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1.
Cells ; 8(6)2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226782

RESUMO

Licochalcone A was isolated from Glycyrrhiza uralensis and previously reported to have antitumor and anti-inflammatory effects. Licochalcone A has also been found to inhibit the levels of Th2-associated cytokines in the bronchoalveolar lavage fluid (BALF) of asthmatic mice. However, the molecular mechanism underlying airway inflammation and how licochalcone A regulates oxidative stress in asthmatic mice are elusive. In this study, we investigated whether licochalcone A could attenuate inflammatory and oxidative responses in tracheal epithelial cells, and whether it could ameliorate oxidative stress and airway inflammation in asthmatic mice. Inflammatory human tracheal epithelial (BEAS-2B) cells were treated with licochalcone A to evaluate oxidative responses and inflammatory cytokine levels. In addition, BALB/c mice were sensitized with ovalbumin (OVA) and injected intraperitoneally with licochalcone A (5 or 10 mg/kg). Licochalcone A significantly inhibited reactive oxygen species, eotaxin, and proinflammatory cytokines in BEAS-2B cells. Licochalcone A also decreased intercellular adhesion molecule 1 levels in inflammatory BEAS-2B cells, blocking monocyte cell adherence. We also found that licochalcone A significantly decreased oxidative responses, reduced malondialdehyde levels, and increased glutathione levels in the lungs of OVA-sensitized mice. Furthermore, licochalcone A decreased airway hyper-responsiveness, eosinophil infiltration, and Th2 cytokine production in the BALF. These findings suggest that licochalcone A alleviates oxidative stress, inflammation, and pathological changes by inhibiting Th2-associated cytokines in asthmatic mice and human tracheal epithelial cells. Thus, licochalcone A demonstrated therapeutic potential for improving asthma.


Assuntos
Asma/complicações , Asma/tratamento farmacológico , Chalconas/uso terapêutico , Estresse Oxidativo , Substâncias Protetoras/uso terapêutico , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/tratamento farmacológico , Animais , Especificidade de Anticorpos , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Adesão Celular/efeitos dos fármacos , Chalconas/farmacologia , Quimiocinas/metabolismo , Colágeno/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dano ao DNA , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/patologia , Feminino , Glutationa/metabolismo , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Humanos , Hiperplasia , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , Ovalbumina , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Células THP-1
2.
Phytomedicine ; 61: 152835, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31035047

RESUMO

BACKGROUND: Siraitia grosvenorii fruits are used in traditional medicine to treat cough, sore throat, bronchitis, and asthma. PURPOSE: This study aimed to investigate the anti-inflammatory and anti-asthmatic effects of S. grosvenorii residual extract (SGRE) on ovalbumin (OVA)-induced asthma in mice. METHODS: Asthma was induced in BALB/c mice by systemic sensitization to OVA, followed by intratracheal, intraperitoneal, and aerosol allergen challenges. SGRE was orally administered for four weeks. We investigated the effects of SGRE on airway hyper-responsiveness, OVA-specific IgE production, histological analysis of lung and trachea, immune cell phenotyping, Th1/Th2 cytokine production in bronchoalveolar lavage fluid (BAL) fluid and splenocytes, and gene expression in the lung. RESULTS: SGRE ameliorated OVA-driven airway hyper-responsiveness, serum IgE production, and histopathological changes in the lung and trachea. SGRE reduced the total number of cells in the lung and BAL, the total number of lymphocytes, neutrophils, monocytes, and eosinophils in the lung and BAL, the absolute number of CD4+/CD69+ T cells in the lung, and the absolute number of CD4+/CD8+ T cells and CD11b+/Gr-1+ granulocytes in the lung and BAL. SGRE also reduced Th2 cytokines (IL-4, IL-5, and IL-13) and increased the Th1 cytokine IFN-γ in the BAL fluid and supernatant of splenocyte cultures. SGRE decreased the OVA-induced increase of IL-13, TARC, MUC5AC, TNF-α, and IL-17 expression in the lung. CONCLUSION: SGRE exerts anti-asthmatic effects via the inhibition of Th2 and Th17 cytokines and the increase of Th1 cytokines, suggesting that SGRE may be a potential therapeutic agent for allergic lung inflammation, such as asthma.


Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Cucurbitaceae/química , Extratos Vegetais/farmacologia , Pneumonia/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/patologia , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Mucina-5AC/genética , Mucina-5AC/metabolismo , Ovalbumina/imunologia , Ovalbumina/toxicidade , Pneumonia/induzido quimicamente , Pneumonia/patologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/tratamento farmacológico , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologia
3.
Int Immunopharmacol ; 69: 1-10, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30660871

RESUMO

Cyanidin-3-O-ß-glucoside (Cy-3-g), a typical and abundant monomer of anthocyanins, exhibits a variety of biological activities, such as anti-atherosclerosis, anti-obesity, and anticancer effects. However, to date little is known about its effects on asthma. This study aimed to investigate the efficacy of dietary Cy-3-g on allergic asthma in an animal model. BALB/c mice were sensitized and challenged with ovalbumin (OVA) to induce allergic asthma. The pathological changes of the lung tissues, type 2 helper (Th2)-associated cytokine production in bronchoalveolar lavage fluid (BALF), and the interleukin 4 receptor alpha (IL-4Rα)-signal transducer and activator of transcription 6 (STAT6) signaling pathway activities were assessed. We found that Cy-3-g significantly inhibited OVA-induced inflammatory cell infiltration and mucus hyper-production in lung tissues, reduced the production of interleukin 4 (IL-4), interleukin 5 (IL-5) and interleukin 13 (IL-13) in BALF. Furthermore, Cy-3-g effectively suppressed OVA-induced up-regulation of the IL-4Rα-STAT6 signaling pathway activity of the lung tissues. These results demonstrated that dietary Cy-3-g could attenuate allergic airway inflammation in a murine asthma model, and Cy-3-g might be used as an agent for asthma prevention and/or treatment in the future.


Assuntos
Antocianinas/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Glucosídeos/uso terapêutico , Pulmão/imunologia , Hipersensibilidade Respiratória/tratamento farmacológico , Alérgenos/imunologia , Animais , Citocinas/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Receptores de Superfície Celular/metabolismo , Fator de Transcrição STAT6/metabolismo , Células Th2/imunologia
4.
Drug Chem Toxicol ; 42(3): 286-294, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-29683006

RESUMO

The anti-inflammatory and antioxidant effects of Ocimum basilicum (O. basilicum) was shown previously. In the present study, the effect of O. basilicum on tracheal responsiveness (TR) to methacholine and ovalbumin (OVA), bronchoalveolar lavage fluid (BALF) levels of oxidant-antioxidant biomarkers as well as total and differential white blood cell (WBC) in sensitized rats was examined. Six groups of rats including control (group C), sensitized rats to OVA (group S), S groups treated with three concentrations of O. basilicum (0.75, 1.50, and 3.00 mg/ml) and one concentration of dexamethasone (1.25 µg/ml) (n = 8 for all groups) were studied. TR to methacholine and OVA, total WBC count, percentages of eosinophils, monocytes, neutrophils, and levels of oxidant biomarkers were significantly increased but other measured parameters were significantly decreased in group S compared to group C. TR to methacholine and OVA, percentages of eosinophils, monocytes, neutrophils, and levels of oxidant biomarkers were significantly decreased but lymphocytes and antioxidant biomarkers were significantly increased in S groups treated with dexamethasone and at least two higher concentrations of the extract compared to group S. Total WBC count was also decreased in treated S groups with dexamethasone and high extract concentration. The effect of extract on most measured parameters was significantly lower than dexamethasone treatment. The effects of two higher concentrations of the extract on most variables were significantly higher than the effect of low extract concentration. These results showed the concentration-dependent effect of O. basilicum on tracheal responses, lung inflammatory cells, and oxidant-antioxidant parameters in sensitized rats.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Pulmão/efeitos dos fármacos , Ocimum basilicum/química , Extratos Vegetais/uso terapêutico , Hipersensibilidade Respiratória/tratamento farmacológico , Traqueia/efeitos dos fármacos , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Leucócitos , Leucócitos/efeitos dos fármacos , Pulmão/citologia , Pulmão/imunologia , Cloreto de Metacolina/imunologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/imunologia , Ovalbumina/imunologia , Oxidantes/metabolismo , Extratos Vegetais/isolamento & purificação , Ratos Wistar , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Traqueia/imunologia
5.
Am J Respir Cell Mol Biol ; 60(2): 198-208, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30240285

RESUMO

We have previously reported that the mouse gut microbiome contributes to pulmonary responses to ozone, a common asthma trigger, and that short-chain fatty acids, end products of bacterial fermentation, likely contribute to this role of the microbiome. A growing body of evidence indicates that there are sex-related differences in gut microbiota and these differences can have important functional consequences. The purpose of this study was to determine whether there are sex-related differences in the impact of the gut microbiota on pulmonary responses to ozone. After acute exposure to ozone, male mice developed greater airway hyperresponsiveness than female mice. This difference was abolished after antibiotic ablation of the gut microbiome. Moreover, weanling female pups housed in cages conditioned by adult male mice developed greater ozone-induced airway hyperresponsiveness than weanling female pups raised in cages conditioned by adult females. Finally, ad libitum oral administration via drinking water of the short-chain fatty acid propionate resulted in augmented ozone-induced airway hyperresponsiveness in male, but not female, mice. Overall, these data are consistent with the hypothesis that the microbiome contributes to sex differences in ozone-induced airway hyperresponsiveness, likely as a result of sex differences in the response to short-chain fatty acids.


Assuntos
Pulmão/efeitos dos fármacos , Microbiota/efeitos dos fármacos , Microbiota/fisiologia , Ozônio/efeitos adversos , Hipersensibilidade Respiratória/microbiologia , Animais , Antibacterianos/farmacologia , Líquido da Lavagem Broncoalveolar/microbiologia , Ácidos Graxos Voláteis/metabolismo , Feminino , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Propionatos/farmacologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/tratamento farmacológico , Fatores Sexuais
6.
Am J Respir Cell Mol Biol ; 60(1): 68-83, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30153047

RESUMO

NF-κB/RelA triggers innate inflammation by binding to bromodomain-containing protein 4 (BRD4), an atypical histone acetyltransferase (HAT). Although RelA·BRD4 HAT mediates acute neutrophilic inflammation, its role in chronic and functional airway remodeling is not known. We observed that BRD4 is required for Toll-like receptor 3 (TLR3)-mediated mesenchymal transition, a cell-state change that is characteristic of remodeling. We therefore tested two novel highly selective BRD4 inhibitors, ZL0420 and ZL0454, for their effects on chronic airway remodeling produced by repetitive TLR3 agonist challenges, and compared their efficacy with that of two nonselective bromodomain and extraterminal (BET) protein inhibitors, JQ1 and RVX208. We observed that ZL0420 and ZL0454 more potently reduced polyinosinic:polycytidylic acid-induced weight loss and fibrosis as assessed by microcomputed tomography and second harmonic generation microscopy. These measures correlated with the collagen deposition observed in histopathology. Importantly, the ZL inhibitors were more effective than the nonselective BET inhibitors at equivalent doses. The ZL inhibitors had significant effects on lung physiology, reversing TLR3-associated airway hyperresponsiveness and increasing lung compliance in vivo. At the molecular level, ZL inhibitors reduced elaboration of the transforming growth factor-ß-induced growth program, thereby preventing mucosal mesenchymal transition and disrupting BRD4 HAT activity and complex formation with RelA. We also observed that ZL0454 treatment blocked polyinosinic:polycytidylic acid-associated expansion of the α-SMA1+/COL1A+ myofibroblast population and prevented myofibroblast transition in a coculture system. We conclude that 1) BRD4 is a central effector of the mesenchymal transition that results in paracrine activation of myofibroblasts, mechanistically linking innate inflammation to airway hyperresponsiveness and fibrosis, and 2) highly selective BRD4 inhibitors may be effective in reversing the effects of repetitive airway viral infections on innate inflammation-mediated remodeling.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Inflamação/fisiopatologia , Proteínas Nucleares/antagonistas & inibidores , Fibrose Pulmonar/tratamento farmacológico , Mucosa Respiratória/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Remodelação das Vias Aéreas/fisiologia , Animais , Proteínas de Ciclo Celular , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal , Humanos , Imunidade Inata/imunologia , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , RNA Interferente Pequeno/genética , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais , Receptor 3 Toll-Like/metabolismo
8.
Int J Mol Sci ; 19(12)2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30545126

RESUMO

Asthma is an inflammatory disease caused by an imbalance of Th1 and Th2 cells. In general, asthma is characterized by a stronger Th2 response. Most conventional asthma treatment focuses on improving airway flow or suppression of airway inflammation. To reduce the side effects of currently used asthma medicines, we have conducted studies on natural products that have no side effects. 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucoside (TSG), the main compound of Polygonum multiflorum (PM), has various biological activities, including anti-inflammation and anti-oxidation activities. However, the effect of TSG on asthma has not been studied yet. We examined the effects of TSG on Th2 immune responses using an OVA-induced asthma animal model. OVA-sensitized mice were treated with TSG. 24 h after the last intranasal challenge, airway hyperresponsiveness (AHR) was measured or serum and bronchoalveolar lavage fluid (BALF) were harvested. We measured typical Th1 and Th2 cytokines in serum and BALF. As a result, TSG suppressed Th2 responses, as shown by the lower levels of IL-4, IL-5, total IgE, OVA-specific IgE, and OVA-specific IgG1. On the other hand, TSG increased Th1 responses, as shown by the levels of IFN-gamma. Collectively, these results confirm the potential of TSG for asthma treatment through modulation of inflammatory responses. Considering that the cytotoxic effect of PM extract is due to the cis isomer of TSG, if the effect of TSG on asthma treatment is found to be non-toxic in clinical trials, it would be more effective to use it as a purified component than PM extract as an asthma treatment agent.


Assuntos
Asma/tratamento farmacológico , Glucosídeos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Estilbenos/uso terapêutico , Animais , Asma/sangue , Asma/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Citocinas/biossíntese , Modelos Animais de Doenças , Feminino , Glucosídeos/química , Glucosídeos/farmacologia , Switching de Imunoglobulina , Inflamação/sangue , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Ovalbumina , Substâncias Protetoras/farmacologia , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/fisiopatologia , Estilbenos/química , Estilbenos/farmacologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
9.
JCI Insight ; 3(21)2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30385725

RESUMO

Patients with severe, treatment-refractory asthma are at risk for death from acute exacerbations. The cytokine IL17A has been associated with airway inflammation in severe asthma, and novel therapeutic targets within this pathway are urgently needed. We recently showed that IL17A increases airway contractility by activating the procontractile GTPase RhoA. Here, we explore the therapeutic potential of targeting the RhoA pathway activated by IL17A by inhibiting RhoA guanine nucleotide exchange factors (RhoGEFs), intracellular activators of RhoA. We first used a ribosomal pulldown approach to profile mouse airway smooth muscle by qPCR and identified Arhgef12 as highly expressed among a panel of RhoGEFs. ARHGEF12 was also the most highly expressed RhoGEF in patients with asthma, as found by RNA sequencing. Tracheal rings from Arhgef12-KO mice and WT rings treated with a RhoGEF inhibitor had evidence of decreased contractility and RhoA activation in response to IL17A treatment. In a house dust mite model of allergic sensitization, Arhgef12-KO mice had decreased airway hyperresponsiveness without effects on airway inflammation. Taken together, our results show that Arhgef12 is necessary for IL17A-induced airway contractility and identify a therapeutic target for severe asthma.


Assuntos
Asma/metabolismo , Interleucina-17/metabolismo , Contração Muscular/efeitos dos fármacos , Hipersensibilidade Respiratória/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Proteína rhoA de Ligação ao GTP/efeitos dos fármacos , Idoso , Animais , Asma/tratamento farmacológico , Asma/fisiopatologia , Progressão da Doença , Feminino , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Fatores de Troca do Nucleotídeo Guanina/farmacologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Contração Muscular/fisiologia , Hipersensibilidade Respiratória/tratamento farmacológico , Análise de Sequência de RNA/métodos , Índice de Gravidade de Doença , Proteína rhoA de Ligação ao GTP/metabolismo
10.
Clin Exp Allergy ; 48(12): 1665-1675, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30159930

RESUMO

BACKGROUND: Clinical and experimental studies have identified a crucial role for IL-33 and its receptor ST2 in allergic asthma. Inhalation of traffic-related pollutants, such as diesel exhaust particles (DEP), facilitates the development of asthma and can cause exacerbations of asthma. However, it is unknown whether IL-33/ST2 signalling contributes to the enhancing effects of air pollutants on allergic airway responses. OBJECTIVE: We aim to investigate the functional role of IL-33/ST2 signalling in DEP-enhanced allergic airway responses, using an established murine model. METHODS: C57BL/6J mice were exposed to saline, DEP alone, house dust mite (HDM) alone or combined DEP+HDM. To inhibit IL-33 signalling, recombinant soluble ST2 (r-sST2) was given prophylactically (ie, during the whole experimental protocol) or therapeutically (ie, at the end of the experimental protocol). Airway hyperresponsiveness and the airway inflammatory responses were assessed in bronchoalveolar lavage fluid (BALF) and lung. RESULTS: Combined exposure to DEP+HDM increased IL-33 and ST2 expression in lung, elevated inflammatory responses and bronchial hyperresponsiveness compared to saline, sole DEP or sole HDM exposure. Prophylactic interference with the IL-33/ST2 signalling pathway impaired the DEP-enhanced allergic airway inflammation in the BALF, whereas effects on lung inflammation and airway hyperresponsiveness were minimal. Treatment with r-sST2 at the end of the experimental protocol did not modulate the DEP-enhanced allergic airway responses. CONCLUSION: Our data suggest that the IL-33/ST2 pathway contributes to the onset of DEP-enhanced allergic airway inflammation.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Interleucina-33/metabolismo , Hipersensibilidade Respiratória/etiologia , Hipersensibilidade Respiratória/metabolismo , Transdução de Sinais , Alérgenos/imunologia , Animais , Biomarcadores , Modelos Animais de Doenças , Feminino , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos , Material Particulado/efeitos adversos , Pyroglyphidae/imunologia , Proteínas Recombinantes/farmacologia , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/patologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo
11.
Thorax ; 73(10): 908-917, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29853649

RESUMO

BACKGROUND: Exacerbation in asthma is associated with decreased expression of specific host defence peptides (HDPs) in the lungs. We examined the effects of a synthetic derivative of HDP, innate defence regulator (IDR) peptide IDR-1002, in house dust mite (HDM)-challenged murine model of asthma, in interleukin (IL)-33-challenged mice and in human primary bronchial epithelial cells (PBECs). METHODS: IDR-1002 (6 mg/kg per mouse) was administered (subcutaneously) in HDM-challenged and/or IL-33-challenged BALB/c mice. Lung function analysis was performed with increasing dose of methacholine by flexiVent small animal ventilator, cell differentials in bronchoalveolar lavage performed by modified Wright-Giemsa staining, and cytokines monitored by MesoScale Discovery assay and ELISA. PBECs stimulated with tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), with or without IDR-1002, were analysed by western blots. RESULTS: IDR-1002 blunted HDM challenge-induced airway hyper-responsiveness (AHR), and lung leucocyte accumulation including that of eosinophils and neutrophils, in HDM-challenged mice. Concomitantly, IDR-1002 suppressed HDM-induced IL-33 in the lungs. IFN-γ/TNF-α-induced IL-33 production was abrogated by IDR-1002 in PBECs. Administration of IL-33 in HDM-challenged mice, or challenge with IL-33 alone, mitigated the ability of IDR-1002 to control leucocyte accumulation in the lungs, suggesting that the suppression of IL-33 is essential for the anti-inflammatory activity of IDR-1002. In contrast, the peptide significantly reduced either HDM, IL-33 or HDM+IL-33 co-challenge-induced AHR in vivo. CONCLUSION: This study demonstrates that an immunomodulatory IDR peptide controls the pathophysiology of asthma in a murine model. As IL-33 is implicated in steroid-refractory severe asthma, our findings on the effects of IDR-1002 may contribute to the development of novel therapies for steroid-refractory severe asthma.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Asma/tratamento farmacológico , Citocinas/metabolismo , Imunomodulação/efeitos dos fármacos , Hipersensibilidade Respiratória/tratamento farmacológico , Animais , Asma/imunologia , Asma/metabolismo , Western Blotting , Líquido da Lavagem Broncoalveolar/citologia , Técnicas de Cultura de Células , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo
12.
Mol Immunol ; 97: 94-100, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29609129

RESUMO

Nebulized lidocaine has been suggested to be beneficial in asthma therapy, but the underlying mechanisms are little known. We aimed to investigate whether Toll-like receptor (TLR) 2 was involved in the protective effect of lidocaine on allergic airway inflammation. Female C57BL/6 mice were sensitized and challenged with ovalbumin (OVA). Meanwhile, some of the mice were treated with TLR2 agonist (Pam3CSK4, 100 µg) intraperitoneally in combination with OVA on day 0. Just after allergen provocation, mice were treated with inhaled lidocaine or vehicle for 30 min. In this model, we found that lidocaine markedly attenuated OVA-evoked airway inflammation, leukocyte recruitment and mucus production. Moreover, lidocaine abrogated the increased concentrations of T cytokines and TNF-α in bronchoalveolar lavage fluid (BALF) of allergic mice, as well as reducing the expression of phosphorylated nuclear factor (P-NF)-κBp65 and the NOD-like receptor pyridine containing 3 (NLRP3), which are important for the production of pro-inflammatory cytokines. In addition, our study showed that lidocaine dramatically decreased OVA-induced increased expression of TLR2 in the lung tissues. Furthermore, activation of TLR2 aggravated OVA-challenged airway inflammation, meanwhile, it also elevated OVA-induced expression of P-NF-κBp65 and NLRP3 in the lungs. However, lidocaine effectively inhibited airway inflammation and counteracted the expression of P-NF-κBp65 and NLRP3 in allergic mice pretreated with Pam3CSK4. Taken together, the present study demonstrated that lidocaine prevented allergic airway inflammation via TLR2 in an OVA-induced murine allergic airway inflammation model. TLR2/NF-κB/NLRP3 pathway may serve as a promising therapeutic strategy for allergic airway inflammation.


Assuntos
Inflamação/prevenção & controle , Lidocaína/administração & dosagem , Hipersensibilidade Respiratória/tratamento farmacológico , Administração por Inalação , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Feminino , Inflamação/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Nebulizadores e Vaporizadores , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo
13.
Cytokine ; 108: 136-144, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29605763

RESUMO

Antrodia camphorata mycelium is used in traditional Chinese medicine in Taiwan. The wild-type mycelium is rare and expensive, so a solid-state-cultured mycelium of A. camphorata (SCMAC) has been developed. Previous studies have found SCMAC to have anti-inflammatory effects. However, the immunomodulatory effects of SCMAC and of its active phytosterol compounds EK100 and 9A on asthma remain unknown. In this study, BALB/c mice were repeatedly exposed to Dermatogoides pteronyssinus (Der p) at 1-week intervals and were orally administered crude SCMAC extract before the Der p challenge. The mice were sacrificed 72 h after the last challenge to examine the airway remodeling, inflammation, and expression profiles of cytokines and various genes. Then, 30-µg/mL Der p-stimulated MH-S cells with 9A or EK100 were collected for real-time PCR analysis, and the effects of 9A and EK100 on macrophages were evaluated. The crude extract reduced Der p-induced airway hyperresponsiveness, total serum immunoglobulin E levels, and recruitment of inflammatory cells to the bronchoalveolar lavage fluid through cytokine downregulation and Th1/Th2/Th17 response modulation. Additionally, 9A and EK100 inhibited IL-1ß and IL-6 expression in alveolar macrophages. These results indicate that the pharmacologically active compounds in a crude SCMAC extract exert synergistic effects on multiple targets to relieve asthma symptoms.


Assuntos
Corticosteroides/farmacologia , Antrodia/química , Proteínas Fúngicas/farmacologia , Macrófagos/efeitos dos fármacos , Hipersensibilidade Respiratória/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Modelos Animais de Doenças , Inflamação , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Micélio/química , Reação em Cadeia da Polimerase em Tempo Real , Organismos Livres de Patógenos Específicos
14.
J Allergy Clin Immunol ; 142(4): 1243-1256.e17, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29627423

RESUMO

BACKGROUND: Exposure to traffic-related particulate matter promotes asthma and allergic diseases. However, the precise cellular and molecular mechanisms by which particulate matter exposure acts to mediate these effects remain unclear. OBJECTIVE: We sought to elucidate the cellular targets and signaling pathways critical for augmentation of allergic airway inflammation induced by ambient ultrafine particles (UFP). METHODS: We used in vitro cell-culture assays with lung-derived antigen-presenting cells and allergen-specific T cells and in vivo mouse models of allergic airway inflammation with myeloid lineage-specific gene deletions, cellular reconstitution approaches, and antibody inhibition studies. RESULTS: We identified lung alveolar macrophages (AM) as the key cellular target of UFP in promoting airway inflammation. Aryl hydrocarbon receptor-dependent induction of Jagged 1 (Jag1) expression in AM was necessary and sufficient for augmentation of allergic airway inflammation by UFP. UFP promoted TH2 and TH17 cell differentiation of allergen-specific T cells in a Jag1- and Notch 4-dependent manner. Treatment of mice with an anti-Notch 4 antibody abrogated exacerbation of allergic airway inflammation induced by UFP. CONCLUSION: UFP exacerbate allergic airway inflammation by promoting a Jag1-Notch 4-dependent interaction between AM and allergen-specific T cells, leading to augmented TH cell differentiation.


Assuntos
Poluentes Atmosféricos/toxicidade , Proteína Jagged-1/imunologia , Macrófagos Alveolares/imunologia , Material Particulado/toxicidade , Receptor Notch4/imunologia , Hipersensibilidade Respiratória/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Células Apresentadoras de Antígenos/imunologia , Imunoglobulina G/imunologia , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptor Notch4/antagonistas & inibidores , Hipersensibilidade Respiratória/tratamento farmacológico
15.
Biochem Biophys Res Commun ; 501(1): 92-99, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29702092

RESUMO

Patients with DOCK8 deficiency are at increased susceptibility to develop allergic diseases such as food allergy and asthma. Here, we aimed to analyze the pathogenesis of asthma in DOCK8-deficient patients. In our mouse model, DOCK8-knockout (KO) mice sensitized with low-dose OVA were challenged with 1.5% OVA to induce allergic asthma. As compared to that in WT mice, remarkable airway hyperresponsiveness was observed in KO mice. Increased inflammatory cells and eosinophils infiltrated in airway lumen in KO mice especially around bronchi. KO mice showed higher levels of serum IgE and OVA-specific IgE and significantly elevated IgE-producing B cells in blood and in spleen. Surprisingly, nasal administration with rmIL-21 significantly reduced the airway hyperresponsiveness, inflammatory infiltration, as well as the serum IgE and IgE-producing B cells. DOCK8-knockout mice are susceptible to low-dose OVA induced allergic airway inflammation and airway hyperresponsiveness. Supplementary nasal administration of rmIL-21 alleviates allergic asthma in this mouse model.


Assuntos
Asma/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/deficiência , Interleucinas/uso terapêutico , Administração Intranasal , Animais , Asma/genética , Asma/imunologia , Linfócitos B/imunologia , Modelos Animais de Doenças , Fatores de Troca do Nucleotídeo Guanina/genética , Imunoglobulina E/biossíntese , Imunoglobulina E/sangue , Interleucinas/administração & dosagem , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Hipersensibilidade Respiratória/tratamento farmacológico
17.
Biomed Res Int ; 2018: 3298378, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29511677

RESUMO

Severe asthma with fungal sensitization predominates in the population suffering from allergic asthma, to which there is no cure. While corticosteroids are the mainstay in current treatment, other means of controlling inflammation may be beneficial. Herein, we hypothesized that mannan from Saccharomyces cerevisiae would dampen the characteristics of fungal allergic asthma by altering the pulmonary immune responses. Using wild-type and transgenic mice expressing the human mannose receptor on smooth muscle cells, we explored the outcome of mannan administration during allergen exposure on the pathogenesis of fungal asthma through measurement of cardinal features of disease such as inflammation, goblet cell number, and airway hyperresponsiveness. Mannan treatment did not alter most hallmarks of allergic airways disease in wild-type mice. Transgenic mice treated with mannan during allergen exposure had an equivalent response to non-mannan-treated allergic mice except for a prominent granulocytic influx into airways and cytokine availability. Our studies suggest no role for mannan as an inflammatory regulator during fungal allergy.


Assuntos
Asma/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Inflamação/tratamento farmacológico , Mananas/administração & dosagem , Alérgenos/imunologia , Alérgenos/toxicidade , Animais , Aspergillus/imunologia , Aspergillus/patogenicidade , Asma/imunologia , Asma/microbiologia , Asma/patologia , Citocinas/genética , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/microbiologia , Hipersensibilidade/patologia , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Inflamação/imunologia , Inflamação/microbiologia , Mananas/química , Camundongos , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/imunologia , Saccharomyces cerevisiae/química
18.
J Allergy Clin Immunol ; 142(6): 1808-1817.e3, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29522849

RESUMO

BACKGROUND: Altered epithelial physical and functional barrier properties along with TH1/TH2 immune dysregulation are features of allergic asthma. Regulation of junction proteins to improve barrier function of airway epithelial cells has the potential for alleviation of allergic airway inflammation. OBJECTIVE: We sought to determine the immunomodulatory effect of knob protein of the adenoviral capsid on allergic asthma and to investigate its mechanism of action on airway epithelial junction proteins and barrier function. METHODS: Airway inflammation, including junction protein expression, was evaluated in allergen-challenged mice with and without treatment with knob. Human bronchial epithelial cells were exposed to knob, and its effects on expression of junction proteins and barrier integrity were determined. RESULTS: Administration of knob to allergen-challenged mice suppressed airway inflammation (eosinophilia, airway hyperresponsiveness, and IL-5 levels) and prevented allergen-induced loss of airway epithelial occludin and E-cadherin expression. Additionally, knob decreased expression of TH2-promoting inflammatory mediators, specifically IL-33, by murine lung epithelial cells. At a cellular level, treatment of human bronchial epithelial cells with knob activated c-Jun N-terminal kinase, increased expression of occludin and E-cadherin, and enhanced epithelial barrier integrity. CONCLUSION: Increased expression of junction proteins mediated by knob leading to enhanced epithelial barrier function might mitigate the allergen-induced airway inflammatory response, including asthma.


Assuntos
Proteínas do Capsídeo/farmacologia , Proteínas do Capsídeo/uso terapêutico , Células Epiteliais/efeitos dos fármacos , Adenoviridae , Idoso , Animais , Brônquios/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Caderinas/metabolismo , Linhagem Celular , Citocinas/imunologia , Eosinofilia/imunologia , Células Epiteliais/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Ocludina/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/imunologia
19.
Am J Respir Cell Mol Biol ; 59(3): 346-354, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29529379

RESUMO

Previous reports demonstrate that the microbiome impacts allergic airway responses, including airway hyperresponsiveness, a characteristic feature of asthma. Here we examined the role of the microbiome in pulmonary responses to a nonallergic asthma trigger, ozone. We depleted the microbiota of conventional mice with either a single antibiotic (ampicillin, metronidazole, neomycin, or vancomycin) or a cocktail of all four antibiotics given via the drinking water. Mice were then exposed to room air or ozone. In air-exposed mice, airway responsiveness did not differ between antibiotic- and control water-treated mice. Ozone caused airway hyperresponsiveness, the magnitude of which was decreased in antibiotic cocktail-treated mice versus water-treated mice. Except for neomycin, single antibiotics had effects similar to those observed with the cocktail. Compared with conventional mice, germ-free mice also had attenuated airway responsiveness after ozone. 16S ribosomal RNA gene sequencing of fecal DNA to characterize the gut microbiome indicated that bacterial genera that were decreased in mice with reduced ozone-induced airway hyperresponsiveness after antibiotic treatment were short-chain fatty acid producers. Serum analysis indicated reduced concentrations of the short-chain fatty acid propionate in cocktail-treated mice but not in neomycin-treated mice. Dietary enrichment with pectin, which increased serum short-chain fatty acids, also augmented ozone-induced airway hyperresponsiveness. Furthermore, propionate supplementation of the drinking water augmented ozone-induced airway hyperresponsiveness in conventional mice. Our data indicate that the microbiome contributes to ozone-induced airway hyperresponsiveness, likely via its ability to produce short-chain fatty acids.


Assuntos
Antibacterianos/farmacologia , Microbiota/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Ozônio/efeitos adversos , Animais , Líquido da Lavagem Broncoalveolar/citologia , Camundongos , Microbiota/fisiologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
20.
Sci Rep ; 8(1): 5105, 2018 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-29572536

RESUMO

Alternatively activated (M2 or YM1+) macrophages have been associated with the development of asthma but their contribution to disease initiation and progression remains unclear. To assess the therapeutic potential of modulating these M2 macrophages, we have studied inhibition of M2 polarisation during and after development of allergic lung inflammation by treating with cynaropicrin, a galectin-3 pathway inhibitor. Mice that were treated with this inhibitor of M2 polarisation during induction of allergic inflammation developed less severe eosinophilic lung inflammation and less collagen deposition around airways, while the airway α-smooth muscle actin layer was unaffected. When we treated with cynaropicrin after induction of inflammation, eosinophilic lung inflammation and collagen deposition were also inhibited though to a lesser extent. Unexpectedly, both during and after induction of allergic inflammation, inhibition of M2 polarisation resulted in a shift towards neutrophilic inflammation. Moreover, airway hyperresponsiveness was worse in mice treated with cynaropicrin as compared to allergic mice without inhibitor. These results show that M2 macrophages are associated with remodeling and development of eosinophilic lung inflammation, but prevent development of neutrophilic lung inflammation and worsening of airway hyperresponsiveness. This study suggests that macrophages contribute to determining development of eosinophilic or neutrophilic lung inflammation in asthma.


Assuntos
Asma/tratamento farmacológico , Lactonas/uso terapêutico , Macrófagos/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Animais , Asma/imunologia , Asma/patologia , Polaridade Celular/efeitos dos fármacos , Feminino , Macrófagos/imunologia , Macrófagos/patologia , Camundongos Endogâmicos BALB C , Pneumonia/imunologia , Pneumonia/patologia , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia
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