Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.905
Filtrar
2.
Nat Commun ; 10(1): 4246, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534137

RESUMO

Allergic asthma is an inflammatory disorder of the airway without satisfactory traditional therapies capable of controlling the underlying pathology. New approaches that can overcome the detrimental effects of immune dysregulation are thus desirable. Here we adoptively transfer ovalbumin (OVA) peptide-primed CD4-CD8- double negative T (DNT) cells intravenously into a mouse model of OVA-induced allergic asthma to find that OVA-induced airway hyperresponsiveness, lung inflammation, mucus production and OVA-specific IgG/IgE production are significantly suppressed. The immunosuppressive function of the OVA-specific DNT cells is dependent on the inhibition of CD11b+ dendritic cell function, T follicular helper cell proliferation, and IL-21 production. Mechanistically, Lag3 contributes to MHC-II antigen recognition and trogocytosis, thereby modulating the antigen-specific immune regulation by DNT cells. The effectiveness of ex vivo-generated allergen-specific DNT cells in alleviating airway inflammation thus supports the potential utilization of DNT cell-based therapy for the treatment of allergic asthma.


Assuntos
Antígenos CD/metabolismo , Asma/fisiopatologia , Asma/terapia , Hiper-Reatividade Brônquica/imunologia , Linfócitos T Reguladores/transplante , Células Th2/imunologia , Transferência Adotiva , Alérgenos/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/terapia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Antígenos de Histocompatibilidade Classe II , Imunoglobulina E/biossíntese , Imunoglobulina G/biossíntese , Interleucinas/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina , Linfócitos T Reguladores/imunologia
3.
J Immunol Res ; 2019: 9705327, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214624

RESUMO

Galectin-1 (Gal-1) has immunomodulatory activities in various allergic inflammatory disorders, but its potential anti-inflammatory properties on allergic airway diseases have not been confirmed. We explored the pharmacological effects of Gal-1 on the progression of allergic airway inflammation and investigated the underlying mechanism. Female C57BL/6 mice were sensitized on day 0 and challenged with ovalbumin (OVA) on days 14-17 to establish an allergic airway inflammation model. In the challenge phase, a subset of mice was treated intraperitoneally with recombinant Gal-1 (rGal-1) or dexamethasone (Dex). We found that rGal-1 inhibited pulmonary inflammatory cell recruitment, mucus secretion, bronchoalveolar lavage fluid (BALF) inflammatory cell infiltration, and cytokine production. The treatment also suppressed the infiltration of eosinophils into the allergic lung as indicated by decreased expression levels of eotaxin and eosinophil peroxidase (EPX). However, only the expression levels of IL-25, neither IL-33 nor TSLP, were significantly decreased in the lung by rGal-1 treatment. These immunomodulatory effects in the allergic lung were correlated with the activation of extracellular signal-regulated kinase (ERK) signaling pathway and downregulation of endogenous Gal-1. In addition, rGal-1 reduced the plasma concentrations of anti-OVA immunoglobulin E (IgE) and IL-17. Our findings suggest that rGal-1 is an effective therapy for allergic airway inflammation in a murine model and may be a potential pharmacological target for allergic airway inflammatory diseases.


Assuntos
Antineoplásicos/farmacologia , Hiper-Reatividade Brônquica/imunologia , Galectina 1/farmacologia , Alérgenos/imunologia , Animais , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Eosinófilos/patologia , Feminino , Expressão Gênica , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Sistema de Sinalização das MAP Quinases , Camundongos
4.
Free Radic Res ; 53(7): 780-790, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31185753

RESUMO

Oxidative stress is a key mechanism underlying ozone-induced lung injury. Mitochondria can release mitochondrial reactive oxidative species (mtROS), which may lead to the activation of NLRP3 inflammasome. The goal of this study was to examine the roles of mtROS and NLRP3 inflammasome in acute ozone-induced airway inflammation and bronchial hyperresponsiveness (BHR). C57/BL6 mice (n = 8/group) were intraperitoneally treated with vehicle (phosphate buffered saline, PBS) or mitoTEMPO (mtROS inhibitor, 20 mg/kg), or orally treated with VX-765 (caspse-1 inhibitor, 100 mg/kg) 1 h before the ozone exposure (2.5 ppm, 3 h). Compared to the PBS-treated ozone-exposed mice, mitoTEMPO reduced the level of total malondialdehyde in bronchoalveolar lavage (BAL) fluid and increased the expression of mitochondrial complexes II and IV in the lung 24 h after single ozone exposure. VX-765 inhibited ozone-induced BHR, BAL total cells including neutrophils and eosinophils, and BAL inflammatory cytokines including IL-1α, IL-1ß, KC, and IL-6. Both mitoTEMPO and VX-765 reduced ozone-induced mtROS and inhibited capase-1 activity in lung tissue whilst VX-765 further inhibited DRP1 and MFF expression, increased MFN2 expression, and down-regulated caspase-1 expression in the lung tissue. These results indicate that acute ozone exposure induces mitochondrial dysfunction and NLRP3 inflammasome activation, while the latter has a critical role in the pathogenesis of ozone-induced airway inflammation and BHR.


Assuntos
Hiper-Reatividade Brônquica/metabolismo , Inflamassomos/metabolismo , Inflamação/metabolismo , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Hiper-Reatividade Brônquica/imunologia , Modelos Animais de Doenças , Inflamassomos/imunologia , Inflamação/imunologia , Masculino , Camundongos , Mitocôndrias/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Espécies Reativas de Oxigênio/imunologia
5.
Int J Mol Sci ; 20(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216735

RESUMO

Bronchial asthma is a chronic disease characterized by reversible airway obstruction, mucus production, and bronchial hyperresponsiveness (BHR). Although Th2 cell-mediated eosinophilic inflammation is an important disease mechanism in the majority of patients with bronchial asthma, recent studies suggest the possible development of Th2-independent airway inflammation and BHR. These non-Th2 endotype patients seem to consist of multiple subgroups, and often do not respond to inhaled corticosteroids. Therefore, to understand the pathogenesis of asthma, it is important to characterize these non-Th2 subgroups. Recently, we demonstrated that Th9 cells induce eosinophil infiltration and eosinophil-independent BHR, and Th9 cells-mediated BHR may be resistant to glucocorticoid. In this review, we summarize the contribution of several T cell subsets in the development of bronchial asthma and introduce our recent study demonstrating Th9 cell-mediated and eosinophil-independent BHR.


Assuntos
Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Asma/tratamento farmacológico , Asma/imunologia , Asma/metabolismo , Hiper-Reatividade Brônquica/tratamento farmacológico , Humanos , Subpopulações de Linfócitos T/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo
6.
Immunology ; 157(3): 257-267, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31120548

RESUMO

Asthma is a chronic inflammatory disease that involves a variety of cytokines and cells. Interleukin-16 (IL-16) is highly expressed during allergic airway inflammation and is involved in its development. However, its specific mechanism of action remains unclear. In the present study, we used an animal model of ovalbumin (OVA)-induced allergic asthma with mice harboring an IL-16 gene deletion to investigate the role of this cytokine in asthma, in addition to its underlying mechanism. Increased IL-16 expression was observed during OVA-induced asthma in C57BL/6J mice. However, when OVA was used to induce asthma in IL-16-/- mice, a diminished inflammatory reaction, decreased bronchoalveolar lavage fluid (BALF) eosinophil numbers, and the suppression of OVA-specific IgE levels in the serum and BALF were observed. The results also demonstrated decreased levels of T helper type 2 (Th2) and Th17 cytokines upon OVA-induced asthma in IL-16-/- mice. Hence, we confirmed that IL-16 enhances the lung allergic inflammatory response and suggest a mechanism possibly associated with the up-regulation of IgE and the promotion of Th2 and Th17 cytokine production. This work explored the mechanism underlying the regulation of IL-16 in asthma and provides a new target for the clinical treatment of asthma.


Assuntos
Asma/metabolismo , Hiper-Reatividade Brônquica/metabolismo , Interleucina-16/metabolismo , Pulmão/metabolismo , Ovalbumina , Células Th17/metabolismo , Células Th2/metabolismo , Animais , Asma/imunologia , Asma/fisiopatologia , Asma/prevenção & controle , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Hiper-Reatividade Brônquica/prevenção & controle , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Broncoconstrição , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-16/deficiência , Interleucina-16/genética , Pulmão/imunologia , Pulmão/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Células Th17/imunologia , Células Th2/imunologia
7.
Int J Biol Macromol ; 135: 1-11, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31121228

RESUMO

Microalgae are the lowest plant organisms producing a wide range of metabolites that make them interesting organisms for industrial applications. Cultivation of green microalgal species Chlorella vulgaris resulted a significant production of extracellular polysaccharide (EPS). Preliminary chemico-spectroscopic studies on EPS revealed its molecular profile, a complex primary structure consisting of six monosaccharide units occurring in both furano and pyrano forms, a high sugar binding variability and the presence of partially methylated derivatives of some sugar constituents. Biological activity tests showed that EPS caused significant bronchodilatory, anti-inflammatory and antitussive effects in test animals. Chlorella EPS appears to be a promising agent for the prevention of chronic airway inflammation, which is the basic pathogenic mechanism of many respiratory diseases, including bronchial asthma.


Assuntos
Antiasmáticos/química , Antiasmáticos/farmacologia , Chlorella vulgaris/metabolismo , Polissacarídeos/química , Polissacarídeos/farmacologia , Alérgenos , Animais , Antiasmáticos/metabolismo , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Fenômenos Químicos , Citocinas/metabolismo , Modelos Animais de Doenças , Espaço Extracelular/metabolismo , Cobaias , Mediadores da Inflamação/metabolismo , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso/imunologia , Músculo Liso/metabolismo , Polissacarídeos/biossíntese , Análise Espectral
8.
Science ; 364(6442)2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31123109

RESUMO

Although spontaneous protein crystallization is a rare event in vivo, Charcot-Leyden crystals (CLCs) consisting of galectin-10 (Gal10) protein are frequently observed in eosinophilic diseases, such as asthma. We found that CLCs derived from patients showed crystal packing and Gal10 structure identical to those of Gal10 crystals grown in vitro. When administered to the airways, crystalline Gal10 stimulated innate and adaptive immunity and acted as a type 2 adjuvant. By contrast, a soluble Gal10 mutein was inert. Antibodies directed against key epitopes of the CLC crystallization interface dissolved preexisting CLCs in patient-derived mucus within hours and reversed crystal-driven inflammation, goblet-cell metaplasia, immunoglobulin E (IgE) synthesis, and bronchial hyperreactivity (BHR) in a humanized mouse model of asthma. Thus, protein crystals may promote hallmark features of asthma and are targetable by crystal-dissolving antibodies.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Asma/terapia , Glicoproteínas/química , Glicoproteínas/farmacologia , Imunidade Inata/efeitos dos fármacos , Lisofosfolipase/química , Lisofosfolipase/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Asma/imunologia , Asma/patologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/terapia , Cristalização , Modelos Animais de Doenças , Glicoproteínas/administração & dosagem , Glicoproteínas/imunologia , Células Caliciformes/imunologia , Células Caliciformes/patologia , Humanos , Epitopos Imunodominantes/imunologia , Imunoglobulina E/imunologia , Lisofosfolipase/administração & dosagem , Lisofosfolipase/imunologia , Metaplasia , Camundongos , Camundongos Endogâmicos C57BL , Muco/imunologia
9.
Ter Arkh ; 91(3): 31-35, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31094456

RESUMO

AIM: The aim of the research was to study the state of the bronchial mucosa epi-thelium in relation to the severity of clinical manifestations in severe uncon-trolled asthma depending on the pattern of inflammation and the presence of cold airway hyperresponsiveness. MATERIALS AND METHODS: In 48 patients with severe uncontrolled asthma, there were assessed asthma symptoms, clinical signs of cold airway hyperre-sponsiveness, and lung function; the samples of slides were analyzed in the cytological examination of the sputum; the degree of damage to epithelial cells and granulocytes was estimated using the total cell destruction index (CDI). RESULTS: According to the analysis of sputum cytograms, the patients were divided into two groups: group I (22 patients) included persons with eosin-ophilic inflammation pattern (31.0±3.1% of eosinophils and 22.0±2.2% of neutrophils), group II (26 patients) was with mixed inflammation pattern (7.2±1.4 and 71.8±4.2%, respectively). The patients of group II had lower disease control according to Asthma Control Test (ACT; 12.1±0.7 and 17.8±0.2 points, respectively; р<0.05), a greater frequency of exacerbations (4.1±0.3 and 3.2±0.2 per year, respectively; р<0.05), greater incidence of clinical signs of cold airway hyperresponsiveness (79 and 19%, respectively; χ2=14.18; р<0.001); lower lung function (midexpiratory flow rate MEF25-75 was 14.6±1.6 and 20.7±1.9%, respectively; р<0.05); they received a higher dose of the combined medications of inhaled glucocorticosteroid in controller anti-inflammatory therapy (salmeterol/fluticasone at a dose of 705.3±19.7 and 650.7±14.8 µg/day for fluticasone propionate; р<0.05) In patients of group II the correlations of epithelial CDI with neutrophil CDI (r=0.61; p<0.01) and eosinophil CDI (r=0.48; p<0.05), as well as correlation of ACT with neutrophil CDI (r=-0.71; p<0.01) and eosinophil CDI (r=-0.53; p<0.05) were found. CONCLUSION: The degree of destruction of the epithelium and granulocytes in the inflammatory patterns has diagnostic relevance for the assessment of the severity of the disease, clinical manifestations of the airway response to the cold trigger, and the inertia of achieving control in patients with severe un-controlled asthma.


Assuntos
Asma/fisiopatologia , Hiper-Reatividade Brônquica/fisiopatologia , Síndromes Periódicas Associadas à Criopirina , Brônquios , Hiper-Reatividade Brônquica/imunologia , Temperatura Baixa/efeitos adversos , Eosinófilos , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Índice de Gravidade de Doença , Escarro/citologia
10.
Respir Res ; 20(1): 51, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845921

RESUMO

Agriculture exposures are associated with reducing the risk of allergy and asthma in early life; yet, repeated exposures later in life are associated with chronic bronchitis and obstructive pulmonary diseases. The objective of this study was to investigate the airway inflammatory response to organic dust extract (ODE) in mice with established ovalbumin (OVA)-induced experimental asthma. C57BL/6 mice were either OVA sensitized/aerosol-exposed or saline (Sal) sensitized/aerosol-challenged. Both groups were then subsequently challenged once with intranasal saline or swine confinement ODE to obtain 4 treatment groups of Sal-Sal, Sal-ODE, OVA-Sal, and OVA-ODE. Airway hyper-responsiveness (AHR) to methacholine, bronchiolar lavage fluid, lung tissues, and serum were collected. Intranasal inhalation of ODE in OVA-treated (asthmatic) mice (OVA-ODE) increased AHR and total cellular influx marked by elevated neutrophil and eosinophil counts. Flow cytometry analysis further demonstrated that populations of CD11chi dendritic cells (DC), CD3+ T cells, CD19+ B cells, and NKp46+ group 3 innate lymphoid cells (ILC3) were increased in lavage fluid of OVA-ODE mice as compared to ODE or OVA alone. Alveolar macrophages, DC, and T cells were significantly increased with co-exposure to OVA-ODE as compared to OVA alone. Lung ILC2 and ILC3 were only increased in OVA-Sal mice. Cytokine/chemokine levels varied with exposure to OVA-ODE reflecting an additive mixture of the pro- and allergic-inflammatory profiles. Collectively, ODE increased airway inflammatory cells and chemotactic mediator release in allergic (OVA) sensitized mice to suggest that persons with allergy/asthma be identified and warned prior to the occupational exposure of potentially worsening airway disease.


Assuntos
Hiper-Reatividade Brônquica/induzido quimicamente , Poeira , Exposição por Inalação/efeitos adversos , Agricultura Orgânica , Ovalbumina/toxicidade , Animais , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Galinhas , Poeira/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Suínos
11.
Chin J Integr Med ; 24(12): 912-919, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30341485

RESUMO

OBJECTIVE: To examine the effect of metanol extract of Petiveria alliacea (PM) on airway inflflammation in a murine model of chronic asthma. METHODS: Two-month-old male BALB/c mice (n=6-8/group) were sensitized on days 0 and 14 by intraperitoneal injection of 20 µg ovalbumin (OVA). On day 25, the mice received an airway challenge with OVA (3%, w/v, in phosphate buffered saline). PM was administered orally by oral gavage to mice at doses of 100, 200 and 400 mg/kg body weight once daily from days 18 to 23. Control mice were orally administered phosphate buffered saline (PBS) to induce a model of asthma. At the end of the test, respiratory reactivity was assayed, the total cell number, interleukin-4 (IL-4), IL-5, IL-13, tumor necrosis factor-alpha (TNF-α) and reactive oxygen species (ROS) in the bronchoalveolar lavage fluid (BALF) were determined and the levels of serum IgE, intercellular cell adhesion molecule 1 (ICAM-1) and eotoxin were measured. In addition, lung tissue was used to qualify the IL-4, IL-5, IL-13, TNF-α and transforming growth factor beta 1 (TGF-ß1). Histologic examination was performed to observe inflammatory cellular infiltration. RESULTS: The administration of PM in comparison with the OVA-only treated group signifificantly attenuated the infifiltration of eosinophils and other inflflammatory cells (P<0.01). Airway resistance (RI) in the OVA-only induced group was significantly higher than that of the PBS control group (P<0.01) when methacholine was added. TNF-α, IgE, TGF-ß1 and cytokine levels IL-4, IL-5, IL-13 in the BALF decreased compared to control mice (P<0.01 or P<0.05). PM treatment also inhibited the production of chemokines, eotaxin and ICAM-1 in BALF (P<0.01), which improved lung function. Histopathological examination revealed that the sensitized treated PM groups had significant lower in inflammatory scores similar to dexamethasone treatments and the untreated group. CONCLUSION: Administration of PM could inhibit airway inflammation, regulate cytokines, chemokines and enhance pulmonary conditions in allergic murine model of asthma.


Assuntos
Alérgenos/imunologia , Asma/tratamento farmacológico , Inflamação/tratamento farmacológico , Pulmão/patologia , Ovalbumina/imunologia , Phytolaccaceae/química , Extratos Vegetais/uso terapêutico , Células Th2/imunologia , Animais , Asma/sangue , Asma/imunologia , Asma/fisiopatologia , Hiper-Reatividade Brônquica/complicações , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Líquido da Lavagem Broncoalveolar , Quimiocinas/metabolismo , Modelos Animais de Doenças , Imunoglobulina E/sangue , Inflamação/sangue , Inflamação/complicações , Inflamação/imunologia , Pulmão/imunologia , Pulmão/fisiopatologia , Masculino , Metanol , Camundongos Endogâmicos BALB C , Muco/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo
12.
Expert Rev Respir Med ; 12(11): 931-939, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30241450

RESUMO

INTRODUCTION: Acute exacerbations of chronic lung disease account for substantial morbidity and health costs. Repeated inflammatory episodes and attendant bronchoconstriction cause structural remodeling of the airway. Remodeling is a multicellular response to mucosal injury that results in epithelial cell-state changes, enhanced extracellular deposition, and expansion of pro-fibrotic myofibroblast populations. Areas covered: This manuscript overviews mechanistic studies identifying key sentinel cell populations in the airway and how pattern recognition signaling induces maladaptive mucosal changes and airway remodeling. Studies elucidating how NFκB couples with an atypical histone acetyltransferase, bromodomain-containing protein 4 (BRD4) that reprograms mucosal fibrogenic responses, are described. The approaches to development and characterization of selective inhibitors of epigenetic reprogramming on innate inflammation and structural remodeling in preclinical models are detailed. Expert commentary: Bronchiolar cells derived from Scgb1a1-expressing progenitors function as major sentinel cells of the airway, responsible for initiating antiviral and aeroallergen responses. In these sentinel cells, activation of innate inflammation is coupled to neutrophilic recruitment, mesenchymal transition and myofibroblast expansion. Therapeutics targeting the NFkB-BRD4 may be efficacious in reducing pathological effects of acute exacerbations in chronic lung disease.


Assuntos
Remodelação das Vias Aéreas/imunologia , Asma/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Imunidade Adaptativa/fisiologia , Alérgenos/imunologia , Hiper-Reatividade Brônquica/imunologia , Bronquíolos/citologia , Proteínas de Ciclo Celular , Exposição Ambiental/efeitos adversos , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Imunidade Inata/fisiologia , Miofibroblastos/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Receptores de Reconhecimento de Padrão/metabolismo , Mucosa Respiratória/imunologia , Receptores Toll-Like/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Viroses/imunologia
13.
Allergol. immunopatol ; 46(4): 354-360, jul.-ago. 2018.
Artigo em Inglês | IBECS | ID: ibc-177866

RESUMO

Background: Probiotics could be beneficial to health and some of them have shown to modulate immune responses. Aim: The aim of this study is to investigate if the probiotic strains including Lactobacillus and Pediococcus strains are able to alleviate allergic reactions in an ovalbumin-induced airway allergy model. Methods: Lactobacillus multi-species preparation (LMP) was gavaged to BALB/c for total six weeks and BALB/c was challenged with ovalbumin in the last two weeks. A barometric whole-body plethysmography was used to assess enhanced pause (Penh) of airway hyperreactivity (AHR). Immunoglobulins (Ig) such as IgE, IgG1, IgG2a and cytokines such as IL-12, IFN-gamma, IL-4, IL-5, TNF-alfa and IL-13 in bronchoalveolar lavage fluid were assayed using ELISA kits. Results: The results showed this LMP significantly reduced Th2 cytokines and enhanced Th1 cytokines production. OVA-specific IgE and IgG1 was lower in the probiotics-treated mice whereas IgG2a was increased. Most importantly, this murine model showed LMP supplementation significantly reduced AHR. Conclusions: Overall, this Lactobacillus multi-species preparation seemed to suppress OVA-sensitized airway hyperreactivity, thus serving as a possible candidate for therapeutic uses for allergic airway symptoms


No disponible


Assuntos
Animais , Camundongos , Hiper-Reatividade Brônquica/imunologia , Pulmão , Probióticos/farmacologia , Asma/imunologia , Hiper-Reatividade Brônquica/induzido quimicamente , Hipersensibilidade/imunologia , Lactobacillus plantarum , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/toxicidade , Pediococcus acidilactici
14.
Sci Rep ; 8(1): 6925, 2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29720689

RESUMO

Animal models of allergic airways inflammation are useful tools in studying the pathogenesis of asthma and potential therapeutic interventions. The different allergic airways inflammation models available to date employ varying doses, frequency, duration and types of allergen, which lead to the development of different features of asthma; showing varying degrees of airways inflammation and hyper-responsiveness (AHR) and airways remodeling. Models that also exhibit airway remodeling, a key feature of asthma, in addition to AHR and airway inflammation typically require 5-12 weeks to develop. In this report, we describe a 4-week mouse model of house dust mite (HDM)-induced allergic airways inflammation, and compare the phenotypic features of two different doses of HDM exposures (10 µg and 25 µg) for 5 days/week with a well-characterized 8-week chronic HDM model. We found that 4 weeks of intranasal HDM (25 µg in 35 µl saline; 5 days/week) resulted in AHR, airway inflammation and airway remodeling that were comparable to the 8-week model. We conclude that this new 4-week HDM model is another useful tool in studies of human asthma that offers advantages of shorter duration for development and decreased costs when compared to other models that require longer durations of exposure (5-12 weeks) to develop.


Assuntos
Remodelação das Vias Aéreas , Alérgenos/imunologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Pyroglyphidae/imunologia , Animais , Biomarcadores , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Imunização , Imunoglobulina E/imunologia , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Camundongos , Fatores de Tempo
15.
Allergol Immunopathol (Madr) ; 46(4): 354-360, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29739682

RESUMO

BACKGROUND: Probiotics could be beneficial to health and some of them have shown to modulate immune responses. AIM: The aim of this study is to investigate if the probiotic strains including Lactobacillus and Pediococcus strains are able to alleviate allergic reactions in an ovalbumin-induced airway allergy model. METHODS: Lactobacillus multi-species preparation (LMP) was gavaged to BALB/c for total six weeks and BALB/c was challenged with ovalbumin in the last two weeks. A barometric whole-body plethysmography was used to assess enhanced pause (Penh) of airway hyperreactivity (AHR). Immunoglobulins (Ig) such as IgE, IgG1, IgG2a and cytokines such as IL-12, IFN-γ, IL-4, IL-5, TNF-α and IL-13 in bronchoalveolar lavage fluid were assayed using ELISA kits. RESULTS: The results showed this LMP significantly reduced Th2 cytokines and enhanced Th1 cytokines production. OVA-specific IgE and IgG1 was lower in the probiotics-treated mice whereas IgG2a was increased. Most importantly, this murine model showed LMP supplementation significantly reduced AHR. CONCLUSIONS: Overall, this Lactobacillus multi-species preparation seemed to suppress OVA-sensitized airway hyperreactivity, thus serving as a possible candidate for therapeutic uses for allergic airway symptoms.


Assuntos
Hiper-Reatividade Brônquica/imunologia , Pulmão/efeitos dos fármacos , Probióticos/farmacologia , Animais , Asma/imunologia , Hiper-Reatividade Brônquica/induzido quimicamente , Hipersensibilidade/imunologia , Lactobacillus plantarum , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/toxicidade , Pediococcus acidilactici
16.
Clin Exp Allergy ; 48(10): 1286-1296, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29786918

RESUMO

BACKGROUND: Asthma is a chronic respiratory disease without a cure, although there exists spontaneous remission. Genome-wide association (GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission. OBJECTIVE: We performed a GWA study to develop insights in asthma remission. METHODS: Clinical remission (ClinR) was defined by the absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long-term follow-up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in 2 independent cohorts (total n = 456), followed by expression quantitative loci (eQTL) analyses of the 4 replicated SNPs in lung tissue and epithelium. RESULTS: Of the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow-up of 15.5 (range 3.3-47.8) years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta-analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta-analysis of the replication cohorts. The top-hit, rs6581895, almost reached genome-wide significance (P-value 4.68 × 10-7 ) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101 was a cis-eQTL in lung tissue for IL1RL1 and IL18R1 and a trans-eQTL for IL13. CONCLUSIONS AND CLINICAL RELEVANCE: By defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2, CCT, IL1RL1, IL18R1 and IL13.


Assuntos
Asma/genética , Asma/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Alelos , Asma/diagnóstico , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/imunologia , Biologia Computacional/métodos , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Avaliação de Resultados da Assistência ao Paciente , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Testes de Função Respiratória , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo
17.
Clin Exp Allergy ; 48(7): 773-786, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29772098

RESUMO

Outdoor air pollution is a major environmental health problem throughout the world. In particular, exposure to particulate matter (PM) has been associated with the development and exacerbation of several respiratory diseases, including asthma. Although the adverse health effects of PM have been demonstrated for many years, the underlying mechanisms have not been fully identified. In this review, we focus on the role of the lung epithelium and specifically highlight multiple cytokines in PM-induced respiratory responses. We describe the available literature on the topic including in vitro studies, findings in humans (ie observations in human cohorts, human controlled exposure and ex vivo studies) and in vivo animal studies. In brief, it has been shown that exposure to PM modulates the airway epithelium and promotes the production of several cytokines, including IL-1, IL-6, IL-8, IL-25, IL-33, TNF-α, TSLP and GM-CSF. Further, we propose that PM-induced type 2-promoting cytokines are important mediators in the acute and aggravating effects of PM on airway inflammation. Targeting these cytokines could therefore be a new approach in the treatment of asthma.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Alérgenos/imunologia , Hiper-Reatividade Brônquica/imunologia , Hipersensibilidade/imunologia , Material Particulado/efeitos adversos , Animais , Asma/imunologia , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Mediadores da Inflamação/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia
18.
Immun Inflamm Dis ; 6(2): 322-331, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29642282

RESUMO

RATIONALE: Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR. OBJECTIVES: An exploratory proof of concept clinical study of N6022 in mild asthma to determine the potential bronchoprotective effects of GSNOR inhibition. Mechanistic studies aimed to provide translational evidence of effect. METHODS: Fourteen mild asthma patients were treated with intravenous N6022 (5 mg) or placebo and observed for 7 days, with repeated assessments of the provocative dose of methacholine causing a 20% fall in FEV1 (methacholine PC20 FEV1), followed by a washout period and crossover treatment and observation. In vitro studies in isolated eosinophils investigated the effect of GSNO and N6022 on apoptosis. MEASUREMENTS AND MAIN RESULTS: This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC20 FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose-doubling increases in PC20 FEV1 for N6022 compared with placebo (21% vs 6%, P < 0.05) over the 7-day observation period. Furthermore, a significant treatment effect was observed in the change in PC20 FEV1 from baseline averaged over the 7-day observation period (mean change: +0.82 mg/ml [N6022] from 1.34 mg/ml [baseline] vs -0.18 mg/ml [placebo] from 1.16 mg/ml [baseline], P = 0.023). N6022 was well tolerated in mild asthmatics. In vitro studies demonstrated enhanced eosinophilic apoptosis with N6022. CONCLUSIONS: In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC20 FEV1 at 24 h, but did have a treatment effect at 7 days compared to baseline. Further investigation of the efficacy of S-nitrosoglutathione reductase inhibition in a patient population with eosinophilic asthma is warranted.


Assuntos
Aldeído Oxirredutases/antagonistas & inibidores , Asma/tratamento farmacológico , Benzamidas/uso terapêutico , Hiper-Reatividade Brônquica/tratamento farmacológico , Pirróis/uso terapêutico , Administração Intravenosa , Adulto , Aldeído Oxirredutases/metabolismo , Asma/diagnóstico , Asma/imunologia , Asma/fisiopatologia , Hiper-Reatividade Brônquica/diagnóstico , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Testes de Provocação Brônquica/métodos , Broncoconstritores/administração & dosagem , Broncoconstritores/imunologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Cloreto de Metacolina/administração & dosagem , Cloreto de Metacolina/imunologia , Pessoa de Meia-Idade , Placebos/administração & dosagem , Estudo de Prova de Conceito , S-Nitrosoglutationa/imunologia , S-Nitrosoglutationa/metabolismo , Resultado do Tratamento , Adulto Jovem
20.
Kurume Med J ; 64(3): 45-55, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29553094

RESUMO

Asthma is an allergic disease characterized by chronic airway inflammation, airway hyperresponsiveness (AHR), reversibility and remodeling. Inhaled corticosteroids (ICS) are effective in many patients with asthma. However, ICS are a controlling, but not but curative treatment, and there are still many patients with refractory and difficult-to-treat asthma. The evaluation of airway inflammation by induced sputum, non-specific AHR by methacholine, and asthmatic reactions by specific allergen challenge techniques are useful not only to investigate the pathogenesis of asthma but also to help develop new drugs for asthma management. Interactions between inflammation and regulation, such as between regulatory T cells (Tregs), and AHR were investigated using these techniques. The phenotypes are Tregs characterized by expression of the forkhead box P3 (Foxp3) and cytotoxic T-lymphocyte antigen 4 (CTLA4), which are potent mediators of dominant self-tolerance. Foxp3 and CTLA4 interact with each other. In patients with mild asthma, airway Tregs were decreased and airway eosinophilic inflammation was activated with accelerated AHR. Human asthmatic attack models by allergen challenge demonstrated that airway Tregs were decreased from the baseline with late asthmatic response (LAR) in patients with dual-responder asthma, and there was a significant correlation between change in airway Tregs and LAR. Airway Tregs were increased with escalation of interleukin-10 by ICS. The investigation of Tregs may lead to new strategies for management of asthma and other allergic diseases.


Assuntos
Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Pulmão/imunologia , Linfócitos T Reguladores/imunologia , Administração por Inalação , Corticosteroides/administração & dosagem , Animais , Antiasmáticos/administração & dosagem , Asma/diagnóstico , Asma/tratamento farmacológico , Asma/fisiopatologia , Hiper-Reatividade Brônquica/diagnóstico , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/fisiopatologia , Broncoconstrição , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Fenótipo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA