Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.384
Filtrar
1.
Pharm Res ; 37(2): 31, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915990

RESUMO

PURPOSE: To assess the efficacy of the novel clinical formulation of fenretinide (LAU-7b) for the treatment of allergic asthma. To study the association between LAU-7b treatment in allergic asthma and the modulation of very long chain ceramides (VLCC). METHODS: We used two allergens (OVA and HDM) to induce asthma in mouse models and we established a treatment protocol with LAU-7b. The severity of allergic asthma reaction was quantified by measuring the airway resistance, quantifying lung inflammatory cell infiltration (Haematoxylin and eosin stain) and mucus production (Periodic acid Schiff satin). IgE levels were measured by ELISA. Immunophenotyping of T cells was done using Fluorescence-activated cell sorting (FACS) analysis. The analysis of the specific species of lipids and markers of oxidation was performed using mass spectrometry. RESULTS: Our data demonstrate that 10 mg/kg of LAU-7b was able to protect OVA- and HDM-challenged mice against increase in airway hyperresponsiveness, influx of inflammatory cells into the airways, and mucus production without affecting IgE levels. Treatment with LAU-7b significantly increased percentage of regulatory T cells and CD4+ IL-10-producing T cells and significantly decreased percentage of CD4+ IL-4-producing T cells. Our data also demonstrate a strong association between the improvement in the lung physiology and histology parameters and the drug-induced normalization of the aberrant distribution of ceramides in allergic mice. CONCLUSION: 9 days of 10 mg/kg of LAU-7b daily treatment protects the mice against allergen-induced asthma and restores VLCC levels in the lungs and plasma.


Assuntos
Alérgenos/imunologia , Asma/tratamento farmacológico , Fenretinida/uso terapêutico , Ovalbumina/imunologia , Pyroglyphidae/imunologia , Animais , Asma/imunologia , Asma/metabolismo , Ceramidas/metabolismo , Protocolos Clínicos , Modelos Animais de Doenças , Composição de Medicamentos , Feminino , Masculino , Metilcelulose/química , Camundongos
2.
Int Arch Allergy Immunol ; 181(1): 56-70, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31707382

RESUMO

INTRODUCTION: Phospholipases are enzymes that occur in many types of human cells, including mast cells, and play an important role in the molecular background of asthma pathogenesis, and the development of inflammation NF-κB activities that affect numerous biological processes has been reported in many inflammatory diseases including asthma. Vitamin D is a widely studied factor that affects many diseases, including asthma. The aim of this study is to assess the influence of 1,25-(OH)2D3 on regulation of chosen phospholipase-A2 (PLA2) expression-selected inflammation mediators. METHODS: LUVA mast cells were stimulated with 1,25(OH)2D3, and inhibitors of NF-κB p65 and ubiquitination. Expression analysis of phospholipases (PLA2G5, PLA2G10, PLA2G12, PLA2G15, PLA2G4A, PLA2G4B, PLA2G4C, PLAA, NF-κB p65, and UBC) was done utilizing real-time PCR and Western blot. Eicosanoid (LTC4, LXA4, 15[S]-HETE, and PGE2) levels and sPLA2 were also measured. RESULTS: We found that 1,25(OH)2D3 decreased the expression of PLA2G5, PLA2G15, PLA2G5,UBC, and NF-κB p65 but increased expression of PLAA and PLA2G4C (p < 0.05). Moreover, the expression of PLA2G5 and PLA2G15 decreased after inhibition of NF-κB p65 and UBC. Increased levels of released LXA4 and 15(S)-HETE, decreased levels of LTC4, and sPLA2s enzymatic activity in response to 1,25(OH)2D3 were also observed. Additionally, NF-κB p65 inhibition led to an increase in the LXA4 concentration. CONCLUSION: Future investigations will be needed to further clarify the role of 1,25(OH)2D3 in the context of asthma and the inflammatory process; however, these results confirm a variety of effects which can be caused by this vitamin. 1,25(OH)2D3-mediated action may result in the development of new therapeutic strategies for asthma treatment.


Assuntos
Asma/metabolismo , Colecalciferol/metabolismo , Inflamação/metabolismo , Mastócitos/metabolismo , NF-kappa B/metabolismo , Fosfolipases A2/metabolismo , Asma/genética , Linhagem Celular Transformada , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Lipoxinas/metabolismo , NF-kappa B/genética , Fosfolipases A2/genética , Transdução de Sinais , Ubiquitinação
3.
Environ Pollut ; 256: 113375, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31662264

RESUMO

Some studies have indicated that formaldehyde, a ubiquitous environmental pollutant, can induce or aggravate allergic asthma. Epidemiological studies have also shown that the relative humidity indoors may be an independent and a key factor associated with the aggravation of allergic asthma. However, the synergy of humidity and formaldehyde on allergic asthma and the mechanism underlying this effect remain largely unknown. In this study, we aim to determine the effect of high relative humidity and/or formaldehyde exposure on allergic asthma and explore the underlying mechanisms. Male Balb/c mice were modeled with ovalbumin (OVA) and exposure to 0.5 mg/m3 formaldehyde and/or different relative humidity (60%/75%/90%). Histopathological changes, pulmonary function, Th1/Th2 balance, the status of mucus hypersecretion and the levels of inflammatory factors were detected to assess the exacerbation of allergic asthma. The levels of the transient receptor potential vanilloid 4 (TRPV4), calcium ion and the activation of p38 mitogen-activated protein kinases (p38 MAPK) were detected to explore the underlying mechanisms. The results showed that exposure to high relative humidity or to 0.5 mg/m3 formaldehyde alone had a slight, but not significant, affect on allergic asthma. However, the pathological response and airway hyperresponsiveness (AHR) were greatly aggravated by simultaneous exposure to 0.5 mg/m3 formaldehyde and 90% relative humidity. Blocking TRPV4or p38 MAPK using HC-067047 and SB203580 respectively, effectively alleviated the exacerbation of allergic asthma induced by this simultaneous exposure to formaldehyde and high relative humidity. The results show that when formaldehyde and high relative humidity are present this can enhance the activation of the TRPV4 ion channel in the lung leading to the aggravation of the p38 MAPK activation, resulting in the exacerbation of inflammation and hypersecretion of mucus in the airways.


Assuntos
Asma/induzido quimicamente , Formaldeído/toxicidade , Umidade/efeitos adversos , Canais de Cátion TRPV/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Asma/imunologia , Asma/metabolismo , Modelos Animais de Doenças , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Testes de Função Respiratória
4.
Life Sci ; 241: 117120, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31825792

RESUMO

AIMS: The present study explored the function and regulatory mechanism of High mobility group box 1 (HMGB1) in asthma. MAIN METHODS: OVA (ovalbumin)-induced asthmatic mice model and LPS-treated cellular model were established in this study. Airway inflammation was measured through detecting the expression of IL-4, IL-5, IL-13 and Interferon-γ (IFN-γ) in serum and BALF (bronchoalveolar lavage fluid) by ELISA kits. Bioinformatics predictive analysis, ChIP assays, Luciferase reporter assay and Western blotting were used to explore the relation between HMGB1 and HSF1 (Heat shock factor 1). KEY FINDINGS: HMGB1 expression was increased in OVA-induced asthmatic mice. Silencing HMGB1 attenuated the increasing of IgE, inflammatory factors (IL-4, IL-5 and IL-13), and airway hyperresponsiveness that induced by OVA. In addition, our study found that HSF1 directly bind with the HMGB1 promoter and negatively regulation of HMGB1. HSF-1 were upregulated in OVA-induced asthmatic mice, and knockdown of HSF1 aggravated the OVA-induced airway inflammation and airway hyperreactivity in mice may through promoting the expression of HMGB1 and the activation of the Toll-like receptor 4 (TLR4)/Myeloid differentiation primary response 88 (MyD88)/Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signal pathway. SIGNIFICANCE: The expression of HMGB1 could be negatively regulated by HSF1, and the TLR4/MyD88/NF-κB signal pathway was involved in HSF1/HMGB1-mediated regulation of asthma.


Assuntos
Asma/patologia , Proteína HMGB1/metabolismo , Fatores de Transcrição de Choque Térmico/fisiologia , Inflamação/patologia , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose , Asma/induzido quimicamente , Asma/genética , Asma/metabolismo , Sequência de Bases , Hiper-Reatividade Brônquica/etiologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Citocinas/metabolismo , Células HEK293 , Proteína HMGB1/genética , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , Ovalbumina/toxicidade , Regiões Promotoras Genéticas , Transdução de Sinais , Receptor 4 Toll-Like/genética
5.
BMC Complement Altern Med ; 19(1): 349, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801507

RESUMO

BACKGROUND: Ocimum species (Lamiaceae) has been traditionally used for treatment of upper respiratory tract infections, bronchitis, coughs, sore throat, and wound healing. The Immunomodulatory and anti-inflammatory effects of hydro-ethanolic extract of Ocimum basilicum (O. basilicum) leaves was examined in ovalbumin sensitized animals. METHODS: Wistar rats were divided to six groups; non-sensitized, sensitized to ovalbumin, sensitized and treated with dexamethasone (1.25 µg/mL), and O. basilicum extract (0.75, 1.50 and 3.00 mg/mL) in drinking water for 21 days. The levels of interleukin 4 (IL-4), interferon gamma (IFN-γ), IFN-γ/IL-4 ratio, immunoglobulin E (IgE), phospholipase A2 (PLA2) and total protein (TP) in BALF, and lung pathological changes were examined. RESULTS: A significant increase in IL-4, IgE, PLA2 and TP levels, all lung pathological indices as well as significant decrease in IFN-γ/IL-4 ratio was seen in the asthmatic compared to the control rats (P < 0.05 to P < 0.001). Treatment with O. basilicum extract resulted in decreased IL-4, IgE, PLA2 and TP levels, but increased IFN-γ/IL-4 ratio compared to untreated sensitized rats (P < 0.01 to P < 0.001). The plant significantly improved the pathological changes of sensitized rats (P < 0.05 to P < 0.01). The improvement effects of higher concentrations of the O. basilicum extract were significantly more than those of dexamethasone (P < 0.05 to P < 0.001). CONCLUSION: The improvement effects of O. basilicum on pathological changes, immunological and inflammatory markers in sensitized rats comparable or even more potent than dexamethasone suggests the therapeutic potential of the plant in asthma.


Assuntos
Anti-Inflamatórios/farmacologia , Asma , Pulmão , Ocimum basilicum , Extratos Vegetais/farmacologia , Animais , Asma/induzido quimicamente , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Ovalbumina/efeitos adversos , Folhas de Planta/química , Ratos , Ratos Wistar
6.
BMC Complement Altern Med ; 19(1): 316, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744482

RESUMO

BACKGROUND: Icariin (ICA) is the major active ingredient extracted from Chinese herbal medicine Epimedium, which has the effects of improving cardiovascular function, inducing tumor cell differentiation and increasing bone formation. It is still rarely reported that ICA can exert its therapeutic potential in asthma via anti-airway remodeling. The point of the study was to estimate the role of ICA in anti-. airway remodeling and its possible mechanism of action in a mouse ovalbumin. (OVA)-induced asthma model. METHODS: Hematoxylin and Eosin Staining were performed for measuring airway remodeling related indicators. ELISA, Western blot and Immunohistochemistr-. y (IHC) were used for analyzing the level of protein. RT-PCR was used for analyzing the level of mRNA. RESULTS: On days 1 and 8, mice were sensitized to OVA by intraperitoneal injection. From day 16 to day 43, previously sensitized mice were exposed to OVA once daily by nebulizer. Interventions were performed orally with ICA (ICA low, medium and high dose groups) or dexamethasone 1 h prior to each OVA exposure. ICA improves pulmonary function, attenuates pulmonary inflammation and airway remodeling in mice exposed to OVA. Histological and Western blot analysis of the lungs show that ICA suppressed transforming growth factor beta 1 and vascular endothelial growth factor expression. Increase in interleukin 13 and endothelin-1 in serum and bronchoalveolar lavage fluid in OVA-induced asthmatic mice are also decreased by ICA. ICA attenuates airway smooth muscle cell proliferation, as well as key factors in the MAPK/Erk pathway. CONCLUSIONS: The fact that ICA can alleviate OVA-induced asthma at least partly through inhibition of ASMC proliferation via MAPK/Erk pathway provides a solid theoretical basis for ICA as a replacement therapy for asthma. These data reveal the underlying reasons of the use of ICA-rich herbs in Traditional Chinese Medicine to achieve good results in treating asthma.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Epimedium/química , Flavonoides/administração & dosagem , Animais , Asma/genética , Asma/metabolismo , Asma/fisiopatologia , Endotelina-1/genética , Endotelina-1/metabolismo , Feminino , Humanos , Interleucina-13/genética , Interleucina-13/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Biomed Environ Sci ; 32(9): 659-672, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31635682

RESUMO

OBJECTIVE: Asthma and chronic obstructive pulmonary disease (COPD) feature different inflammatory and cellular profiles in the airways, indicating that the cellular metabolic pathways regulating these disorders are distinct. METHODS: We aimed to compare the serum metabolomic profiles among mild persistent asthmatic patients, individuals with stable COPD, and healthy subjects and to explore the potential metabolic biomarkers and pathways. The serum metabolomic profiles of 17 subjects with mild persistent asthma, 17 subjects with stable COPD, and 15 healthy subjects were determined by an untargeted metabolomic analysis utilizing liquid chromatography-mass spectrometry. A series of multivariate statistical analyses was subsequently used. RESULTS: Multivariate analysis indicated a distinct separation between the asthmatic patients and healthy controls in electrospray positive and negative ions modes, respectively. A total of 19 differential metabolites were identified. Similarly, a distinct separation between asthma and COPD subjects was detected in the two ions modes. A total of 16 differential metabolites were identified. Among the identified metabolites, the serum levels of hypoxanthine were markedly higher in asthmatic subjects compared with those in COPD or healthy subjects. CONCLUSION: Patients with asthma present a unique serum metabolome, which can distinguish them from individuals with COPD and healthy subjects. Purine metabolism alteration may be distinct and involved in the pathogenesis of asthma.


Assuntos
Asma/metabolismo , Metaboloma , Doença Pulmonar Obstrutiva Crônica/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Pequim , Estudos de Casos e Controles , Cromatografia Líquida , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Análise Multivariada , Soro/química , Espectrometria de Massas por Ionização por Electrospray
8.
Toxicol Lett ; 317: 59-67, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31577921

RESUMO

Toluene-diisocyanate (TDI) is mainly used in the manufacturing process of polyurethane foams, and is a potent inducer of occupational asthma characterized by airway inflammation and airway hyperreactivity. Thymic stromal lymphopoietin (TSLP) plays an important role in the development of asthma, and correlating with the differentiation of Th2 and Th17 cells. However, the role of TSLP in TDI-induced asthma remains unclear. In this study, 96 TDI-exposed workers as well as a mouse model of TDI-induced asthma were investigated. The air exposure assessment result of TDI in the workplace showed that workers were exposed to inhalation of a very high concentration of TDI, approximately 8 times the recommended level, leading to a decrease in pulmonary function and an increase in inflammatory cells, as well as TSLP and IgE levels in the supernatant of sputum obtained from exposed workers. In order to further investigate the role of TSLP in the pathogenesis of TDI-induced asthma, a mouse model of TDI-induced asthma was also employed. Histopathological analysis of mouse lung and bronchus showed an obvious infiltration of inflammatory cells around the bronchus. The levels of inflammatory cells, IFN-γ, IL-4 and IL-17 in bronchoalveolar lavage fluid (BALF), the expression levels of TSLP protein and ROR-γt and IL-17 mRNA in mouse lung tissues were also significantly increased. However, after treatment with TSLP neutralizing antibody (TSLP-Ab), the degree of pulmonary and bronchial inflammation in mice was significantly alleviated, and the levels of inflammatory cells, IFN-γ, IL-4 and IL-17 in BALF, and the expression levels of ROR-γt and IL-17 mRNA in lung tissue were significantly decreased. Our data shows that TSLP plays an important role in the pathogenesis of TDI-induced asthma, and that TSLP-Ab can effectively alleviate TDI-induced airway inflammation of asthma.


Assuntos
Anti-Inflamatórios/farmacologia , Anticorpos Neutralizantes/farmacologia , Asma/prevenção & controle , Citocinas/antagonistas & inibidores , Mediadores da Inflamação/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pneumonia/prevenção & controle , Tolueno 2,4-Di-Isocianato/efeitos adversos , Adulto , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Imunoglobulina E/imunologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Exposição por Inalação/efeitos adversos , Interleucina-17/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Allergol. immunopatol ; 47(5): 411-416, sept.-oct. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-186514

RESUMO

Background: Some studies have showed that seasonality is an important determinant of vitamin D (vitD) status. Objective: We evaluated whether there are differences in individual trends of serum vitD level over one year in asthmatic and rhinitic children. Materials and methods: Ninety-two asthmatic and rhinitic paediatric patients were followed up for one year and their serum vitD level was detected at three-month intervals, once in each season. Results: We observed higher vitD levels at the end of summer and lower at the end of winter. However, the individual seasonal trend was very variable and unpredictable. If it is true that in a given season the majority of patients followed one direction (increase or decrease of serum vitD levels), nevertheless a substantial percentage behaved differently and unpredictably. For example, at the end of spring, 70% of patients showed an increase in serum vitD levels, but 30% showed a decrease. In addition, five individuals had a value ≥ 50 ng/ml in September and showed serum vitD levels ≥ 30ng/ml throughout the year; 16 patients presented vitD value ≥ 40 ng/ml in September and always had ≥ 20 ng/ml in the other months. Conclusions: The wide and unpredictable variability of the individual trend of serum vitD levels should be taken into account before deciding whether or not a drug supplementation is appropriate


No disponible


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Asma/metabolismo , Rinite Alérgica/metabolismo , Estações do Ano , Vitamina D/sangue , Variação Biológica da População , Suplementos Nutricionais , Seguimentos
10.
Mol Immunol ; 114: 571-577, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31525576

RESUMO

Asthma is a chronic inflammatory disorder of airway affecting people from childhood to old age, and is characterized by airway epithelial dysfunction. Cucurbitacin E (CuE), a tetracyclic triterpene isolated from Cucurbitaceae plants, has been recently proved to exert anti-inflammation and immunology regulation activities. Nevertheless, its roles in asthma remains poorly defined. In the current study, CuE had little cytotoxicity on cell viability of human bronchial epithelial cell line BEAS-2B. Moreover, lipopolysaccharide (LPS) exposure inhibited cell viability and induced cell apoptosis, which was reversed following CuE pretreatment. Additionally, CuE administration suppressed LPS-induced inflammatory cytokine production, including TNF-α, IL-6, and IL-8. Simultaneously, supplementation with CuE decreased the transcripts and releases of mucin 5AC (MUC5AC) in LPS-treated BEAS-2B cells. Intriguingly, CuE inhibited LPS-evoked activation of the high-mobility group box1 (HMGB1)-TLR4-NF-κB signaling by reducing the expression of HMGB1, TLR4 and p-p65 NF-κB. Notably, restoring this pathway by elevating HMGB1 expression largely offset the protective function of CuE against LPS-triggered cell injury, inflammatory response and MUC5AC expression. Consequently, these findings highlight that CuE can ameliorate human bronchial epithelial cell insult and inflammation under LPS-simulated asthmatic conditions by blocking the HMGB1-TLR4-NF-κB signaling, thereby supporting its usefulness as a promising therapeutic agent against asthma.


Assuntos
Brônquios/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Inflamação/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Asma/tratamento farmacológico , Asma/metabolismo , Brônquios/metabolismo , Linhagem Celular , Células Cultivadas , Células Epiteliais/metabolismo , Proteína HMGB1/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Mucina-5AC/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Triterpenos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Toxicol Lett ; 316: 147-153, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520700

RESUMO

Asthma is a common chronic inflammatory disease which severely reduces the quality of life in patients. Studies have demonstrated that both PM2.5 and cold stress contribute to the development of asthma. However, the combined effects of these two risking factors are unknown. In this study, we investigated the combined effects of PM2.5 exposure and cold stress (PMCS) on asthma, as well as the underlying mechanisms by using a murine model. After different exposures, the immune-pathological changes and redox states in groups were evaluated. Besides, the balance of TH1/TH2 cells and the acetylation levels of H3K9 and H3K14 in IL-4 gene promotor were detected. Our results showed that, compared with other exposures, PMCS led to an increased inflammation and redox levels in mice. It also significantly increased the percentage of TH2 T cells, which was correlated with hyperacetylation of H3K9 and H3K14 in IL-4 gene promoter in CD4+T cells. Furthermore, a significantly increased P300 and decreased HDAC1 were detected in CD4 + T cells in PMCS group. In conclusion, our findings demonstrated that PMCS exacerbated asthma in mice by increasing H3K9 and H3K14 acetylation in IL-4 gene promoter in CD4 + T cells, and P300 and HDAC1 might contribute to their combined effects.


Assuntos
Asma/induzido quimicamente , Temperatura Baixa/efeitos adversos , Histonas/metabolismo , Interleucina-4/metabolismo , Pulmão/efeitos dos fármacos , Material Particulado/toxicidade , Regiões Promotoras Genéticas , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Acetilação , Animais , Asma/genética , Asma/imunologia , Asma/metabolismo , Modelos Animais de Doenças , Proteína p300 Associada a E1A/metabolismo , Histona Desacetilase 1/metabolismo , Interleucina-4/genética , Interleucina-4/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Ovalbumina , Tamanho da Partícula , Processamento de Proteína Pós-Traducional , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
12.
Iran J Allergy Asthma Immunol ; 18(4): 369-378, 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31522445

RESUMO

Interleukin (IL)-4-producing-CD8 (cytotoxic T cells, Tc) contribute to lung eosinophilia and airway hyper-responsiveness (AHR) to an antigen. CD4+CD25+ regulatory T cells (Tregs) attenuate airway inflammation and AHR. This study investigated whether Tregs decrease Tc2frequencies in ovalbumin (OVA)-induced asthma model of mice. Female C57BL/6 mice were sensitized with OVA intraperitoneally and challenged with OVA intranasally to induce allergic asthma model. Tregs were sorted by fluorescence activated cell sorting (FACS) and magnetic activated cell sorting (MACS) microbeads. OVA-sensitized mice were injected with Tregs or phosphate buffer saline (PBS) by tail vein ahead of the first challenge. Airway inflammation and airway hyper-responsiveness (AHR)were evaluated by histological analysis and invasive method, respectively. OVA-specific IgE and cytokine levels were detected by ELISA. Flow cytometry was used to detect the percentages of Tc1 and Tc2. Gata3 and T-bet mRNA was determined by quantitative PCR (qPCR). OVA-sensitized and challenged mice displayed typical asthma features, which included eosinophilic airway inflammation, higher levels of Th2 cytokines and AHR. Gata3 mRNA, Tc2 frequencies and OVA-specific IgE levels were significantly increased in OVA-sensitized and challenged mice. Compared to PBS treatment, Tregs decreased Tc2 frequencies, airway inflammation, Th2 cytokine levels and AHR in OVA-sensitized and challenged mice. IL-13 levels were negatively correlated with Tc1 frequencies and with IFNg levels in experimental mice. Our results demonstrated that Tregs could prevent airway inflammation and AHR by decreasing Tc2 frequencies and cytokine levels in OVA-induced asthma model of mice, supporting Tregmight be as a potent therapeutic target for alleviating airway inflammation and AHR.


Assuntos
Asma/imunologia , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/imunologia , Linfócitos T Reguladores/imunologia , Alérgenos/imunologia , Animais , Asma/metabolismo , Biomarcadores , Antígenos CD4/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-4/metabolismo , Contagem de Linfócitos , Camundongos , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
13.
Mol Med Rep ; 20(5): 4425-4432, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545493

RESUMO

Dendritic cells (DCs) have an important role in initiating and maintaining the immune inflammatory response in allergic asthma, and CC chemokine receptor 7 (CCR7) is directly involved in the pathogenesis of DC­ and T cell­mediated allergic asthma. The present study aimed to investigate the effects of CCR7 on DC­mediated immune tolerance in allergic asthma. In the present study, bone marrow­derived DCs were transfected with an adenovirus encoding the rat CCR7 gene or a short hairpin RNA targeting CCR7 (sh­CCR7). Rats injected with DCs overexpressing CCR7 or presenting CCR7 knockdown were examined. After the rats were injected with DCs via the tail vein, bronchoalveolar lavage fluid was collected to assess its cellular composition. The protein expression levels of CCR7 in DCs were determined using immunohistochemistry and western blot analysis. The protein expression levels of interferon­Î³ (IFN­Î³), interleukin­4 (IL­4), IL­10, IL­12, transforming growth factor­ß (TGF­ß) and immunoglobulin E (IgE) were determined by ELISA. Compared with the control group, the protein expression level of CCR7 was significantly higher in the CCR7 overexpression group and significantly lower in sh­CCR7 group. Similarly, the number of DCs was higher in the CCR7 overexpression group and lower in the sh­CCR7 group. The protein expression levels of IL­10 and TGF­ß were significantly lower in the CCR7 overexpression group and higher in the sh­CCR7 group. In addition, the expression levels of IL­4, IL­12, IFN­Î³ and IgE were higher in the CCR7 overexpression group and lower in the sh­CCR7 group. The present results suggested that the role of cytokines and IgE in immune inflammation and immune tolerance in allergic asthma may be associated with the expression level of CCR7 in DCs, suggesting that CCR7 may serve a role in DC­mediated immune tolerance in allergic asthma.


Assuntos
Asma/etiologia , Asma/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Tolerância Imunológica , Receptores CCR7/metabolismo , Animais , Asma/patologia , Biomarcadores , Citocinas/metabolismo , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Imunoglobulina E/imunologia , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Ratos , Receptores CCR7/genética
14.
J Zhejiang Univ Sci B ; 20(10): 828-837, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31489802

RESUMO

BACKGROUND: Asthma is a common cause of breathing difficulty in children and adults, and is characterized by chronic airway inflammation that is poorly controlled by available treatments. This results in severe disability and applies a huge burden to the public health system. Methane has been demonstrated to function as a therapeutic agent in many diseases. The aim of the present study was to explore the effect of methane-rich saline (MRS) on the pathophysiology of a mouse model of asthma and its underlying mechanism. METHODS: A murine model of ovalbumin (OVA)-induced allergic asthma was applied in this study. Mice were divided into three groups: a control group, an OVA group, and OVA-induced asthmatic mice treated with MRS as the third group. Lung resistance index (RI) and dynamic compliance (Cdyn) were measured to determine airway hyper-responsiveness (AHR). Haematoxylin and eosin (H&E) staining was performed and scored to show histopathological changes. Cell counts of bronchoalveolar lavage fluid (BALF) were recorded. Cytokines interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor α (TNF-α), and C-X-C motif chemokine ligand 15 (CXCL15) from BALF and serum were measured by enzyme-linked immunosorbent assay (ELISA). The oxidative stress indexes, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), myeloperoxidase (MPO), and 8-hydroxydeoxyguanosine (8-OHdG), were determined using commercial kits. Apoptosis was evaluated by western blot, quantitative real-time polymerase chain reaction (qRT-PCR), and biochemical examination. RESULTS: MRS administration reversed the OVA-induced AHR, attenuated the pathological inflammatory infiltration, and decreased the cytokines IL-4, IL-5, IL-13, TNF-α, and CXCL15 in serum and BALF. Moreover, following MRS administration, the oxidative stress was alleviated as indicated by decreased MDA, MPO, and 8-OHdG, and elevated SOD and GSH. In addition, MRS exhibited an anti-apoptotic effect in this model, protecting epithelial cells from damage. CONCLUSIONS: Methane improves pulmonary function and decreases infiltrative inflammatory cells in the allergic asthmatic mouse model. This may be associated with its anti-inflammatory, antioxidative, and anti-apoptotic properties.


Assuntos
Apoptose/efeitos dos fármacos , Asma/tratamento farmacológico , Inflamação/prevenção & controle , Metano/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Asma/imunologia , Asma/metabolismo , Hiper-Reatividade Brônquica/tratamento farmacológico , Citocinas/análise , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Solução Salina
15.
Int J Mol Sci ; 20(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470652

RESUMO

Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide. It is a chronic, relapsing and pruritic skin disorder which results from epidermal barrier abnormalities and immune dysregulation, both modulated by environmental factors. AD is strongly associated with asthma and allergic rhinitis in the so-called 'atopic march.' Xenobiotic receptors and their mates are ligand-activated transcription factors expressed in the skin where they control cellular detoxification pathways. Moreover, they regulate the expression of genes in pathways involved in AD in epithelial cells and immune cells. Activation or overexpression of xenobiotic receptors in the skin can be deleterious or beneficial, depending on context, ligand and activation duration. Moreover, their impact on skin might be amplified by crosstalk among xenobiotic receptors and their mates. Because they are activated by a broad range of endogenous molecules, drugs and pollutants owing to their promiscuous ligand affinity, they have recently crystalized the attention of researchers, including in dermatology and especially in the AD field. This review examines the putative roles of these receptors in AD by critically evaluating the conditions under which the proteins and their ligands have been studied. This information should provide new insights into AD pathogenesis and ways to develop new therapeutic interventions.


Assuntos
Dermatite Atópica/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Pele/metabolismo , Xenobióticos/metabolismo , Asma/genética , Asma/imunologia , Asma/metabolismo , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Eczema/genética , Eczema/imunologia , Eczema/metabolismo , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Regulação da Expressão Gênica/imunologia , Ligantes , Receptores Citoplasmáticos e Nucleares/genética , Rinite Alérgica/genética , Rinite Alérgica/imunologia , Rinite Alérgica/metabolismo , Pele/imunologia , Pele/patologia
16.
Biol Pharm Bull ; 42(10): 1746-1752, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31391381

RESUMO

Genetic variations in glucocorticoid-induced transcript 1 (GLCCI1) have been associated with the response to corticosteroid treatment. However, the associations of GLCCI1 polymorphisms or gene expression with the prognosis of asthma and pathophysiological factors related to steroid insensitivity remain unclear. We sought to investigate the associations of GLCCI1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and histone deacetylase 2 (HDAC2) mRNA expression levels and the GLCCI1 rs37973 polymorphism with asthma severity and future exacerbation in patients with asthma. Subjects included 25 patients with severe asthma and 127 patients with nonsevere asthma. mRNA expression levels in peripheral blood mononuclear cells were measured and evaluated as predictors of severe asthma using receiver operating characteristic (ROC) analysis. The hazard ratios of the mRNA expression levels for time to first exacerbation in the 1-year follow-up period were calculated. GLCCI1, Nrf2, and HDAC2 mRNA expression levels were significantly lower in patients with severe asthma than in patients with nonsevere asthma and could predict severe asthma with an area under the ROC curve of 0.68, 0.71, and 0.65, respectively. In contrast, no relationship was found between the GLCCI1 rs37973 polymorphism and severe asthma. The hazard ratios for asthma exacerbation in patients with low GLCCI1, Nrf2, and HDAC2 mRNA expression levels were 3.24 (95% confidence interval, 1.42-7.40), 3.13 (1.37-7.16), and 2.98 (1.22-7.25), respectively. Patients with severe asthma could be distinguished by lower GLCCI1, Nrf2, and HDAC2 mRNA levels in peripheral blood cells, and all of these gene signatures could predict future asthma exacerbations.


Assuntos
Corticosteroides/uso terapêutico , Asma/genética , Genótipo , Polimorfismo de Nucleotídeo Único , Receptores de Glucocorticoides/metabolismo , Índice de Gravidade de Doença , Administração por Inalação , Idoso , Área Sob a Curva , Asma/tratamento farmacológico , Asma/metabolismo , Feminino , Expressão Gênica , Glucocorticoides/metabolismo , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/metabolismo , Curva ROC , Receptores de Glucocorticoides/genética
17.
BMC Pulm Med ; 19(1): 144, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395050

RESUMO

BACKGROUND: Asthma is a heterogeneous disease and understanding this heterogeneity will enable the realisation of precision medicine. We sought to compare the sputum and serum inflammatory profiles in moderate-to-severe asthma during stable disease and exacerbation events. METHODS: We recruited 102 adults and 34 children with asthma. The adults were assessed at baseline, 3, 6, and 12-month follow-up visits. Thirty-seven subjects were assessed at onset of severe exacerbation. Forty sputum mediators and 43 serum mediators were measured. Receiver-operator characteristic (ROC) curves were constructed to identify mediators that distinguish between stable disease and exacerbation events. The strongest discriminating sputum mediators in the adults were validated in the children. RESULTS: The mediators that were significantly increased at exacerbations versus stable disease and by ≥1.5-fold were sputum IL-1ß, IL-6, IL-6R, IL-18, CXCL9, CXCL10, CCL5, TNFα, TNF-R1, TNF-R2, and CHTR and serum CXCL11. No mediators decreased ≥1.5-fold at exacerbation. The strongest discriminators of an exacerbation in adults (ROC area under the curve [AUC]) were sputum TNF-R2 0.69 (95% CI: 0.60 to 0.78) and IL-6R 0.68 (95% CI: 0.58 to 0.78). Sputum TNF-R2 and IL-6R were also discriminatory in children (ROC AUC 0.85 [95% CI: 0.71 to 0.99] and 0.80 [0.64 to 0.96] respectively). CONCLUSIONS: Severe asthma exacerbations are associated with increased pro-inflammatory and Type 1 (T1) immune mediators. In adults, sputum TNF-R2 and IL-6R were the strongest discriminators of an exacerbation, which were verified in children.


Assuntos
Asma/imunologia , Asma/metabolismo , Citocinas/metabolismo , Receptores de Interleucina-6/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Área Sob a Curva , Biomarcadores/metabolismo , Criança , Progressão da Doença , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Curva ROC , Índice de Gravidade de Doença , Escarro/imunologia , Escarro/metabolismo
18.
EBioMedicine ; 46: 399-410, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31399385

RESUMO

BACKGROUND: We recently demonstrated that maternal dietary supplementation with fish oil-derived n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) during pregnancy reduces the risk of asthma in the offspring but the mechanisms involved are unknown. METHODS: Here we investigated potential metabolic mechanisms using untargeted liquid chromatography-mass spectrometry-based metabolomics on 577 plasma samples collected at age 6 months in the offspring of mothers participating in the n-3 LCPUFA randomized controlled trial. First, associations between the n-3 LCPUFA supplementation groups and child metabolite levels were investigated using univariate regression models and data-driven partial least square discriminant analyses (PLS-DA). Second, we analyzed the association between the n-3 LCPUFA metabolomic profile and asthma development using Cox-regression. Third, we conducted mediation analyses to investigate whether the protective effect of n-3 LCPUFA on asthma was mediated via the metabolome. FINDINGS: The univariate analyses and the PLS-DA showed that maternal fish oil supplementation affected the child's metabolome, especially with lower levels of the n-6 LCPUFA pathway-related metabolites and saturated and monounsaturated long-chain fatty acids-containing compounds, lower levels of metabolites of the tryptophan pathway, and higher levels of metabolites in the tyrosine and glutamic acid pathway. This fish oil-related metabolic profile at age 6 months was significantly associated with a reduced risk of asthma by age 5 and the metabolic profile explained 24% of the observed asthma-protective effect in the mediation analysis. INTERPRETATION: Several of the observed pathways may be involved in the asthma-protective effect of maternal n-3 LCPUFA supplementation and act as mediators between the intervention and disease development. FUNDING: COPSAC is funded by private and public research funds all listed on www.copsac.com.


Assuntos
Asma/etiologia , Asma/metabolismo , Suplementos Nutricionais , Óleos de Peixe/administração & dosagem , Exposição Materna , Metabolômica , Efeitos Tardios da Exposição Pré-Natal , Asma/epidemiologia , Biomarcadores , Pré-Escolar , Cromatografia Líquida , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Espectrometria de Massas , Metaboloma , Gravidez , Medição de Risco , Fatores de Risco
19.
Clin Drug Investig ; 39(11): 1021-1030, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31377981

RESUMO

Successful treatment for respiratory diseases relies on effective delivery of medication to the lungs using an inhalation device. Different inhalers have distinct characteristics affecting drug administration and patient adherence, which can impact clinical outcomes. We report on the development of the Respimat® soft mist inhaler (SMI) and compare key attributes with metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). The Respimat SMI, a pocket-sized device generating a single-breath, inhalable aerosol, was designed to enhance drug delivery to the lungs, reduce the requirements for patient coordination and inspiratory effort, and improve the patients' experience and ease of use. The drug deposition profile with Respimat SMI is favorable compared with MDIs and DPIs, with higher drug deposition to the lung and peripheral airways. The slow velocity and long spray duration of the Respimat SMI aerosol also aid patient coordination. Clinical equivalence has been demonstrated for maintenance treatment of chronic obstructive pulmonary disease using once-daily tiotropium between Respimat SMI (5 µg) and HandiHaler DPI (18 µg). In comparative studies, patients preferred Respimat SMI to MDIs and DPIs; they reported that Respimat SMI was easy to use and felt the inhaled dose was delivered. The Respimat SMI, designed to generate a slow-moving and fine mist, is easy to use and effectively delivers drug treatment to the lungs. The patient-centered design of Respimat SMI improved patient satisfaction, and may help to promote long-term adherence and improve clinical outcomes with asthma and chronic obstructive pulmonary disease.


Assuntos
Combinação Albuterol e Ipratrópio/administração & dosagem , Broncodilatadores/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Desenho de Equipamento/métodos , Inaladores Dosimetrados , Administração por Inalação , Combinação Albuterol e Ipratrópio/metabolismo , Asma/tratamento farmacológico , Asma/metabolismo , Broncodilatadores/metabolismo , Sistemas de Liberação de Medicamentos/instrumentação , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo
20.
Life Sci ; 234: 116780, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430453

RESUMO

Bronchial asthma and obesity are common health problems. Obesity is already responsible for 300,000 deaths per year. AIMS: The aim of the present study was to assess whether apocynin, alpha lipoic acid and probiotic administration in combination with low-fat diet supplementation influences the levels of antioxidant enzymes in the pulmonary tissues of obese asthmatic mice. MAIN METHODS: The study was performed on male C57/BL6 mice divided into 10 groups: (I) control; (II) asthma; (III) obesity; (IV) asthma + obesity; (V) asthma + obesity + apocynin p.o. 15 mg/kg/day for 12 weeks; (VI) asthma + obesity + low-fat diet for 12 weeks; (VII) asthma + obesity + low-fat diet for 12 weeks with apocynin p.o. 15 mg/kg/day; (VIII) asthma + obesity + low-fat diet with probiotics for 12 weeks; (IX) asthma + obesity + low-fat diet for 12 weeks with lipoic acid p.o. 100 mg/kg/day for 12 weeks; (X) asthma + obesity + standard diet with probiotics for 12 weeks. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activity were examined. The administration of apocynin alone and apocynin in combination with a low-fat diet resulted in a significant increase in SOD values (respectively p < 0.001; p = 0.010). Application of probiotics resulted in a decrease in CAT activity (p = 0.037) and an increase in GPx activity (p < 0.001) compared to obese asthmatic mice. The administration of lipoic acid resulted in an increase in GR activity (p = 0.024 vs. control). KEY FINDINGS: Supplementation containing apocynin, lipoic acid and probiotics has a positive influence on the antioxidant capacity of the pulmonary tissues of obese asthmatic mice. SIGNIFICANCE: These results may contribute to the development of new therapeutic approaches.


Assuntos
Acetofenonas/uso terapêutico , Antioxidantes/uso terapêutico , Asma/tratamento farmacológico , Obesidade/tratamento farmacológico , Probióticos/uso terapêutico , Ácido Tióctico/uso terapêutico , Animais , Asma/complicações , Asma/metabolismo , Catalase/análise , Catalase/metabolismo , Glutationa Peroxidase/análise , Glutationa Peroxidase/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/análise , Superóxido Dismutase/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA