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1.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L728-L741, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877223

RESUMO

Airway epithelial homeostasis is under constant threat due to continuous exposure to the external environment, and abnormally robust sensitivity to external stimuli is critical to the development of airway diseases, including asthma. Ku is a key nonhomologous end-joining DNA repair protein with diverse cellular functions such as VDJ recombination and telomere length maintenance. Here, we show a novel function of Ku in alleviating features of allergic airway inflammation via the regulation of mitochondrial and endoplasmic reticulum (ER) stress. We first determined that airway epithelial cells derived from both asthmatic lungs and murine asthma models demonstrate increased expression of 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Ku protein expression was dramatically reduced in the bronchial epithelium of patients with asthma as well as in human bronchial epithelial cells exposed to oxidative stress. Knockdown of Ku70 or Ku80 in naïve mice elicited mitochondrial collapse or ER stress, leading to bronchial epithelial cell apoptosis and spontaneous development of asthma-like features, including airway hyperresponsiveness, airway inflammation, and subepithelial fibrosis. These findings demonstrate an essential noncanonical role for Ku proteins in asthma pathogenesis, likely via maintenance of organelle homeostasis. This novel function of Ku proteins may also be important in other disease processes associated with organelle stress.


Assuntos
Células Epiteliais/metabolismo , Homeostase/fisiologia , Inflamação/prevenção & controle , Autoantígeno Ku/metabolismo , Animais , Asma/patologia , Asma/prevenção & controle , Estresse do Retículo Endoplasmático/fisiologia , Células Epiteliais/patologia , Humanos , Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Estresse Oxidativo/fisiologia , Hipersensibilidade Respiratória/patologia
2.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L693-L709, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783616

RESUMO

Many mouse models of allergic asthma exhibit eosinophil-predominant cellularity rather than the mixed-granulocytic cytology in steroid-unresponsive severe disease. Therefore, we sought to implement a novel mouse model of antigen-driven, mixed-granulocytic, severe allergic asthma to determine biomarkers of the disease process and potential therapeutic targets. C57BL/6J wild-type, interleukin-6 knockout (IL-6-/-), and IL-6 receptor knockout (IL-6R-/-), mice were injected with an emulsion of complete Freund's adjuvant and house dust mite antigen (CFA/HDM) on day 1. Dexamethasone, a lymphocyte-depleting biological, or anti-IL-17A was administered during the intranasal HDM challenge on days 19-22. On day 23, the CFA/HDM model elicited mixed bronchoalveolar lavage (BAL) cellularity (typically 80% neutrophils and 10% eosinophils), airway hyperresponsiveness (AHR) to methacholine, diffusion impairment, lung damage, body weight loss, corticosteroid resistance, and elevated levels of serum amyloid A (SAA), pro-inflammatory cytokines, and T helper type 1/ T helper type 17 (Th1/Th17) cytokines compared with eosinophilic models of HDM-driven allergic airway disease. BAL cells in IL-6- or IL-6R-deficient mice were predominantly eosinophilic and associated with elevated T helper type 2 (Th2) and reduced Th1/Th17 cytokine production, along with an absence of SAA. Nevertheless, AHR remained in IL-6-deficient mice even when dexamethasone was administered. However, combined administration of anti-IL-17A and systemic corticosteroid significantly attenuated both overall and neutrophilic airway inflammation and also reduced AHR and body weight loss. Inhibition of IL-17A combined with systemic corticosteroid treatment during antigen-driven exacerbations may provide a novel therapeutic approach to prevent the pathological pulmonary and constitutional changes that greatly impact patients with the mixed-granulocytic endotype of severe asthma.


Assuntos
Corticosteroides/farmacologia , Asma/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Alérgenos/efeitos dos fármacos , Alérgenos/imunologia , Animais , Asma/patologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Hipersensibilidade Respiratória/patologia , Células Th17/imunologia
3.
Toxicol Lett ; 333: 222-231, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798538

RESUMO

Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN's developmental effects are increasing. To understand if in utero GEN exposure modulated postnatal respiratory allergies in the middle age, we conducted a time course study in the B6C3F1 offspring (PND 240-330) using a common household allergen (house dust mites: HDM; 10 µg/mouse for PND 240 and 290, and 50 µg/mouse for PND 330, a middle age in mice) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20 mg/kg body weight). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly dosings of HDM extracts, and they were euthanized at day 3 following the final HDM exposure. In utero exposure to GEN decreased HDM allergen-induced respiratory allergy in male B6C3F1 offspring at PND 330 as reflected by decreases in airway hyperresponsiveness (e.g., Penh value), HDM-specific IgG1 (a Th2 type Ab) and the activity of eosinophil peroxidase in the lung (an indication of eosinophil recruitment to the lungs). However, in utero exposure to GEN had minimal effects on HDM allergen-induced respiratory allergy in the middle-aged female offspring. Changes in serum total IgE, HDM-specific IgE, and lung histopathology scores in both male and female offspring were not biologically significant. Overall, in utero GEN exposure exerted a protective effect on respiratory allergy in the middle-aged male, but not female, B6C3F1 offspring following later-life HDM exposures.


Assuntos
Envelhecimento/imunologia , Genisteína/farmacologia , Pulmão/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Hipersensibilidade Respiratória/prevenção & controle , Envelhecimento/sangue , Alérgenos/imunologia , Animais , Peroxidase de Eosinófilo/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/enzimologia , Feminino , Genisteína/administração & dosagem , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Pulmão/embriologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Exposição Materna , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia
4.
PLoS One ; 15(7): e0236744, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730309

RESUMO

Repeated exposures to environmental allergens in susceptible individuals drive the development of type 2 inflammatory conditions such as asthma, which have been traditionally considered to be mainly mediated by Th2 cells. However, emerging evidence suggest that a new innate cell type, group 2 innate lymphoid cells (ILC2), plays a central role in initiating and amplifying a type 2 response, even in the absence of adaptive immunity. At present, the regulatory mechanisms for controlling ILC2 activation remain poorly understood. Here we report that respiratory delivery of immunogenic extracellular RNA (exRNAs) derived from RNA- and DNA-virus infected cells, was able to activate a protective response against acute type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus, in mice. Mechanistically, we found that the innate immune responses triggered by exRNAs had a potent suppressive effect in vivo on the proliferation and function of ILC2 without the involvement of adaptive immunity. We further provided the loss-of-function genetic evidence that the TLR3- and MAVS-mediated signaling axis is essential for the inhibitory effects of exRNAs in mouse lungs. Thus, our results indicate that the host detection of extracellular immunostimulatory RNAs generated during respiratory viral infections have an important function in the regulation of ILC2-driven acute lung inflammation.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Pneumonia/imunologia , RNA/imunologia , Hipersensibilidade Respiratória/imunologia , Imunidade Adaptativa , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Alérgenos/imunologia , Alérgenos/metabolismo , Animais , Citocinas/metabolismo , Armadilhas Extracelulares/metabolismo , Interleucina-33/imunologia , Interleucina-33/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/metabolismo , Pneumonia/patologia , RNA/metabolismo , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais , Células Th2/imunologia , Células Th2/metabolismo , Receptor 3 Toll-Like/fisiologia
6.
Sci Rep ; 10(1): 4214, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144294

RESUMO

Studies demonstrated that pneumonia can decrease vitamin A productions and vitamin A reduction/deficiency may promote asthma development. Our previous study showed that neonatal Streptococcus pneumoniae (S. pneumoniae) infection promoted asthma development. Whether neonatal S. pneumoniae pneumonia induced asthma was associated with vitamin A levels remains unclear. The aim of this study was to investigate the effects of neonatal S. pneumoniae pneumonia on vitamin A expressions, to explore the effects of vitamin A supplement after neonatal S. pneumoniae pneumonia on adulthood asthma development. Non-lethal S. pneumoniae pneumonia was established by intranasal inoculation of neonatal (1-week-old) female BALB/c mice with D39. S. pneumoniae pneumonia mice were supplemented with or without all-trans retinoic acid 24 hours after infection. Vitamin A concentrations in lung, serum and liver were measured post pneumonia until early adulthood. Four weeks after pneumonia, mice were sensitized and challenged with OVA to induce allergic airway disease (AAD). Twenty-four hours after the final challenge, the lungs and bronchoalveolar lavage fluid (BALF) were collected to assess AAD. We stated that serum vitamin A levels in neonatal S. pneumoniae pneumonia mice were lower than 0.7µmol/L from day 2-7 post infection, while pulmonary vitamin A productions were significantly lower than those in the control mice from day 7-28 post infection. Vitamin A supplement after neonatal S. pneumoniae pneumonia significantly promoted Foxp3+Treg and Th1 productions, decreased Th2 and Th17 cells expressions, alleviated airway hyperresponsiveness (AHR) and inflammatory cells infiltration during AAD. Our data suggest that neonatal S. pneumoniae pneumonia induce serum vitamin A deficiency and long-time lung vitamin A reduction, vitamin A supplement after neonatal S. pneumoniae pneumonia inhibit the progression of asthma by altering CD4+T cell subsets.


Assuntos
Asma/prevenção & controle , Suplementos Nutricionais , Pneumonia Pneumocócica/complicações , Hipersensibilidade Respiratória/prevenção & controle , Streptococcus pneumoniae/imunologia , Subpopulações de Linfócitos T/imunologia , Vitamina A/administração & dosagem , Animais , Animais Recém-Nascidos , Asma/etiologia , Asma/metabolismo , Asma/patologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/metabolismo , Hipersensibilidade Respiratória/etiologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Streptococcus pneumoniae/isolamento & purificação , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Vitamina A/metabolismo , Vitaminas/administração & dosagem , Vitaminas/metabolismo
7.
Am J Physiol Lung Cell Mol Physiol ; 318(3): L459-L471, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913654

RESUMO

We investigated the mechanisms involved in the development of airway hyperresponsiveness (AHR) following exposure of mice to halogens. Male mice (C57BL/6; 20-25 g) exposed to either bromine (Br2) or Cl2 (600 or 400 ppm, respectively, for 30 min) developed AHR 24 h after exposure. Nifedipine (5 mg/kg body wt; an L-type calcium channel blocker), administered subcutaneously after Br2 or Cl2 exposure, produced higher AHR compared with Br2 or Cl2 alone. In contrast, diltiazem (5 mg/kg body wt; a nondihydropyridine L-type calcium channel blocker) decreased AHR to control (air) values. Exposure of immortalized human airway smooth muscle cells (hASMC) to Br2 resulted in membrane potential depolarization (Vm Air: 62 ± 3 mV; 3 h post Br2:-45 ± 5 mV; means ± 1 SE; P < 0.001), increased intracellular [Ca2+]i, and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br2 and nifedipine-induced Vm depolarization and [Ca2+]i increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br2 reversed the effects of Br2 and nifedipine on AHR. Incubation of hASMC with low-molecular-weight hyaluronan (LMW-HA), generated by exposing high-molecular-weight hyaluronan (HMW-HA) to Br2, caused Vm depolarization, [Ca2+]i increase, and Ca-SR expression to a similar extent as exposure to Br2 and Cl2. The addition of HMW-HA to cells or mice exposed to Br2, Cl2, or LMW-HA reversed these effects in vitro and improved AHR in vivo. We conclude that detrimental effects of halogen exposure on AHR are mediated via activation of the Ca-SR by LMW-HA.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Ácido Hialurônico/farmacologia , Músculo Liso/efeitos dos fármacos , Receptores de Detecção de Cálcio/metabolismo , Hipersensibilidade Respiratória/tratamento farmacológico , Viscossuplementos/farmacologia , Animais , Bromo/toxicidade , Células Cultivadas , Cloretos/toxicidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Músculo Liso/metabolismo , Receptores de Detecção de Cálcio/antagonistas & inibidores , Receptores de Detecção de Cálcio/genética , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia
8.
Cell Rep ; 29(13): 4509-4524.e5, 2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31875557

RESUMO

Group 2 innate lymphoid cells (ILC2s) can initiate pathologic inflammation in allergic asthma by secreting copious amounts of type 2 cytokines, promoting lung eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. We discovered that the TNF/TNFR2 axis is a central immune checkpoint in murine and human ILC2s. ILC2s selectively express TNFR2, and blocking the TNF/TNFR2 axis inhibits survival and cytokine production and reduces ILC2-dependent AHR. The mechanism of action of TNFR2 in ILC2s is through the non-canonical NF-κB pathway as an NF-κB-inducing kinase (NIK) inhibitor blocks the costimulatory effect of TNF-α. Similarly, human ILC2s selectively express TNFR2, and using hILC2s, we show that TNFR2 engagement promotes AHR through a NIK-dependent pathway in alymphoid murine recipients. These findings highlight the role of the TNF/TNFR2 axis in pulmonary ILC2s, suggesting that targeting TNFR2 or relevant signaling is a different strategy for treating patients with ILC2-dependent asthma.


Assuntos
Linfócitos/imunologia , Proteínas Serina-Treonina Quinases/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Hipersensibilidade Respiratória/imunologia , Transdução de Sinais/imunologia , Transferência Adotiva , Animais , Sobrevivência Celular , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Pulmão/imunologia , Pulmão/patologia , Transfusão de Linfócitos , Linfócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
9.
PLoS One ; 14(11): e0224163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31675376

RESUMO

The angiotensin-(1-7) [Ang-(1-7)]/MAS1 receptor signaling axis is a key endogenous anti-inflammatory signaling pathway. However, the mechanisms by which its mediates the anti-inflammatory effects are not completely understood. Using an allergic murine model of asthma, we investigated whether Ang-1(1-7)/MAS1 receptor axis a): inhibits allergic inflammation via modulation of Src-dependent transactivation of the epidermal growth factor receptor (EGFR) and downstream signaling effectors such as ERK1/2, and b): directly inhibits neutrophil and/or eosinophil chemotaxis ex vivo. Ovalbumin (OVA)-induced allergic inflammation resulted in increased phosphorylation of Src kinase, EGFR, and ERK1/2. In addition, OVA challenge increased airway cellular influx, perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyperresponsiveness (AHR). Treatment with Ang-(1-7) inhibited phosphorylation of Src kinase, EGFR, ERK1/2, the cellular and histopathological changes and AHR. Ang-(1-7) treatment also inhibited neutrophil and eosinophil chemotaxis ex vivo. These changes were reversed following pre-treatment with A779. These data show that the anti-inflammatory actions of Ang-(1-7)/ MAS1 receptor axis are mediated, at least in part, via inhibition of Src-dependent transactivation of EGFR and downstream signaling molecules such as ERK1/2. This study therefore shows that inhibition of the Src/EGRF/ERK1/2 dependent signaling pathway is one of the mechanisms by which the Ang-(1-7)/ MAS1 receptor axis mediates it anti-inflammatory effects in diseases such as asthma.


Assuntos
Angiotensina I/metabolismo , Asma/metabolismo , Receptores ErbB/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Hipersensibilidade Respiratória/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismo , Animais , Western Blotting , Líquido da Lavagem Broncoalveolar/citologia , Quimiotaxia de Leucócito , Modelos Animais de Doenças , Imunofluorescência , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade Respiratória/patologia
10.
Sci Rep ; 9(1): 15601, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666643

RESUMO

Patients with asthma with obesity experience severe symptoms, are unresponsive to conventional asthma treatment, and lack proper pharmacotherapy. Empagliflozin and dulaglutide, developed for diabetes, reduce weight, decrease insulin resistance, and exert additive effects. We evaluated the efficacy of empagliflozin, dulaglutide, and their combination on obesity-induced airway hyperresponsiveness (AHR) and lung fibrosis using a murine model. We assigned C57BL/6J mice to five groups: control, high-fat diet (HFD), and HFD with empagliflozin, dulaglutide, or both. Mice received a 12-week HFD, empagliflozin (5 days/week, oral gavage), and dulaglutide (once weekly, intraperitoneally). Both drugs significantly attenuated HFD-induced weight increase, abnormal glucose metabolism, and abnormal serum levels of leptin and insulin, and co-treatment was more effective. Both drugs significantly alleviated HFD-induced AHR, increased macrophages in bronchoalveolar lavage fluid (BALF), and co-treatment was more effective on AHR. HFD-induced lung fibrosis was decreased by both drugs alone and combined. HFD induced interleukin (IL)-17, transforming growth factor (TGF)-ß1, and IL-1ß mRNA and protein expression, which was significantly reduced by empagliflozin, dulaglutide, and their combination. Tumour necrosis factor (TNF)-α and IL-6 showed similar patterns without significant differences. HFD-enhanced T helper (Th) 1 and Th17 cell differentiation was improved by both drugs. Empagliflozin and dulaglutide could be a promising therapy for obesity-induced asthma and showed additive effects in combination.


Assuntos
Compostos Benzidrílicos/farmacologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Glucosídeos/farmacologia , Fragmentos Fc das Imunoglobulinas/farmacologia , Obesidade/complicações , Proteínas Recombinantes de Fusão/farmacologia , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/etiologia , Animais , Compostos Benzidrílicos/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Citocinas/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Glucosídeos/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Camundongos , RNA Mensageiro/genética , Proteínas Recombinantes de Fusão/uso terapêutico , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/patologia , Células Th1/citologia , Células Th1/efeitos dos fármacos , Células Th17/citologia , Células Th17/efeitos dos fármacos
11.
Part Fibre Toxicol ; 16(1): 39, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660999

RESUMO

BACKGROUND: Engineered nanoparticles (NPs) have been shown to enhance allergic airways disease in mice. However, the influence of the different physicochemical properties of these particles on their adjuvant properties is largely unknown. Here we investigate the effects of chemical composition and redox activity of poorly soluble NPs on their adjuvant potency in a mouse model of airway hypersensitivity. RESULTS: NPs of roughly similar sizes with different chemical composition and redox activity, including CeO2, Zr-doped CeO2, Co3O4, Fe-doped Co3O4(using Fe2O3 or Fe3O4) and TiO2 NPs, all showed adjuvant activity. OVA induced immune responses following intranasal exposure of BALB/c mice to 0.02% OVA in combination with 200 µg NPs during sensitization (on day 1, 3, 6 and 8) and 0.5% OVA only during challenge (day 22, 23 and 24) were more pronounced compared to the same OVA treatment regime without NPs. Changes in OVA-specific IgE and IgG1 plasma levels, differential cell count and cytokines in bronchoalveolar lavage fluid (BALF), and histopathological detection of mucosa cell metaplasia and eosinophil density in the conducting airways were observed. Adjuvant activity of the CeO2 NPs was primarily mediated via the Th2 response, while that of the Co3O4 NPs was characterised by no or less marked increases in IgE plasma levels, BALF IL-4 and IL-5 concentrations and percentages of eosinophils in BALF and more pronounced increases in BALF IL-6 concentrations and percentages of lymphocytes in BALF. Co-exposure to Co3O4 NPs with OVA and subsequent OVA challenge also induced perivascular and peribronchiolar lymphoid cell accumulation and formation of ectopic lymphoid tissue in lungs. Responses to OVA combined with various NPs were not affected by the amount of doping or redox activity of the NPs. CONCLUSIONS: The findings indicate that chemical composition of NPs influences both the relative potency of NPs to exacerbate allergic airway sensitization and the type of immune response. However, no relation between the acellular redox activity and the observed adjuvant activity of the different NPs was found. Further research is needed to pinpoint the precise physiological properties of NPs and biological mechanisms determining adjuvant activity in order to facilitate a safe-by-design approach to NP development.


Assuntos
Pulmão/efeitos dos fármacos , Nanoestruturas/química , Nanoestruturas/toxicidade , Hipersensibilidade Respiratória/induzido quimicamente , Administração Intranasal , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Interleucinas/análise , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Oxirredução , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia , Solubilidade
12.
Int J Nanomedicine ; 14: 5215-5228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371957

RESUMO

Background: Resveratrol (RSV) has attracted interest as an alternative drug for the treatment of acute lung injury (ALI) and other pulmonary diseases, but its poor oral bioavailability is a limitation. In this study, we employed drug delivery nanotechnology to improve the stability, lung localization and efficacy of orally administered resveratrol to control lung damage leading to ALI. Methods and materials: RSV-loaded lipid-core nanocapsules (RSV-LNCs), prepared by interfacial deposition of biodegradable polymers, were given orally to A/J mice prior to lipopolysaccharide (LPS) intranasal instillation. Inflammatory changes, oxidative stress and lung tissue elastance were assessed 24 h after LPS challenge. Results: RSV-LNCs (5 mg/kg), given 1, 4, 6 or 12 h but not 24 h before provocation, inhibited LPS-induced leukocyte accumulation in the bronchoalveolar fluid (BALF), whereas unloaded nanocapsules (ULNCs) or free RSV (5 mg/kg) were ineffective. RSV-LNCs (2.5-10 mg/kg) but not ULNCs or RSV improved lung function and prevented total leukocyte and neutrophil accumulation equally in both BALF and lung tissue when given 4 h before LPS challenge. Similar findings were seen concerning the generation of a range of pro-inflammatory cytokines such as IL-6, KC, MIP-1α, MIP-2, MCP-1 and RANTES in lung tissue. In addition, only RSV-LNCs inhibited MDA levels and SOD activity in parallel with blockade of the ERK and PI3K/Akt pathways following LPS provocation. Conclusion: Nanoformulation of RSV in biodegradable oil-core polymers is an effective strategy to improve the anti-ALI activity of RSV, suggesting that the modified-release formulation of this plant polyphenol may be of great value in clinical conditions associated with ALI and respiratory failure.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Nanocápsulas/química , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resveratrol/administração & dosagem , Resveratrol/uso terapêutico , Transdução de Sinais , Lesão Pulmonar Aguda/complicações , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Masculino , Camundongos Endogâmicos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/patologia , Resveratrol/farmacologia
13.
Oxid Med Cell Longev ; 2019: 7450151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281589

RESUMO

Exposure to fine particulate matter (PM2.5) has been associated with lung inflammation and airway hyperresponsiveness (AHR). Transient receptor potential (TRP) vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) both may play important roles in lung inflammation and AHR. We investigated whether PM2.5-induced lung inflammation and AHR could be prevented by blocking TRPV1 and TRPA1 channels. Mice were injected intraperitoneally with AMG9810 (30 mg/kg, a TRPV1 antagonist) or A967079 (30 mg/kg, a TRPA1 antagonist) or their combination or vehicle (PBS) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or vehicle (PBS) for two consecutive days, and then the mice were studied 24 h later. All pretreatments inhibited PM2.5-induced AHR and inflammatory infiltration in the lung tissue and decreased inflammatory cytokine levels in the bronchoalveolar lavage fluid, together with oxidant levels in the lung. AMG9810 inhibited MFF expression and increased MFN2 expression while A967079 inhibited DRP1 expression and increased OPA1 expression; combined pretreatment reduced MFF and DPR1 expression and increased MFN2 and OPA1 expression. All pretreatments inhibited the activation of the TLR4/NF-κB pathway, while A967079 alone, and combined with AMG9810 also reduced the activation of the NLRP3/caspase-1 pathway. Both TRPV1 and TRPA1 channels play an important role in PM2.5-induced lung inflammation and AHR. However, inhibition of the TRPA1 channel or combined inhibition of TRPA1 and TRPV1 channels resulted in greater inhibitory effect on PM2.5-induced lung injury through regulating the mitochondrial fission/fusion proteins and inhibiting the TLR4/NF-κB and NLRP3/caspase-1 pathways.


Assuntos
Material Particulado/toxicidade , Pneumonia/etiologia , Hipersensibilidade Respiratória/etiologia , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Acrilamidas/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Oximas/farmacologia , Tamanho da Partícula , Pneumonia/metabolismo , Pneumonia/patologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais/efeitos dos fármacos , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/biossíntese , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/biossíntese
14.
J Biosci ; 44(2)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31180054

RESUMO

This study was conducted to determine whether exposure to particulate matter 2.5 (PM2.5) affects the immune tolerance of neonatal mice via the regulation of PD-L1 expression. One-week-old BALB/c mice were exposed to PM2.5 for 8 days. From day 8 to day 18, the mice were treated with 5 µg house dust mite (HDM) (i. n.) every two days. Adenovirus-carried PD-L1 overexpression vectors were infected into mice via nasal inhalation 6 days after exposure to PM2.5. Airway hyperresponsiveness (AHR) was examined in mice 19 days after exposure to PM2.5, and the related parameters of airway inflammation were studied on day 22. Co-exposure to PM2.5 and HDM reduced PD-L1 expression but greatly increased infiltration of inflammatory cells, which was reversed by PD-L1 overexpression. Co-exposure to PM2.5 and HDM also elevated serum IL-4, IL-5 and IL-13 levels and reduced TGF-ß level. Exposure to PM2.5 alone slightly increased the numbers of dendritic cells (DCs) but reduced the numbers of antigen-presenting cells expressing PD-L1 and Treg cells. Therefore, early exposure to PM2.5 reduced PD-L1 expression in the lungs of neonatal mice, which interfered with immune tolerance establishment and subsequently resulted in allergic airway inflammation.


Assuntos
Antígeno B7-H1/imunologia , Células Dendríticas/efeitos dos fármacos , Tolerância Imunológica/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Material Particulado/administração & dosagem , Hipersensibilidade Respiratória/imunologia , Adenoviridae/genética , Adenoviridae/imunologia , Administração por Inalação , Animais , Animais Recém-Nascidos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Células Dendríticas/imunologia , Células Dendríticas/patologia , Regulação da Expressão Gênica , Vetores Genéticos/administração & dosagem , Vetores Genéticos/química , Vetores Genéticos/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Pyroglyphidae/química , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/patologia , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia
15.
Int Arch Allergy Immunol ; 180(1): 1-9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242493

RESUMO

BACKGROUND: An inverse relation between Helicobacter pylori infection and asthma has been shown in epidemiological studies. Infection with H. pylori, or application of an extract of it before or after sensitization, inhibits allergic airway disease in mice. OBJECTIVES: The aim of this study was to investigate the effect of an extract of H. pylori on allergic airway disease induced by repeated allergen exposure in mice that were sensitized and challenged prior to extract application. METHOD: C57BL/6 mice were intranasally (i.n.) sensitized and challenged with house dust mite (HDM). After a minimum of 4 weeks, mice received the H. pylori extract intraperitoneally and were rechallenged i.n. with HDM. Allergen-specific antibodies were measured by ELISA. Cells present in the bronchoalveolar lavage fluid and dendritic cell (DC) subsets in the lung tissue were analyzed by flow cytometry. Tissue inflammation and goblet cell hyperplasia were assessed by histology. Cells of the mediastinal lymph node (mLN) were isolated and in vitro restimulated with HDM or H. pylori extract. RESULTS: Treatment with H. pylori extract before rechallenge reduced allergen-specific IgE, the DC numbers in the tissue, and goblet cell hyperplasia. Cells isolated from mLN of mice treated with the extract produced significantly more IL-10 and IL-17 after in vitro restimulation with HDM. mLN cells of H. pylori-treated mice that were re-exposed to the H. pylori extract produced significantly more interferon gamma. CONCLUSIONS: An extract of H. pylori is effective in reducing mucus production and various features of inflammation in HDM rechallenged mice.


Assuntos
Alérgenos/imunologia , Antígenos de Bactérias/imunologia , Células Caliciformes/patologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia , Animais , Biomarcadores , Biópsia , Citocinas/metabolismo , Exposição Ambiental , Feminino , Infecções por Helicobacter/microbiologia , Hiperplasia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Imunofenotipagem , Camundongos , Pyroglyphidae/imunologia
16.
Int Immunopharmacol ; 73: 435-441, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154288

RESUMO

Studies suggest that hydrogen sulfide (H2S) plays a relevant and beneficial role in the pathophysiology of pulmonary allergic diseases, such as asthma. These diseases may be triggered by changes in airway epithelium caused by repeated exposure to environmental allergens. This study aimed to investigate whether H2S protects against bronchial epithelium apoptosis in allergic inflammation in mice. The effects of H2S on the production of Th2 cytokines and on the infiltration of pulmonary inflammatory cells were also studied. Female BALB/c mice previously sensitized with ovalbumin (OVA) were treated with H2S donor (sodium hydrosulfide [NaHS]) 30 min prior to OVA challenge. After euthanasia (48 h post challenge), the right lung was homogenized to study apoptosis protein expression and to analyze cytokine levels in lung tissue. The left lobe was fixed in formalin for morphological analysis of lung tissue and verification of apoptosis in situ by the TUNEL assay. Histological results showed that NaHS reduced the airway inflammatory infiltrate and prevented an increase in the IL-4, IL-5 and IL-25 levels caused by OVA challenge. Activation of caspase 3 and FasL in response to the allergen was also fully prevented by NaHS treatment. TUNEL staining showed that the challenge from OVA significantly increased the rate of apoptosis in the bronchiolar epithelium, and that this incremental apoptosis was abolished by NaHS treatment. In conclusion, our results showed that H2S donor has a protective effect against airway epithelium damage caused by an allergic reaction, and represents a potential agent in treating allergic lung disorders, such as asthma.


Assuntos
Citocinas/imunologia , Epitélio/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Hipersensibilidade Respiratória/imunologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Epitélio/imunologia , Epitélio/patologia , Feminino , Sulfeto de Hidrogênio , Pulmão/imunologia , Pulmão/patologia , Camundongos Endogâmicos BALB C , Ovalbumina , Hipersensibilidade Respiratória/patologia , Sulfetos/farmacologia
18.
Semin Immunopathol ; 41(3): 349-358, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953160

RESUMO

CD69 is an activation marker on leukocytes. Early studies showed that the CD69+ cells were detected in the lung of patients with asthmatic and eosinophilic pneumonia, suggesting that CD69 might play crucial roles in the pathogenesis of such inflammatory diseases, rather than simply being an activation marker. Intensive studies using mouse models have since clarified that CD69 is a functional molecule regulating the immune responses. We discovered that Myosin light chain 9, 12a, 12b (Myl9/12) are ligands for CD69 and that platelet-derived Myl9 forms a net-like structure (Myl9 nets) that is strongly detected inside blood vessels in inflamed lung. CD69-expressing activated T cells attached to the Myl9 nets can thereby migrate into the inflamed tissues through a system known as the CD69-Myl9 system. In this review, we summarize the discovery of the CD69-Myl9 system and discuss how this system is important in inflammatory immune responses. In addition, we discuss our recent finding that CD69 controls the exhaustion status of tumor-infiltrating T cells and that the blockade of the CD69 function enhances anti-tumor immunity. Finally, we discuss the possibility of CD69 as a new therapeutic target for patients with intractable inflammatory disorders and tumors.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Biomarcadores , Imunidade , Lectinas Tipo C/metabolismo , Cadeias Leves de Miosina/metabolismo , Animais , Antígenos CD/química , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/química , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Transformação Celular Neoplásica , Suscetibilidade a Doenças , Expressão Gênica , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Lectinas Tipo C/química , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Ligantes , Terapia de Alvo Molecular , Cadeias Leves de Miosina/química , Cadeias Leves de Miosina/genética , Cadeias Leves de Miosina/imunologia , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Ligação Proteica , Hipersensibilidade Respiratória/etiologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Relação Estrutura-Atividade
19.
Environ Toxicol Pharmacol ; 68: 155-163, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30986632

RESUMO

OBJECTIVE: To observe the effects of prolonged exposure to high concentrations of PM2.5 on the trachea and lungs of mice and to determine whether the damages to the trachea and lung are induced by necroptosis. METHODS: Six- to eight-week-old female Balb/C mice of PM group were restrained in an animal restraining device using a nose-only "PM2.5 online enrichment system" for 8 weeks, in Shijiazhuang, Hebei, China. Anti -Fas group was exposed to PM2.5 inhalation and anti-Fas treatment via intranasal instillation. The mice in the control group inhaled filtered clean air. PM2.5 sample was collected and analyzed. Airway Hyperresponsiveness (AHR) was tested. Lung tissue and bronchoalveolar lavage fluid (BALF) were analyzed for Hematoxylin and eosin (HE) staining, electron microscopy, cellular inflammation, cytokines, Tunel, Fas, RIPK3 and MLKL expression. RESULTS: Compared to the other two groups, PM group displayed significantly increased AHR, neutrophils in BALF, significant bronchitis and alveolar epithelial hyperplasia and inflammation and necroptosis which were indicated by increased TUNEL, Fas, RIPK3 and MLKL measure. CONCLUSION: Our findings suggest that PM2.5 can enhance AHR and these changes are induced by necroptosis-related inflammation.


Assuntos
Poluentes Atmosféricos/toxicidade , Material Particulado/toxicidade , Hipersensibilidade Respiratória/induzido quimicamente , Fenômenos Fisiológicos Respiratórios/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/metabolismo , Feminino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiologia , Pulmão/ultraestrutura , Camundongos Endogâmicos BALB C , Necrose/induzido quimicamente , Necrose/metabolismo , Necrose/patologia , Necrose/fisiopatologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Hipersensibilidade Respiratória/fisiopatologia , Traqueia/efeitos dos fármacos , Traqueia/patologia , Traqueia/fisiologia , Traqueia/ultraestrutura
20.
Br J Pharmacol ; 176(13): 2195-2208, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30883698

RESUMO

BACKGROUND AND PURPOSE: There is growing interest in stem cell-derived exosomes for their therapeutic and regenerative benefits given their manufacturing and regulatory advantages over cell-based therapies. As existing fibrosis impedes the viability and efficacy of stem cell/exosome-based strategies for treating chronic diseases, here we tested the effects of the anti-fibrotic drug, serelaxin, on the therapeutic efficacy of human amnion epithelial cell (AEC)-derived exosomes in experimental lung disease. EXPERIMENTAL APPROACH: Female Balb/c mice were subjected to either the 9.5-week model of ovalbumin and naphthalene (OVA/NA)-induced chronic allergic airway disease (AAD) or 3-week model of bleomycin (BLM)-induced pulmonary fibrosis; then administered increasing concentrations of AEC-exosomes (5 µg or 25µg), with or without serelaxin (0.5mg/kg/day) for 7-days. 1x106 AECs co-administered with serelaxin over the corresponding time-period were included for comparison in both models, as was pirfenidone-treatment of the BLM model. Control groups received saline/corn oil or saline, respectively. KEY RESULTS: Both experimental models presented with significant tissue inflammation, remodelling, fibrosis and airway/lung dysfunction at the time-points studied. While AEC-exosome (5 µg or 25µg)-administration alone demonstrated some benefits in each model, serelaxin was required for AEC-exosomes (25µg) to rapidly normalise chronic AAD-induced airway fibrosis and airway reactivity, and BLM-induced lung inflammation, epithelial damage and subepithelial/basement membrane fibrosis. Combining serelaxin with AEC-exosomes (25µg) also demonstrated broader protection compared to co-administration of serelaxin with 1x106 AECs or pirfenidone. CONCLUSIONS AND IMPLICATIONS: Serelaxin enhanced the therapeutic efficacy of AEC-exosomes in treating basement membrane-induced fibrosis and related airway dysfunction.


Assuntos
Exossomos , Fibrose Pulmonar/terapia , Relaxina/uso terapêutico , Hipersensibilidade Respiratória/terapia , Remodelação das Vias Aéreas/efeitos dos fármacos , Âmnio/citologia , Animais , Modelos Animais de Doenças , Células Epiteliais , Feminino , Humanos , Camundongos Endogâmicos BALB C , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Relaxina/farmacologia , Hipersensibilidade Respiratória/patologia , Hipersensibilidade Respiratória/fisiopatologia
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