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1.
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
2.
Behav Sleep Med ; 18(1): 10-22, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30252506

RESUMO

Background/Objective: Insomnia is common among adults with asthma and is associated with worse asthma control. Cognitive-behavioral therapy for insomnia (CBT-I) is an effective treatment for insomnia with medical comorbidities, but it has not been tested in asthma. The purpose of this study was to assess the feasibility and acceptability of an Internet-based CBT-I intervention, called Sleep Healthy Using the Internet (SHUTi), among adults with asthma and comorbid insomnia, and to gather preliminary efficacy data on changes in insomnia severity, sleep quality, asthma control, and asthma-related quality of life. Methods: A single-group, pretest-posttest design was employed, where all participants completed the SHUTi program. Online questionnaires were completed pre- and postintervention. Individual telephone interviews were conducted after posttreatment data collection to obtain participants' experiences with SHUTi and suggestions for improvement. Results: The sample (N = 23) comprised men and women aged 18-75 years with moderate to severe, not well-controlled asthma, and comorbid insomnia. Nineteen (83%) completed postintervention assessments. Improvements on the Insomnia Severity Index, Pittsburgh Sleep Quality Index, Asthma Control Test, and Asthma Quality of Life Questionnair-Marks were observed at postintervention. Data from the telephone interviews suggest that most participants had a positive experience with SHUTi. Participants suggested incorporating asthma-specific content into future versions of the intervention. Conclusions: Internet-based CBT-I is a potential treatment option for adults with asthma and comorbid insomnia.


Assuntos
Asma/complicações , Asma/terapia , Terapia Cognitivo-Comportamental/métodos , Qualidade de Vida/psicologia , Distúrbios do Início e da Manutenção do Sono/terapia , Adolescente , Adulto , Idoso , Asma/patologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
3.
Ecotoxicol Environ Saf ; 188: 109867, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31689658

RESUMO

BACKGROUND: Accumulating epidemiological studies showed that prenatal and early life exposure to ambient air pollution was important contributor to the development of childhood asthma. However, the effects and mechanisms of prenatal exposure to ozone (O3), a type of ambient air pollution, on the progression of asthma in offspring remain unclear. OBJECTIVE: This study aimed to determine the effects and mechanism of asthma in offspring after prenatal O3 exposure. METHODS: Pregnant BALB/c mice were exposed to O3 or air on gestational days (GDs) 13-18. Their offspring were sensitized and challenged to ovalbumin (OVA) to establish asthma model, and the asthma features were evaluated. The splenic natural killer (NK) cells in the offspring were measured to explore the mechanism on the effects of asthma in the offspring. The responses of the pregnant mice and dams after O3 exposure were evaluated. RESULTS: Airway inflammation, mucus secretion, OVA-specific immunoglobulin (Ig) E, T helper (Th) 2-skewed response, the frequency of CD3ε-CD49b+ splenic NK cells, the expression of tumor necrosis factor (TNF)-α, and IL (interleukin)-17 were significantly exacerbated in the OVA-induced asthma offspring after prenatal O3 exposure. In addition, airway inflammation, a lower number of CD3ε-CD49b+ splenic NK cells, and systemic oxidative stress were caused at the end of pregnancy after O3 exposure, which did not recover at the end of lactation for the first two responses. CONCLUSIONS: Prenatal O3 exposure increased the severity of OVA-induced asthma in the offspring, which might be directly induced by CD3ε-CD49b+ splenic NK cells in the offspring and indirectly related to the damaged maternal immune system.


Assuntos
Poluentes Atmosféricos/toxicidade , Asma/induzido quimicamente , Asma/patologia , Ovalbumina , Ozônio/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Asma/imunologia , Feminino , Células Matadoras Naturais/imunologia , Masculino , Camundongos Endogâmicos BALB C , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Equilíbrio Th1-Th2
4.
Life Sci ; 241: 117172, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31843529

RESUMO

AIMS: Allergic airway inflammation is one of the major pathological events involved in asthma, and dysregulation of regulatory T cells (Treg) plays a crucial role in the development of allergic airway inflammation. Here, we attempted to investigate the regulatory effects of B cell-activating factor (BAFF) on Tregs in allergic airway inflammation. MAIN METHODS: BAFF expression was analyzed by ELISA, quantitative reverse transcription PCR (RT-PCR) and Western blot assays. The levels of IL-4, TGF-ß, IL-2, and IL-10 were tested using ELISA kits. Flow cytometry was conducted to analyze the populations of CTLA4+ Foxp3+ Tregs. KEY FINDINGS: BAFF was found to be aberrantly expressed in sputum and lungs in patients with asthma as well as OVA sensitized mice. BAFF silencing by lentiviral BAFF shRNA reduced the number of eosinophils and levels of IL-4 in the BAL fluid, as well as the Fizz1 expression in the lungs of OVA mice. Additionally, the population of CTLA4+ Foxp3+ Tregs were significantly decreased in OVA mice and had a negative correlation to BAFF levels in asthmatic patients and OVA mice. BAFF silencing in vivo increased levels of CTLA4+ Foxp3+ Tregs and the secretion of IL-10, and improved the regulatory phenotype and suppressor function of Tregs in vitro. Furthermore, BAFF can affect Tregs generation by regulating the production of the pro-Treg cytokines IL-2 and TGF-ß. SIGNIFICANCE: BAFF has an inhibitory effect on the generation and suppressor function of Tregs by affecting pro-Tregs cytokines, thereby contributing to the development of allergic airway inflammation.


Assuntos
Asma/prevenção & controle , Fator Ativador de Células B/antagonistas & inibidores , Citocinas/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , Inflamação/prevenção & controle , Linfócitos T Reguladores/imunologia , Adulto , Animais , Asma/etiologia , Asma/imunologia , Asma/patologia , Fator Ativador de Células B/genética , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/etiologia , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Ovalbumina/toxicidade
5.
Life Sci ; 242: 117222, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881223

RESUMO

BACKGROUND: Asthma is a complex inflammatory disease which affects multiple individuals worldwide especially pediatric ages. AIMS: This study aimed to assess the possible protective effect of carvacrol, as natural antioxidant anti-inflammatory drug, against bronchial asthma induced experimentally in rats. MAIN METHODS: Rats were randomly allocated into 5 groups; a normal control group, control drug group received only carvacrol, an asthma control group, a standard treatment group receiving dexamethasone (DEXA) and carvacrol treatment group. Bronchial asthma was induced by sensitization with i.p dose followed by challenge with intranasal dose of ovalbumin (OVA). 24 h after the last challenge, absolute eosinophil count (AEC) were determined in bronchoalveolar lavage fluids (BALF). Immunoglobulin E (IgE) was determined in serum. Inflammatory biomarkers like Interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin 13 (IL-13), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were also measured in BALF. Nitrosative stress biomarker namely inducible nitric oxide synthase (iNOS) was determined in BALF as well as oxidative stress biomarkers namely superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) were determined in lung tissue. Additionally, histopathological study, immunohistochemical study of UCN and western blot analysis of SP-D were performed. KEY FINDINGS: Carvacrol administration significantly reduced the values of AEC, IgE, IL-4, IL-5, IL-13, TNF-α, IFN-γ, iNOS and MDA, while it significantly increased the values of SOD and GSH as compared to the asthmatic group. Histopathological, immunohistochemical and western blot study reinforced the biochemical results. SIGNIFICANCE: Carvacrol may be a promising protective agent against bronchial asthma induced experimentally in rats.


Assuntos
Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Fatores Imunológicos/farmacologia , Animais , Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/induzido quimicamente , Asma/patologia , Western Blotting , Modelos Animais de Doenças , Fatores Imunológicos/uso terapêutico , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Ovalbumina/farmacologia , Proteína D Associada a Surfactante Pulmonar/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
6.
Pol J Vet Sci ; 22(4): 653-659, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31867937

RESUMO

Asthma is one of the most common non-infectious respiratory diseases in horses. Ultrasound examination is a widely available non-invasive additional diagnostic tool. To date, there are no studies focusing on ultrasonographic findings in horses with asthma. The aim of this study was to analyse the prevalence and severity of ultrasound lesions in lung tissue in horses with asthma. Lung ultrasonography was carried out on six healthy horses (controls) and 12 horses with asthma (six with mild and six with severe asthma). The sonographic changes in three lung sections were assessed using a scoring system. The most common changes present in all the animals were comet- tail artefacts. More advanced lesions were present in horses with severe asthma. Statistically significant differences in the overall average intensity of the ultrasound changes were seen between the controls and the study group and between the horses with mild and severe asthma. The lesions were usually located in the caudal lung regions, but they were also present in other areas as the disease progressed. Ultrasonography is a useful additional diagnostic tool enabling an assessment of the stage of the asthma progression. It is a very sensitive technique that visualizes minor lesions in the lung tissue even in clinically healthy animals. Due to its low specificity, it cannot replace endoscopy and the bronchoalveolar lavage in horses with asthma.


Assuntos
Asma/veterinária , Doenças dos Cavalos/diagnóstico por imagem , Ultrassonografia/veterinária , Animais , Asma/diagnóstico por imagem , Asma/patologia , Feminino , Doenças dos Cavalos/patologia , Cavalos , Masculino
7.
Life Sci ; 239: 117017, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678284

RESUMO

Saxagliptin (Saxa), a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, is widely used for the treatment of type 2 diabetes mellitus. It has been documented to have immunomodulatory and anti-inflammatory actions. Our objective was to delineate the protective effect and the underlying mechanism of Saxa-in comparison with Dexamethasone (Dexa) - in airway inflammation induced by ovalbumin (OVA) in mice. METHODS: Mice were OVA-sensitized and challenged for the induction of acute asthma. Mice were orally administrated Saxa or Dexa. Total and differential cell counts, lactate dehydrogenase (LDH) and total protein concentrations were assessed in bronchoalveolar lavage fluid (BALF). The toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-kB), reduced glutathione (GSH), and total nitrate/nitrite products (NOx) levels as well as myeloperoxidase (MPO) activity in lung tissues were measured. Histopathological examination of the lung specimens was carried out using the hematoxylin and eosin (H & E) staining. RESULTS: Histopathological examination revealed that both Saxa and Dexa ameliorated OVA-induced inflammatory changes and significantly reduced total and differential leukocyte counts, LDH and total protein level in BALF upon comparison with OVA group. In addition, both treatments significantly mitigated OVA-induced oxidative stress as evidenced by diminished lung NOx level and MPO activity and elevated GSH level. The elevation of TLR4 and NF-kB levels in lung tissue were ameliorated by Saxa and Dexa administration. CONCLUSION: Saxa had marked antiasthmatic effect in OVA-induced allergic asthma through modulation of TLR4 and NF-κB signaling. Also, Saxa may represent a promising therapeutic agent for acute allergic asthma.


Assuntos
Adamantano/análogos & derivados , Asma/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , NF-kappa B/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Doença Aguda , Adamantano/uso terapêutico , Animais , Asma/induzido quimicamente , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Dexametasona/uso terapêutico , L-Lactato Desidrogenase/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Ovalbumina , Peroxidase/metabolismo
8.
Immunity ; 51(6): 1102-1118.e7, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31757673

RESUMO

Young children are more susceptible to developing allergic asthma than adults. As neural innervation of the peripheral tissue continues to develop after birth, neurons may modulate tissue inflammation in an age-related manner. Here we showed that sympathetic nerves underwent a dopaminergic-to-adrenergic transition during post-natal development of the lung in mice and humans. Dopamine signaled through a specific dopamine receptor (DRD4) to promote T helper 2 (Th2) cell differentiation. The dopamine-DRD4 pathway acted synergistically with the cytokine IL-4 by upregulating IL-2-STAT5 signaling and reducing inhibitory histone trimethylation at Th2 gene loci. In murine models of allergen exposure, the dopamine-DRD4 pathway augmented Th2 inflammation in the lungs of young mice. However, this pathway operated marginally after sympathetic nerves became adrenergic in the adult lung. Taken together, the communication between dopaminergic nerves and CD4+ T cells provides an age-related mechanism underlying the susceptibility to allergic inflammation in the early lung.


Assuntos
Neurônios Adrenérgicos/citologia , Asma/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Pulmão/patologia , Células Th2/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Animais , Asma/imunologia , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Interleucina-2/metabolismo , Interleucina-4/imunologia , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neurogênese/fisiologia , Receptores de Dopamina D4/metabolismo , Fator de Transcrição STAT5/metabolismo , Sistema Nervoso Simpático/citologia
9.
Life Sci ; 236: 116790, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626791

RESUMO

AIMS: Although the bulk of research into the biology of serotonin 5-HT2A receptors has focused on its role in the CNS, selective activation of these receptors in peripheral tissues can produce profound anti-inflammatory effects. We previously demonstrated that the small molecule 5-HT2 receptor agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] inhibits TNF-α-mediated proinflammatory signaling cascades and inflammation via 5-HT2A receptor activation and prevents the development of, and inflammation associated with, acute allergic asthma in a mouse ovalbumin (OVA) model. Here, we investigated the ability of (R)-DOI to reverse inflammation and symptoms associated with established asthma in a newly developed model of chronic asthma. METHODS: An 18-week ovalbumin challenge period was performed to generate persistent, chronic asthma in BALB/c mice. Four once daily intranasal treatments of (R)-DOI were administered one week after allergen cessation, with respiratory parameters being measured by whole-body plethysmography (WBP). Cytokine and chemokine levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) in homogenized lung tissue, bronchoalveolar (BALF) fluid was analyzed for chemokine modulation by multiplex assays, and Periodic Acid-Schiff and Masson's Trichrome staining was performed to determine goblet cell infiltration and overall changes to lung morphology. KEY FINDINGS: 5-HT2 activation via (R)-DOI attenuates elevated airway hyperresponsiveness to methacholine, reduces pulmonary inflammation and mucus production, and reduces airway structural remodeling and collagen deposition by nearly 70%. SIGNIFICANCE: Overall, these data provide support for the therapeutic potential of (R)-DOI and 5-HT2 receptor activation for the treatment of asthma, and identifies (R)-DOI as a novel therapeutic compound against pulmonary fibrosis.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Anfetaminas/farmacologia , Asma/tratamento farmacológico , Pneumonia/prevenção & controle , Receptores 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Remodelação das Vias Aéreas/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Doença Crônica , Feminino , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Hipersensibilidade/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Pneumonia/imunologia , Pneumonia/patologia
10.
Life Sci ; 238: 116953, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626793

RESUMO

AIMS: This study focused on investigating whether NS8593 reverses airway smooth muscle (ASM) contraction and the underlying mechanism. MAIN METHODS: ASM contraction in mouse tracheal rings and lung slices was measured. Currents mediated by voltage dependent Ca2+ channels (VDCCs) and ACH-activated channels were measured using the whole-cell patch-clamp technique in single tracheal smooth muscle cells (TSMCs). Intracellular Ca2+ level and cell length were measured using an LSM 700 laser confocal microscope and a Zen 2010 software. Mouse respiratory system resistance (Rrs) was assessed using a FlexiVent FX system. KEY FINDINGS: High K+ (80 mM K+) and ACH induced ASM contraction in mouse tracheal rings and lung slices, which was partially relaxed by nifedipine (blocker of L-type VDCCs, LVDCCs), YM-58483 (blocker of store-operated Ca2+ entry (SOCE), transient receptor potential C3 (TRPC3) and TRPC5 channels), respectively. However, the contraction was completely reversed by NS8593, whereas, slightly relaxed by formoterol. ACH activated inward currents, which displayed linear and reversed around 0 mV, indicating the currents were mediated by non-selective cation channels (NSCCs). Moreover, these currents were blocked by YM-58483. In addition, such currents were abolished by NS8593, implicating that NS8593 inhibits the same channels. Besides, NS8593 inhibited increases of intracellular Ca2+ and the associated cell shortening. Finally, NS8593 inhibited ACH-induced increases of mouse respirator system resistance (Rrs). SIGNIFICANCE: Our results indicate that NS8593 inhibits LVDCCs and NSCCs, resulting in decreases of intracellular Ca2+ and then leading to ASM relaxation. These data suggest that NS8593 might be a new bronchodilator.


Assuntos
1-Naftilamina/análogos & derivados , Asma/tratamento farmacológico , Canais de Cálcio Tipo L/química , Cálcio/metabolismo , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , 1-Naftilamina/farmacologia , Animais , Antialérgicos/farmacologia , Asma/induzido quimicamente , Asma/patologia , Canais de Cálcio Tipo L/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso/metabolismo , Músculo Liso/patologia , Ovalbumina/toxicidade
11.
Elife ; 82019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31603425

RESUMO

IL-10-producing Tr1 cells promote tolerance but their contributions to tolerogenic memory are unclear. Using 10BiT mice that carry a Foxp3-eGFP reporter and stably express CD90.1 following IL-10 production, we characterized the spatiotemporal dynamics of Tr1 cells in a house dust mite model of allergic airway inflammation. CD90.1+Foxp3-IL-10+ Tr1 cells arise from memory cells and rejoin the tissue-resident memory T-cell pool after cessation of IL-10 production. Persistent antigenic stimulation is necessary to sustain IL-10 production and Irf1 and Batf expression distinguishes CD90.1+Foxp3-IL-10+ Tr1 cells from CD90.1+Foxp3-IL-10- 'former' Tr1. Depletion of Tr1-like cells after primary sensitization exacerbates allergic airway inflammation. However, neither transfer nor depletion of former Tr1 cells influences either Tr1 numbers or the inflammatory response during subsequent allergen memory re-challenge weeks later. Together these data suggest that naturally-arising Tr1 cells do not necessarily give rise to more Tr1 upon allergen re-challenge or contribute to tolerogenic memory. This phenotypic instability may limit efforts to re-establish tolerance by expanding Tr1 in vivo.


Assuntos
Asma/patologia , Tolerância Imunológica , Memória Imunológica , Linfócitos T Reguladores/imunologia , Alérgenos/imunologia , Animais , Modelos Animais de Doenças , Camundongos , Pyroglyphidae/imunologia
12.
Adv Gerontol ; 32(3): 445-450, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31512433

RESUMO

This study looks at the assessment parameters and their informing value for the phenotypic stratification of elderly patients with chronic obstructive pulmonary disease (COPD). Using cluster analysis all patients were divided into subgroups (phenotypes). For women, phenotypic cluster K1: patients with a normal body weight, with disease duration more than 5 years; with a frequency of exacerbations less than 2 times a year. Phenotypic cluster K2: elderly patients, but younger than in K1, overweight, with a disease duration less than 5 years, with a frequency of exacerbations less than 2 times a year, but lesser than in K1, with a history of asthma in 66% of cases. 3 phenotypes were identified for men: K1 - overweight, disease duration of about 6 years, with a frequency of exacerbations more than 2 times a year; K2 - patients with body weight deficiency, disease duration more than 7 years, frequency of exacerbations less than 2 times a year; K3 - overweight, disease duration more than 8 years, with a frequency of exacerbations less than 2 times a year. COPD main signs of phenotyping in elderly patients were determined: gender, disease duration, body mass index, frequency of exacerbations. This allowed to identify 2 phenotypes in women: COPD with in frequent exacerbations and phenotype with presence of syndrome BA-COPD; in men - 3 phenotypes: bronchitis's, emphysematous and COPD with a slowly progressive course.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Idoso , Asma/patologia , Progressão da Doença , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Fenótipo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/patologia
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.
Phytomedicine ; 64: 153076, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473579

RESUMO

BACKGROUND: Long-term exposure to aeroallergens such as house dust mite (HDM) could result in airway inflammation and airway remodeling, characteristic features of allergic asthma. Huangqi-Fangfeng (HF), an important "couplet medicines" of Yu-Ping-Feng-San (YPFS), mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. PURPOSE: To evaluate the effects of HF on airway remodeling of allergic asthma in a murine model and to investigate the underlying mechanisms in vivo and in vitro. METHODS: The main components of HF were analyzed by HPLC. The HDM-induced asthma mice model was established to study the effects of HF on airway inflammation and airway remodeling in vivo. Enhanced pause (Penh) index value was used as an indicator of airway hyper-reactivity. Bronchoalveolar lavage fluid (BALF) was processed for differential cell counting and determination of cytokines production. The lungs were fixed in 4% paraformaldehyde for histological examination after staining with H&E, trichrome and IHC. Production of interleukin (IL)-4, IL-5, IL-13, and transforming growth factor beta-1 (TGF-ß1) in BALF and lung tissues, IgE in serum were measured by ELISAs. Expression of epithelial markers and mesenchymal markers were detected by immunohistochemistry and western blots. The effects of HF and its components on epithelial-mesenchymal transition (EMT) were detected in human bronchial epithelial cells (16HBE) treated with TGF-ß1 and HDM. RESULTS: The main components of Huangqi-Fangfeng detected by HPLC were Calycosin, Formononetin and Cimifugin. In HDM-induced allergic asthma mice model, respiratory exposure to HDM lead to airway hyperresponsiveness and thickening of the smooth muscle layer in the airway. TGF-ß1 levels increased in mice airways while epithelial cells lost expression of E-cadherin and gained expression of the mesenchymal proteins N-cadherin, α-SMA and collagen І. These changes were relieved by treatment with HF. Furthermore, restored epithelial markers expression treated with individual components were also detectable in 16HBE cells. CONCLUSION: These results demonstrated that Huangqi-Fangfeng protected against allergic airway remodeling through inhibiting epithelial-mesenchymal transition process in mice via regulating epithelial derived TGF-ß1.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Antiasmáticos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Animais , Antiasmáticos/química , Apiaceae/química , Asma/etiologia , Asma/patologia , Brônquios/citologia , Líquido da Lavagem Broncoalveolar , Cromonas/análise , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Células Epiteliais/efeitos dos fármacos , Humanos , Isoflavonas/análise , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Fator de Crescimento Transformador beta1/metabolismo
15.
Int J Mol Sci ; 20(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430856

RESUMO

Asthma is a common chronic airway disease worldwide. Due to its clinical and genetic heterogeneity, the cellular and molecular processes in asthma are highly complex and relatively unknown. To discover novel biomarkers and the molecular mechanisms underlying asthma, several studies have been conducted by focusing on gene expression patterns in epithelium through microarray analysis. However, few robust specific biomarkers were identified and some inconsistent results were observed. Therefore, it is imperative to conduct a robust analysis to solve these problems. Herein, an integrated gene expression analysis of ten independent, publicly available microarray data of bronchial epithelial cells from 348 asthmatic patients and 208 healthy controls was performed. As a result, 78 up- and 75 down-regulated genes were identified in bronchial epithelium of asthmatics. Comprehensive functional enrichment and pathway analysis revealed that response to chemical stimulus, extracellular region, pathways in cancer, and arachidonic acid metabolism were the four most significantly enriched terms. In the protein-protein interaction network, three main communities associated with cytoskeleton, response to lipid, and regulation of response to stimulus were established, and the most highly ranked 6 hub genes (up-regulated CD44, KRT6A, CEACAM5, SERPINB2, and down-regulated LTF and MUC5B) were identified and should be considered as new biomarkers. Pathway cross-talk analysis highlights that signaling pathways mediated by IL-4/13 and transcription factor HIF-1α and FOXA1 play crucial roles in the pathogenesis of asthma. Interestingly, three chemicals, polyphenol catechin, antibiotic lomefloxacin, and natural alkaloid boldine, were predicted and may be potential drugs for asthma treatment. Taken together, our findings shed new light on the common molecular pathogenesis mechanisms of asthma and provide theoretical support for further clinical therapeutic studies.


Assuntos
Asma/diagnóstico , Biologia de Sistemas/métodos , Asma/genética , Asma/metabolismo , Asma/patologia , Biomarcadores/análise , Biomarcadores/metabolismo , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Mapas de Interação de Proteínas , Transcriptoma
16.
Mol Med Rep ; 20(4): 3215-3223, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432168

RESUMO

In 2013, WHO estimated that approximately 235 million people suffered from asthma worldwide. Asthma is a hyper responsive disorder, which is related to an imbalance between the T­helper type 1 and 2 cells (henceforth, Th1 and Th2, respectively). Allium hookeri is a plant that is widely used for culinary purposes and also in traditional Asian medicine. The present study was conducted to elucidate the anti­asthmatic effects and mechanism of action of A. hookeri root extracts (AHRE) in an ovalbumin (OVA)­induced asthma mouse model. The mice were divided into five groups, namely, the control, the OVA­treated group, the dexamethasone­treated group, the 30 mg/kg AHRE­treated group, and the 300 mg/kg AHRE­treated group. The total WBC count and the differential cell count in the bronchoalveolar fluid, the level of serum IgE, the histopathological changes in the lung, and changes in the cell surface molecules, the asthma­related cytokine levels, and Th cell transcription factors were evaluated. AHRE significantly ameliorated asthmatic changes, such as the total WBC count, eosinophil count, and the level of IgE; in addition, it reduced mucus hypersecretion, epithelial hyperplasia, and eosinophil infiltration in the lungs. AHRE significantly inhibited the expression of CD68+ cells and MHC class II+ molecules, Th1 cell transcription factor (T­bet) activation, Th2 cell transcription factor (GATA­3) activation, and TNF­α in the lung tissue. Furthermore, it suppressed cell surface molecules, such as CD4+and CD8+; Th1­related cytokines, such as IFN­Î³ and IL­12p40; Th2­related cytokines, such as IL­4 and IL­5; and Th17­related cytokines, such as IL­6 and TNF­α, in a dose­dependent manner. Thus, AHRE may be considered a promising anti­asthmatic drug.


Assuntos
Allium/química , Asma , Imunomodulação/efeitos dos fármacos , Ovalbumina/toxicidade , Extratos Vegetais , Raízes de Plantas/química , Células Th1 , Células Th2 , Animais , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/imunologia , Asma/patologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células Th1/imunologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologia
17.
Zhonghua Nei Ke Za Zhi ; 58(9): 680-684, 2019 Sep 01.
Artigo em Chinês | MEDLINE | ID: mdl-31461820

RESUMO

Objective: To analyze the clinical features and airway inflammatory phenotypes in patients with severe asthma. Methods: Patients with severe asthma were recruited in this cross-sectional study in our center. History of asthma, blood and sputum samples, and respiratory function were tested and recorded. The phenotypes of inflammation in airway were evaluated. Results: A total of 35 asthmatic patients with the mean age 41.4 years were involved in this study from January 2013 to December 2013. The disease duration were (14.3±13.6) years with mostly male in China-Japan Friendship Hospital. Thirteen patients reported the history of smoking. Twenty-one patients had the complications such as allergic rhinitis, followed by chronic rhinosinusitis of 11 cases, nasal polyp of 7 cases, gastroesophageal reflux disease of 5. The forced expiratory volume in one second/predicted value ratio (FEV(1)%pred) in 29 patients was lower than 80%.Twenty-one participants did not react in bronchial reversibility test. Sixteen patients were administrated with oral cortical steroids (OCS). The average annual cost per patient was 22 thousand RMB. Sixteenrefractory asthmatics were diagnosed as eosinophilic asthma. Conclusions: The clinical features associated with severe asthma include male gender, smoking, persistent airway limitation. Systemic use of corticosteroids is common and treatment costs are high. The eosinophilic asthma is the main inflammatory phenotype in patients with severe asthma.


Assuntos
Resistência das Vias Respiratórias , Asma , Eosinófilos , Inflamação , Adolescente , Adulto , Asma/patologia , Asma/fisiopatologia , China , Estudos Transversais , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Escarro , Adulto Jovem
18.
Int J Mol Sci ; 20(17)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466312

RESUMO

The heterogeneity of asthma involves complex pathogenesis leading to confusion regarding the choice of therapeutic strategy. In the clinic, asthma is commonly classified as having either eosinophilic asthma (EA) or non-eosinophilic asthma (NEA) phenotypes. Microbiota colonizing in airways has been demonstrated to induce distinct phenotypes of asthma and the resistance to steroids. Rhodiola wallichiana var. cholaensis (RWC) has the potential to alleviate asthmatic inflammation according to recent studies, but its pharmacological mechanisms remain unclarified. In our study, murine asthmatic phenotypes were established and treated with RWC and/or dexamethasone (DEX). Combined treatment with RWC and DEX could improve spirometry and airway hyperresponsiveness (AHR) in asthmatic phenotypes, alleviate steroid resistance in NEA, and reduce the inflammatory infiltration of the both phenotypes. The combined treatment increased Th1, regulated the imbalance of Th2/Th1, and decreased the related cytokines in EA. As for NEA, the combined treatment reduced Th17 and promoted the accumulation of regulatory T cells (Tregs) in lung. A microbiome study based on 16S rDNA sequencing technique revealed the significantly changed structure of the lower airway microbiota after combined treatment in NEA, with 4 distinct genera and 2 species identified. OPLS-DA models of metabolomics analysis based on UPLC-Q/TOF-MS technique identified 34 differentiated metabolites and 8 perturbed metabolic pathways. A joint multiomics study predicted that the colonized microbiota in airways might be associated with susceptibility of asthma and steroid resistance, which involved systematic and pulmonary metabolic perturbation. In summary, the pharmacological network of RWC included the complicated interaction mechanisms of immune regulation, microbiota change, and metabolic perturbation.


Assuntos
Asma/tratamento farmacológico , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Extratos Vegetais/uso terapêutico , Rhodiola/química , Animais , Asma/patologia , Citocinas/genética , Citocinas/metabolismo , Dexametasona/administração & dosagem , Dexametasona/farmacologia , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Subpopulações de Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Microbiota/efeitos dos fármacos , Fenótipo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia
19.
Medicine (Baltimore) ; 98(33): e16637, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415357

RESUMO

BACKGROUND: The goal of the current meta-analysis and systematic review was to explore the efficacy of tiotropium in treating patients with moderate-to-severe asthma on the basis of qualified randomized controlled trials (RCTs). METHODS: The following online electronic databases, such as Cochrane, PubMed, and Embase database were screened to identify qualified studies updated to January 2019 through the use of index words. Several literatures that were relevant to the present analysis were also included. To further analyze the main outcomes, we utilized the odds rations (OR), and mean difference (MD) along with its 95% confidence interval (95% CI). RESULTS: A total of 14 RCTs with 4998 patients in the tiotropium group and 5074 patients in the control group were included in the present study. On the basis of the pooled results, tiotropium was significantly associated with improved morning PEF (SMD: 3.29, 95%CI: 2.03-4.55), evening PEF (SMD: 3.36, 95%CI: 2.24-4.48), peak FEV (SMD: 2.67, 95%CI: 1.47-3.88), and trough FEV (SMD: 1.90, 95%CI: 0.87-2.92) vs the control group. Nevertheless, no significant difference was observed in peak FVC (SMD: 0.77, 95%CI: -0.21-1.76), trough FVC (SMD: 0.67, 95%CI: -0.18-1.53), AE (RR: 0.98, 95%CI: 0.94-1.02) and serious AE (RR: 1.08, 95%CI: 0.77-1.52) between the 2 groups. CONCLUSIONS: In this review, we summarized the significant effect of tiotropium for the treatment of moderate-to-severe asthma, mainly in increasing morning PEF, evening PEF, peak FEV and trough FEV based on high-quality RCTs. Nevertheless, no significant difference in peak FVC, trough FVC, AE and serious AE was found between the 2 groups. A close comparison of the 2 groups revealed that more high-quality larger-sample RCTs are needed to gather more strong evidence on the therapeutic efficacy and safety of tiotropium for clinical practice.


Assuntos
Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Brometo de Tiotrópio/uso terapêutico , Adulto , Asma/patologia , Criança , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Pico do Fluxo Expiratório/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Capacidade Vital/efeitos dos fármacos
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