 participants (30-74 year old) from Nagahama city, we investigated the relationship between eosinophil counts and serum levels of fatty acid-related metabolites. The role of MDC1, a gene that is related to eosinophil counts in our previous study and encodes a protein that is thought to be involved in the repair of deoxyribonucleic acid damage, was also examined taking into account its interaction with adiposity. Serum levels of linoleic acid (LA) and ß-hydroxybutyric acid (BHB) were negatively associated with eosinophil counts after adjustment with various confounders; however, there were positive interactions between serum LA and BMI and between serum BHB and BMI/body fat percentages in terms of eosinophil counts. In never-smokers, there was positive interaction for eosinophil counts between the CC genotype of MDC1 rs4713354 and BMI/body fat percentages. In conclusion, both serum LA and BHB have negative impacts on eosinophil counts, while adiposity shows robust positive effects on eosinophil counts, partly via genetic background in never-smokers.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Asma/sangue , Proteínas de Ciclo Celular/genética , Eosinófilos/metabolismo , Obesidade/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Ácido 3-Hidroxibutírico/sangue , Adiposidade/genética , Adulto , Idoso , Asma/genética , Asma/patologia , Contagem de Células Sanguíneas , Índice de Massa Corporal , Eosinófilos/patologia , Feminino , Volume Expiratório Forçado , Humanos , Contagem de Leucócitos , Ácido Linoleico/sangue , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia
8.
Sci Rep ; 11(1): 11522, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075181

RESUMO

Vitamin D deficiency prevalence in children has been rising. Low 25-hydroxyvitamin D3 (25(OH)D3) levels contribute to poor asthma control in children. This study assessed 25(OH)D3 levels in children with asthma from Riyadh with respect to anthropometrics, dietary, and lifestyle variables. Children with asthma (n, 60; 2-17 years) were assessed for serum 25-hydroxy vitamin D3 (25(OH)D3) level and body anthropometrics (weight, height, and body mass index [BMI]). Vitamin D dietary intake, sun exposure, and sociodemographic data were collected using a structured questionnaire. Thirty-one children (52%) had a 25(OH)D3 level < 50 nmol/L, 15 of whom (25%) had a level < 30 nmol/L. 25(OH)D3 level was significantly negatively correlated with age (P < 0.05), weight (P < 0.02), and height (P < 0.05). Children with a 25(OH)D3 level < 30 nmol/L had a significantly higher BMI than children with insufficient and sufficient vitamin D levels (P < 0.01). There was no significant effect of sex on 25(OH)D3 level. Higher 25(OH)D3 level was associated with a greater body area exposure to the sun. This study found that > 50% of the children with asthma had below sufficiency vitamin D levels. The vitamin D screening and supplementation of older and overweight children with asthma is recommended.


Assuntos
Asma/sangue , Índice de Massa Corporal , Calcifediol/sangue , Deficiência de Vitamina D/sangue , Adolescente , Asma/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Arábia Saudita/epidemiologia , Deficiência de Vitamina D/epidemiologia
9.
BMC Pulm Med ; 21(1): 201, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130672

RESUMO

BACKGROUND: Asthma is a common respiratory disorder; some data were present on the correlation between increased levels of trace elements and the risk of asthma development. It was aimed to evaluate the levels of 13 selected blood and tooth elements (magnesium, phosphorus, calcium, chromium, manganese, iron, copper, zinc, strontium, molybdenum, cadmium, lead, mercury) in a well-controlled asthma group and the control group. METHODS: During the study period, 17 asthma patients and 26 age and gender-matched healthy children donated shed deciduous teeth having neither decay nor filling and enrolled for the study. The element levels in blood and teeth matrixes were analyzed with inductively coupled plasma mass spectrometry. Differences in blood and tooth elements in groups were evaluated with generalized linear models after adjusting confounding factors. RESULTS: After adjusting the child's "z scores of body mass index for age", history of iron deficiency anemia, and status of parental smoking, the generalized linear model revealed significantly lower tooth magnesium levels, lower blood zinc levels, and lower blood zinc/copper ratio in the asthma group than the control group (p = 0.042, p = 0.034, p = 0.002, respectively). Other studied elements for tooth and blood matrixes were similar in groups. CONCLUSION: Our study revealed some differences in tooth and blood element levels in the asthma group. Further studies on zinc and magnesium levels of severe asthma cases are necessary for the interpretation of the results.


Assuntos
Asma/diagnóstico , Oligoelementos/análise , Asma/sangue , Estudos de Casos e Controles , Criança , Cobre/sangue , Feminino , Humanos , Magnésio/sangue , Masculino , Análise Multivariada , Dente/química , Zinco/sangue
10.
Allergol Immunopathol (Madr) ; 49(3): 21-29, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33938185

RESUMO

BACKGROUND: Non-allergic asthma caused by obesity is a complication of the low-grade chronic inflammation inherent in obesity. Consequently, the serum concentrations of adipokines such as retinol-binding protein 4 (RBP4) and plasminogen activator inhibitor-1 (PAI-1) increase. No gold standard molecule for the prediction of non-allergic asthma among obese patients has been identified. OBJECTIVE: To evaluate RBP4 and PAI-1 as prognostic biomarkers of non-allergic asthma caused by obesity. METHODS: A cross-sectional study between four groups of adolescents: (1) healthy (n = 35), (2) allergic asthma without obesity (n = 28), (3) obesity without asthma (n = 33), and (4) non-allergic asthma with obesity (n = 18). RESULTS: RBP4 was higher in the non-allergic asthma with obesity group than in the obesity without asthma group (39.2 ng/mL [95% confidence interval (CI): 23.8-76.0] vs. 23.5 ng/mL [95% CI: 3.2-33.5], p < 0.01), and PAI-1 was higher in the non-allergic asthma with obesity group than in the obesity without asthma group (21.9 ng/mL [95% CI: 15.7-26.5] vs. 15.9 ng/mL [95% CI: 9.4-18.2], p < 0.05). Receiver operating characteristic (ROC) curve analysis demonstrated that the serum RBP4 cut-off value was >42.78 ng/mL, with an area under the ROC curve (AUC) of 0.741 (95% CI: 0.599-0.853, p = 0.001), considered acceptable. The PAI-1 cut-off value was >12.0 ng/mL, with an AUC of 0.699 (95% CI: 0.554-0.819, p = 0.008), considered fair. CONCLUSIONS: RBP4 may be useful to predict non-allergic asthma among obese adolescents in clinical practice.


Assuntos
Asma/sangue , Obesidade Pediátrica/complicações , Inibidor 1 de Ativador de Plasminogênio/sangue , Proteínas Plasmáticas de Ligação ao Retinol/análise , Adolescente , Asma/etiologia , Biomarcadores/sangue , Índice de Massa Corporal , Criança , Intervalos de Confiança , Estudos Transversais , Feminino , Humanos , Masculino , Obesidade Pediátrica/sangue , Prognóstico , Curva ROC
11.
Front Immunol ; 12: 649520, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968043

RESUMO

Rhinovirus C (RV-C) infection is associated with severe asthma exacerbations. Since type 2 inflammation is an important disease mechanism in asthma, we hypothesized that RV-C infection, in contrast to RV-A, preferentially stimulates type 2 inflammation, leading to exacerbated eosinophilic inflammation. To test this, we developed a mouse model of RV-C15 airways disease. RV-C15 was generated from the full-length cDNA clone and grown in HeLa-E8 cells expressing human CDHR3. BALB/c mice were inoculated intranasally with 5 x 106 ePFU RV-C15, RV-A1B or sham. Mice inoculated with RV-C15 showed lung viral titers of 1 x 105 TCID50 units 24 h after infection, with levels declining thereafter. IFN-α, ß, γ and λ2 mRNAs peaked 24-72 hrs post-infection. Immunofluorescence verified colocalization of RV-C15, CDHR3 and acetyl-α-tubulin in mouse ciliated airway epithelial cells. Compared to RV-A1B, mice infected with RV-C15 demonstrated higher bronchoalveolar eosinophils, mRNA expression of IL-5, IL-13, IL-25, Muc5ac and Gob5/Clca, protein production of IL-5, IL-13, IL-25, IL-33 and TSLP, and expansion of type 2 innate lymphoid cells. Analogous results were found in mice treated with house dust mite before infection, including increased airway responsiveness. In contrast to Rora fl/fl littermates, RV-C-infected Rora fl/fl Il7r cre mice deficient in ILC2s failed to show eosinophilic inflammation or mRNA expression of IL-13, Muc5ac and Muc5b. We conclude that, compared to RV-A1B, RV-C15 infection induces ILC2-dependent type 2 airway inflammation, providing insight into the mechanism of RV-C-induced asthma exacerbations.


Assuntos
Asma/imunologia , Infecções por Coxsackievirus/imunologia , Enterovirus/imunologia , Eosinofilia/imunologia , Linfócitos/imunologia , Animais , Asma/sangue , Asma/diagnóstico , Asma/virologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Proteínas Relacionadas a Caderinas , Caderinas/genética , Caderinas/metabolismo , Infecções por Coxsackievirus/sangue , Infecções por Coxsackievirus/complicações , Infecções por Coxsackievirus/virologia , Modelos Animais de Doenças , Enterovirus/metabolismo , Eosinofilia/sangue , Eosinofilia/virologia , Eosinófilos/imunologia , Feminino , Células HeLa , Humanos , Imunidade Inata , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Exacerbação dos Sintomas
12.
J Immunol ; 206(10): 2301-2311, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33952618

RESUMO

Na+/H+ exchanger regulatory factor 1 (NHERF1), a class I PDZ-binding protein, regulates G protein-coupled receptor signaling in some cell types. NHERF1 also functions as a scaffolding protein and activates non-G protein-coupled receptor signaling pathways, thereby contributing to the pathogenesis of various diseases. Although we have previously shown that NHERF1 regulates mast cell functions, there is little information regarding the role of NHERF1 in other immune cells. How NHERF1 regulates the pathogenesis of allergic disease such as asthma also remains unknown. In the current study, we show that NHERF1 promotes allergic airway inflammation in a house dust mite extract (HDME)-induced mouse model of asthma. Specifically, HDME-specific serum IgE levels, airway leukocyte numbers, and goblet cell hyperplasia were reduced in NHERF1+/- mice as compared with NHERF1+/+ mice. Interestingly, the gene expression of inflammatory (IL-17a, IL-25, and IL-33) as well as T helper 2 (Th2) cytokines (IL-4, IL-5, and IL-13) and several chemokines that recruit eosinophils, neutrophils, and lymphocytes were also decreased in the lungs of NHERF1+/- mice exposed to HDME. Consistent with these observations, microRNAs regulating mucus production, inflammation, Th2 effector functions, and IL-13 expression were increased in the lungs of HDME-treated NHERF1+/- mice. Overall, our studies reveal a unique role for NHERF1 in regulating asthma pathogenesis, and further elucidation of the mechanisms through which NHERF1 modulates allergic inflammation will lead to the development of new therapeutic strategies for asthma.


Assuntos
Asma/sangue , Asma/imunologia , Fosfoproteínas/metabolismo , Pyroglyphidae/imunologia , Trocadores de Sódio-Hidrogênio/metabolismo , Adolescente , Adulto , Animais , Asma/genética , Asma/patologia , Estudos de Casos e Controles , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Células Caliciformes/patologia , Humanos , Hiperplasia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Inflamação/imunologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Fosfoproteínas/genética , Trocadores de Sódio-Hidrogênio/genética , Adulto Jovem
14.
Int Arch Allergy Immunol ; 182(10): 949-961, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33873187

RESUMO

INTRODUCTION: We previously reported an increased prevalence of asthma in adults who lived in temporary housing after the 2011 Great East Japan Earthquake. The goal of the current study was to investigate changes in asthma prevalence and mite-specific immunoglobulin E (IgE) titers in temporary housing residents during 2014-2019. METHODS: By using the Global Initiative for Asthma guidelines, we diagnosed asthma in Ishinomaki city temporary housing residents aged 15 years or older. We then analyzed serum antigen-specific IgE levels to Dermatophagoides farinae (Der f), Dermatophagoides pteronyssinus (Der p), and Aspergillus fumigatus. RESULTS: The prevalence of asthma exceeded 20% across all age-groups throughout the study period. The proportion of study participants with a "positive" antigen-specific IgE titer (i.e., ≥0.35 IUA/mL) was higher in asthmatics than in nonasthmatics for Der f and Der p but not for Aspergillus fumigatus. Among residents ≥50 years old who were diagnosed with asthma, the percentage with a Der f-specific IgE titer ≥0.10 IUA/mL was higher than the proportion with ≥0.35 IUA/mL. Among study participants, asthma onset occurred before the earthquake, during residence in shelters or temporary housing, and (starting in 2016) after moving out of temporary housing. The Der p-specific IgE level was positively correlated with the duration of temporary housing (p < 0.05, r = 0.41) and inversely correlated with the time elapsed since moving out of temporary housing (p < 0.05, r = -0.35). CONCLUSION: Mite allergen sensitization was found in both asthmatic and nonasthmatic temporary housing residents after the 2011 Japan earthquake and tsunami; asthma developed even after subjects moved out of temporary housing.


Assuntos
Alérgenos/imunologia , Antígenos de Dermatophagoides/imunologia , Asma/epidemiologia , Terremotos , Habitação , Tsunamis , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos de Fungos/imunologia , Aspergillus fumigatus/imunologia , Asma/sangue , Asma/imunologia , Asma/fisiopatologia , Dermatophagoides farinae/imunologia , Dermatophagoides pteronyssinus/imunologia , Feminino , Humanos , Imunoglobulina E/sangue , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Espirometria , Adulto Jovem
15.
Curr Med Sci ; 41(2): 323-328, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33877549

RESUMO

Neutrophilic airway inflammation is one of the features of severe asthma. Neutrophil gelatinase-associated lipocalin (NGAL), or lipocalin-2, is a glycoprotein associated with neutrophilic inflammation and can be detected in blood. Recently, blood NGAL levels have been reported to be elevated in chronic obstructive pulmonary disease. However, the clinical significance of serum NGAL levels in patients with asthma has not been elucidated. The aim of this study was to explore the association between serum NGAL level and clinical parameters in patients with asthma. Sixty-one non-smoking people with stable asthma were enrolled in this study. All patients underwent blood collection and pulmonary function tests. The associations between serum NGAL levels and clinical parameters were analyzed retrospectively. Serum NGAL levels in patients with asthma and obstructive ventilatory defect were higher than those in patients with asthma without obstructive ventilatory defect (76.4±51.4 ng/mL vs. 39.3±27.4 ng/mL, P=0.0019). Serum NGAL levels were correlated with forced expired flow at 50% of vital capacity %predicted and forced expired flow at 75% of vital capacity %predicted (r=-0.3373, P=0.0078 and r=-0.2900, P=0.0234, respectively). Results of a multiple regression analysis demonstrated that serum NGAL level was independently associated with obstructive ventilatory defect. Serum NGAL levels were elevated in patients with asthma and obstructive ventilatory defect. NGAL may be involved in airway remodeling possibly mediated by neutrophilic inflammation in asthma.


Assuntos
Obstrução das Vias Respiratórias/sangue , Asma/sangue , Lipocalina-2/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Adulto Jovem
16.
J Ethnopharmacol ; 275: 114071, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33831464

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM), the leaf of Elaeagnus pungens Thunb. (Family Elaeagnaceae) is a herb documented as an antiasthmatic remedy to treat the severe asthma, bronchitis and other respiratory diseases in the early material medica "Bencao Gangmu" (Ming dynasty, about 442 years ago). AIM OF THE STUDY: This work is purposed to investigate the pharmacological effects and mechanism of total flavonoids from Elaeagnus pungens leaves (FLA) on asthma in vivo and vitro. MATERIALS AND METHODS: Female BALB/c mice were sensitized by intraperitoneal injection of OVA with aluminum hydroxide and intranasal challenged with OVA. After treatment with FLA (10, 20 mg/kg p.o.), the behaviors of mice were observed by score evaluation. Enumeration of total cells and OVA-specific IgE assay in the blood were measured as well as enumeration of total cells and cytokines assay in the BALF. Furthermore, histopathological analysis was performed by HE staining. The in vitro relaxing action on muscle force of FLA (0.0316-10.0 mg/ml) was evaluated using isometric tension in tracheal rings, and VDLCC currents were recorded to explore the relaxation mechanism in the isolated tracheal rings and mouse ASM cells, respectively. In vitro anti-inflammatory actions were assessed with LPS-stimulated RAW 264.7 macrophages. The production of inflammatory mediators and MAPK signaling pathway was estimated using ELISA and Western blotting analysis, respectively. RESULTS: The high dose of flavones from E. pungens leaf (20 mg/kg) can significantly improve the symptom of asthma breakout and relieve the lung swelling. FLA treatment decreased eosinophils and leukocytes numbers in blood and BLAF with a dosedependent manner. Furthermore, the inhibiting effect of FLA on the level of Ig E and inflammatory-related cytokines including TNF-α, IL-5 showed dose-independent. FLA relaxed high K + -induced contraction in a dose-dependent manner. The maximal relaxation produced by FLA was 99.7% (IC 50 = 0.46 mg/ml). The whole-cell VDLCC currents were abolished by FLA (3.16 mg/ml) and FLA significantly decreased the maximal amplitude of VDLCCs. No cytotoxic effect of FLA was observed in RAW264.7 cells under the tested concentrations (1-300 µg/mL). The increased IL-6 and NO by the stimulation of LPS in RAW264.7 cells were significantly inhibited by FLA in the dosedependent manner. Treatment with LPS in the presence of FLA, LPS-induced phosphorylation of ERK1/2 and JNK was inhibited in the macrophages. CONCLUSION: FLA from Elaeagnus pungens leaf can alleviate the inflammation symptom via reducing the eosinophils and leukocytes numbers as well as the production of pro-inflammatory cytokines. This anti-inflammatory effect is related to the modulation of the MAPK signaling pathway. FLA can relax the precontracted TRs by blocking the VDLCCs, which interrupts extracellular Ca 2+ influx and inhibit the rise of [Ca 2+ ]i. It strongly suggests that these flavonoids components are the substances basis of Elaeagnus pungens leaves for allergic action, bronchospasm and inflammation in asthma.


Assuntos
Anti-Inflamatórios/farmacologia , Canais de Cálcio Tipo L/metabolismo , Elaeagnaceae/química , Flavonoides/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Asma/sangue , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/patologia , Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Flavonoides/isolamento & purificação , Flavonoides/uso terapêutico , Imunoglobulina E/sangue , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Células RAW 264.7 , Traqueia/efeitos dos fármacos
17.
Inflamm Res ; 70(5): 569-579, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33852061

RESUMO

BACKGROUND: Asthma is one of the most common noninfectious chronic diseases characterized by type II inflammation. This study aimed to investigate the effects of molecular hydrogen on the pathogenesis of asthma. METHODS: OVA sensitized asthma mouse model and house dust mite treated 16HBE cellular model were established and hydrogen/oxygen mixture was used to treat asthmatic mice and 16HBE cells. Serum and BALF cytokines were measured with specific ELISA assays. E-cadherin and ZO-1 were detected by immunohistochemical staining and expression of caspase 3 and 9, NF-κB, IL-33 and ST2 was assessed by quantitative real-time PCR, western blot and/or immunofluorescence. IL-33 promoter activity was analyzed by dual-luciferase assay. ILC2 population was assayed by flow cytometry and differentially expressed miRNAs were detected using miRNA array. RESULTS: Serum and BALF levels of IL-33 and other alarmin and type II cytokines were greatly increased by OVA and inhibited by H2 in asthmatic mice. The expression of NF-κB (p65) and ST2 was upregulated by OVA and suppressed by H2. ILC2 population was markedly increased in OVA-induced asthmatic mice, and such increase was inhibited by H2. E-cadherin and ZO-1 levels in airway tissues of asthmatic mice were significantly lower than that of control mice, and the reduction was recovered by H2 treatment. H2 alleviated HDM induced apoptosis of 16HBE cells, upregulation of IL-33 and ST2, and elevation of IL-33 promoter activity. A group of miRNAs differentially expressed in HDM and HDM + H2 treated 16HBE cells were identified. CONCLUSIONS: These data demonstrated that H2 is efficient in suppressing allergen-induced asthma and could be developed as a therapeutics for asthma and other conditions of type II inflammation.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Citocinas/imunologia , Hidrogênio/uso terapêutico , Alérgenos/imunologia , Animais , Antiasmáticos/farmacologia , Apoptose/efeitos dos fármacos , Asma/sangue , Asma/imunologia , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linhagem Celular , Citocinas/sangue , Citocinas/genética , Células Epiteliais/imunologia , Feminino , Humanos , Hidrogênio/farmacologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Camundongos Endogâmicos ICR , MicroRNAs/genética , Ovalbumina/imunologia , Pyroglyphidae/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia
18.
Clin Biochem ; 93: 66-72, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33861987

RESUMO

BACKGROUND: Interleukin 4 (IL4) is a key cytokine that regulates the inflammatory cascade in bronchial asthma. We investigated the association between the IL4 and IL4R polymorphisms and the susceptibility for bronchial asthma among Egyptian children. METHODS: IL4 VNTR and IL4R c.1902 A>G p.(Q576R) polymorphisms were investigated among 100 children with bronchial asthma and 100 healthy controls using PCR method. Serum levels of IL4 and immunoglobulin E (IgE) were assessed by ELISA. RESULTS: The frequencies of (A1A2 + A2A2) genotypes and A2-allele of the IL4 VNTR variant were significantly higher among asthmatic patients than controls (p = 0.01, OR = 2.34, 95% CI = 1.24-4.44; p = 0.01, OR = 2.27, 95% CI = 1.29-3.99, respectively). The frequencies of (AG + GG) genotypes and G-allele of the IL4R (A1902G) variant were significantly higher among asthmatic patients than controls (p = 0.003, OR = 2.52, 95% CI = 1.39-4.58; p = 0.002, OR = 2.25, 95% CI = 1.35-3.76, respectively). There was a significant association between (A1A2 + A2A2) genotypes of the IL4 VNTR variant and high serum IL4 level among asthmatic patients (p < 0.001). The (AG + GG) genotypes of the IL4R (A1902G) variant were significantly associated with exposure to triggers, atopic dermatitis and higher serum IgE level in asthmatic patients (p = 0.02, 0.04 and 0.01, respectively). CONCLUSION: IL4 VNTR and IL4R (A1902G) polymorphisms could be associated with higher risks of bronchial asthma among Egyptian children.


Assuntos
Asma/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Asma/sangue , Asma/complicações , Asma/imunologia , Estudos de Casos e Controles , Criança , Dermatite Atópica/sangue , Dermatite Atópica/etiologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Voluntários Saudáveis , Humanos , Imunoglobulina E/sangue , Interleucina-4/sangue , Masculino , Análise de Componente Principal
19.
Ann Allergy Asthma Immunol ; 127(2): 249-256.e2, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33895420

RESUMO

BACKGROUND: Myeloid cells, especially dendritic cells and macrophages, play important roles in asthma pathophysiology. Monocytes (Mo) and macrophages express protease-activated receptor-2 (PAR-2), a proinflammatory serine protease receptor implicated in the pathophysiology of allergic airway inflammation. We have revealed that patients with severe asthma and those with a history of frequent asthma exacerbations exhibit increased PAR-2 expression on peripheral blood monocytes. OBJECTIVE: To determine PAR-2 expression on peripheral blood intermediate monocytes (IMMo) in subjects with increased airway inflammation, either as a result of an asthma exacerbation or after an inhalation allergen challenge. METHODS: A total of 16 adults who presented to the emergency department with asthma exacerbations were recruited after giving an informed consent. After 2 weeks, 10 patients returned for follow-up. A total of 11 patients with mild asthma treated only with as-needed bronchodilators were recruited and underwent inhalation allergen challenge after providing an informed consent. Immune cell profiling was performed by whole blood flow cytometry in both groups of patients. RESULTS: PAR-2 expression in peripheral blood IMMo increased in patients with an asthma exacerbation compared with those with stable disease, but this expression decreased after treatment of the asthma exacerbation. Subjects with mild asthma had an increase in percentages of IMMo expressing PAR-2 after an allergen challenge. Patients who presented to the emergency department had lower dendritic cell and dendritic cell subset numbers in peripheral blood during exacerbation compared with after treatment. CONCLUSION: Increased PAR-2 expression on Mo during periods of increased airway inflammation may initiate a positive feedback loop leading to systemic inflammatory changes.


Assuntos
Asma/sangue , Testes de Provocação Brônquica , Células Dendríticas/imunologia , Leucócitos Mononucleares/metabolismo , Receptor PAR-2/sangue , Adolescente , Adulto , Asma/patologia , Contagem de Células , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor PAR-2/biossíntese , Adulto Jovem
20.
Environ Health ; 20(1): 40, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33836759

RESUMO

BACKGROUND: Asthma represents a syndrome for which our understanding of the molecular processes underlying discrete sub-diseases (i.e., endotypes), beyond atopic asthma, is limited. The public health needs to characterize etiology-associated endotype risks is becoming urgent. In particular, the roles of polyaromatic hydrocarbon (PAH), globally distributed combustion by-products, toward the two known endotypes - T helper 2 cell high (Th2) or T helper 2 cell low (non-Th2) - warrants clarification. OBJECTIVES: To explain ambient B[a]P association with non-atopic asthma (i.e., a proxy of non-Th2 endotype) is markedly different from that with atopic asthma (i.e., a proxy for Th2-high endotype). METHODS: In a case-control study, we compare the non-atopic as well as atopic asthmatic boys and girls against their respective controls in terms of the ambient Benzo[a]pyrene concentration nearest to their home, plasma 15-Ft2-isoprostane (15-Ft2-isoP), urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and lung function deficit. We repeated the analysis for i) dichotomous asthma outcome and ii) multinomial asthma-overweight/obese (OV/OB) combined outcomes. RESULTS: The non-atopic asthma cases are associated with a significantly higher median B[a]P (11.16 ng/m3) compared to that in the non-atopic controls (3.83 ng/m3; P-value < 0.001). In asthma-OV/OB stratified analysis, the non-atopic girls with lean and OV/OB asthma are associated with a step-wisely elevated B[a]P (median,11.16 and 18.00 ng/m3, respectively), compared to the non-atopic lean control girls (median, 4.28 ng/m3, P-value < 0.001). In contrast, atopic asthmatic children (2.73 ng/m3) are not associated with a significantly elevated median B[a]P, compared to the atopic control children (2.60 ng/m3; P-value > 0.05). Based on the logistic regression model, on ln-unit increate in B[a]P is associated with 4.7-times greater odds (95% CI, 1.9-11.5, P = 0.001) of asthma among the non-atopic boys. The same unit increase in B[a]P is associated with 44.8-times greater odds (95% CI, 4.7-428.2, P = 0.001) among the non-atopic girls after adjusting for urinary Cotinine, lung function deficit, 15-Ft2-isoP, and 8-oxodG. CONCLUSIONS: Ambient B[a]P is robustly associated with non-atopic asthma, while it has no clear associations with atopic asthma among lean children. Furthermore, lung function deficit, 15-Ft2-isoP, and 8-oxodG are associated with profound alteration of B[a]P-asthma associations among the non-atopic children.


Assuntos
8-Hidroxi-2'-Desoxiguanosina/urina , Poluentes Atmosféricos/análise , Asma/epidemiologia , Benzo(a)pireno/análise , Dinoprosta/análogos & derivados , Adolescente , Asma/sangue , Asma/fisiopatologia , Asma/urina , Estudos de Casos e Controles , Criança , Pré-Escolar , Cotinina/urina , República Tcheca/epidemiologia , Dinoprosta/sangue , Exposição Ambiental/análise , Feminino , Humanos , Lactente , Pulmão/fisiopatologia , Masculino , Fenótipo
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