Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 742
Filtrar
1.
J Pharmacol Exp Ther ; 373(3): 476-487, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32273303

RESUMO

Zona pellucida binding protein 2 (Zpbp2) and ORMDL sphingolipid biosynthesis regulator 3 (Ormdl3), mapped downstream of Zpbp2, were identified as two genes associated with airway hyper-responsiveness (AHR). Ormdl3 gene product has been shown to regulate the biosynthesis of ceramides. Allergic asthma was shown to be associated with an imbalance between very-long-chain ceramides (VLCCs) and long-chain ceramides (LCCs). We hypothesized that Fenretinide can prevent the allergic asthma-induced augmentation of Ormdl3 gene expression, normalize aberrant levels of VLCCs and LCCs, and treat allergic asthma symptoms. We induced allergic asthma by house dust mite (HDM) in A/J WT mice and Zpbp2 KO mice expressing lower levels of Ormdl3 mRNA than WT. We investigated the effect of a novel formulation of Fenretinide, LAU-7b, on the AHR, inflammatory cell infiltration, mucus production, IgE levels, and ceramide levels. Although lower Ormdl3 expression, which was observed in Zpbp2 KO mice, was associated with lower AHR, allergic Zpbp2 KO mice were not protected from inflammatory cell infiltration, mucus accumulation, or aberrant levels of VLCCs and LCCs induced by HDM. LAU-7b treatment protects both the Zpbp2 KO and WT mice. The treatment significantly lowers the gene expression of Ormdl3, normalizes the VLCCs and LCCs, and corrects all the other phenotypes associated with allergic asthma after HDM challenge, except the elevated levels of IgE. LAU-7b treatment prevents the augmentation of Ormdl3 expression and ceramide imbalance induced by HDM challenge and protects both WT and Zpbp2 KO mice against allergic asthma symptoms. SIGNIFICANCE STATEMENT: Compared with A/J WT mice, KO mice with Zpbp2 gene deletion have lower AHR and lower levels of Ormdl3 expression. The novel oral clinical formulation of Fenretinide (LAU-7b) effectively lowers the AHR and protects against inflammatory cell infiltration and mucus accumulation induced by house dust mite in both Zpbp2 KO and WT A/J mice. LAU-7b prevents Ormdl3 overexpression in WT allergic mice and corrects the aberrant levels of very-long-chain and long-chain ceramides in both WT and Zpbp2 KO allergic mice.


Assuntos
Asma/tratamento farmacológico , Asma/metabolismo , Ceramidas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fenretinida/farmacologia , Proteínas de Membrana/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Knockout , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/metabolismo
2.
Am J Respir Crit Care Med ; 202(5): 672-680, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320637

RESUMO

Rationale: Phthalates are a group of chemicals used in common commercial products. Epidemiological studies suggest that phthalate exposure is associated with development or worsening of allergic diseases such as asthma. However, effects of dibutyl phthalate (DBP) or other phthalates found in high concentrations in indoor air have never been examined in allergic individuals in a controlled exposure setting.Objectives: To investigate the airway effects in humans caused by inhalation of a known concentration of a single phthalate, DBP.Methods: In a randomized crossover study, 16 allergen-sensitized participants were exposed to control air or DBP for 3 hours in an environmental chamber followed immediately by an allergen inhalation challenge. Bronchoalveolar wash and lavage were obtained 24 hours after exposure. Lung function, early allergic response, airway responsiveness, inflammation, immune mediators, and immune cell phenotypes were assessed after DBP exposure.Measurements and Main Results: DBP exposure increased the early allergic response (21.4% decline in FEV1 area under the curve, P = 0.03). Airway responsiveness was increased by 48.1% after DBP exposure in participants without baseline hyperresponsiveness (P = 0.01). DBP increased the recruitment of BAL total macrophages by 4.6% (P = 0.07), whereas the M2 macrophage phenotype increased by 46.9% (P = 0.04). Airway immune mediator levels were modestly affected by DBP.Conclusions: DBP exposure augmented allergen-induced lung function decline, particularly in those without baseline hyperresponsiveness, and exhibited immunomodulatory effects in the airways of allergic individuals. This is the first controlled human exposure study providing biological evidence for phthalate-induced effects in the airways.Clinical trial registered with www.clinicaltrials.gov (NCT02688478).


Assuntos
Poluentes Atmosféricos/efeitos adversos , Dibutilftalato/uso terapêutico , Fluxo Expiratório Forçado/fisiologia , Hipersensibilidade Respiratória/tratamento farmacológico , Sistema Respiratório/imunologia , Adulto , Estudos Cross-Over , Feminino , Fluxo Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Plastificantes/uso terapêutico , Testes de Função Respiratória , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/fisiopatologia , Adulto Jovem
3.
Am J Respir Cell Mol Biol ; 63(1): 57-66, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32182104

RESUMO

It is well known that the prevalence of asthma is higher in athletes, including Olympic athletes, than in the general population. In this study, we analyzed the mechanism of exercise-induced bronchoconstriction by using animal models of athlete asthma. Mice were made to exercise on a treadmill for a total duration of 1 week, 3 weeks, or 5 weeks. We analyzed airway responsiveness, BAL fluid, lung homogenates, and tissue histology for each period. In mice that were treated (i.e., the treatment model), treatments were administered from the fourth to the fifth week. We also collected induced sputum from human athletes with asthma and analyzed the supernatants. Airway responsiveness to methacholine was enhanced with repeated exercise stimulation, although the cell composition in BAL fluid did not change. Exercise induced hypertrophy of airway smooth muscle and subepithelial collagen deposition. Cysteinyl-leukotriene (Cys-LT) levels were significantly increased with exercise duration. Montelukast treatment significantly reduced airway hyperresponsiveness (AHR) and airway remodeling. Expression of PLA2G4 (phospholipase A2 group IV) and leukotriene C4 synthase in the airway epithelium was upregulated in the exercise model, and inhibition of PLA2 ameliorated AHR and airway remodeling, with associated lower levels of Cys-LTs. The levels of Cys-LTs in sputum from athletes did not differ between those with and without sputum eosinophilia. These data suggest that AHR and airway remodeling were caused by repeated and strenuous exercise. Cys-LTs from the airway epithelium, but not inflammatory cells, may play an important role in this mouse model.


Assuntos
Remodelação das Vias Aéreas/fisiologia , Broncoconstrição/fisiologia , Cisteína/metabolismo , Fosfolipases A2 do Grupo II/metabolismo , Leucotrienos/metabolismo , Condicionamento Físico Animal/fisiologia , Acetatos/farmacologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/metabolismo , Broncoconstrição/efeitos dos fármacos , Feminino , Leucotrienos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Quinolinas/farmacologia , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/metabolismo
4.
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
5.
Biomed Pharmacother ; 121: 109584, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31766098

RESUMO

AIM OF THE STUDY: To develop a novel anti-asthma drug. DFSG is a novel herbal cocktail composed of 4 types of herbal medicines. This study explored whether DFSG has the potential to attenuate asthma symptom severity and aimed to determine the immunomodulatory mechanism of DFSG using a chronic asthmatic mouse model induced by repeated challenges with Dermatogoides pteronyssinus (Der p). MATERIALS AND METHODS: BALB/c mice were intratracheally inoculated with Der p (50 µl, 1 mg/ml) once a week for 5 weeks. In addition, 30 min before Der p challenge, the mice were orally administered 1x DFSG (1 g/kg) or 1/2x DFSG (0.5 g/kg). Three days after the final challenge, the mice were sacrificed to evaluate inflammatory cell infiltration, lung histological features, blood total IgE, and cytokine levels in pulmonary alveolar lavage fluid. Furthermore, 30 min after the addition of DFSG, caffeic acid, p-coumaric acid or chlorogenic acid to A549 cells, 10 ng/ml IL-1ß was added to evaluate the effect of the drug on mucin 5AC (MUC5AC) gene expression after stimulation of A549 cells by IL-1ß. RESULTS: DFSG significantly reduced Der p-induced airway hyperresponsiveness, bronchial inflammatory cell infiltration, and total IgE and IgG1 serum levels. Furthermore, DFSG significantly inhibited TH2 cytokines and increased the expression of TH1 cytokines. In addition, immunohistochemical staining demonstrated that DFSG inhibited MUC5AC expression in the bronchial epithelial cells. DFSG and a mixture of caffeic acid, p-coumaric acid, and chlorogenic acid inhibited MUC5AC gene expression in A549 cells after stimulation with IL-1ß. CONCLUSION: These results suggest that by regulating TH1 and TH2 cytokines and MUC5AC expression, DFSG exhibits anti-airway inflammatory cell infiltration and anti-hyperresponsiveness activity and inhibits specific immunity in a chronic asthmatic mouse model. Therefore, DFSG has potential for development into a drug for chronic asthma treatment.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Mucina-5AC/metabolismo , Células A549 , Animais , Antiasmáticos/farmacologia , Antígenos de Dermatophagoides/toxicidade , Asma/induzido quimicamente , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mucina-5AC/antagonistas & inibidores , Distribuição Aleatória , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/metabolismo
6.
Respir Res ; 20(1): 285, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852500

RESUMO

BACKGROUND: ß2 receptor agonists induce airway smooth muscle relaxation by increasing intracellular cAMP production. PKA is the traditional downstream signaling pathway of cAMP. Exchange protein directly activated by cAMP (Epac) was identified as another important signaling molecule of cAMP recently. The role of Epac in asthmatic airway inflammation and airway remodeling is unclear. METHODS: We established OVA-sensitized and -challenged acute and chronic asthma mice models to explore the expression of Epac at first. Then, airway inflammation and airway hyperresponsiveness in acute asthma mice model and airway remodeling in chronic asthma mice model were observed respectively after treatment with Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP (8pCPT) and Epac inhibitor ESI-09. Next, the effects of 8pCPT and ESI-09 on the proliferation and apoptosis of in vitro cultured mouse airway smooth muscle cells (ASMCs) were detected with CCK-8 assays and Annexin-V staining. Lastly, the effects of 8pCPT and ESI-09 on store-operated Ca2+ entry (SOCE) of ASMCs were examined by confocal Ca2+ fluorescence measurement. RESULTS: We found that in lung tissues of acute and chronic asthma mice models, both mRNA and protein expression of Epac1 and Epac2, two isoforms of Epac, were lower than that of control mice. In acute asthma mice model, the airway inflammatory cell infiltration, Th2 cytokines secretion and airway hyperresponsiveness were significantly attenuated by 8pCPT and aggravated by ESI-09. In chronic asthma mice model, 8pCPT decreased airway inflammatory cell infiltration and airway remodeling indexes such as collagen deposition and airway smooth muscle cell proliferation, while ESI-09 increased airway inflammation and airway remodeling. In vitro cultured mice ASMCs, 8pCPT dose-dependently inhibited, whereas ESI-09 promoted ASMCs proliferation. Interestingly, 8pCPT promoted the apoptosis of ASMCs, whereas ESI-09 had no effect on ASMCs apoptosis. Lastly, confocal Ca2+ fluorescence examination found that 8pCPT could inhibit SOCE in ASMCs at 100 µM, and ESI-09 promoted SOCE of ASMCs at 10 µM and 100 µM. In addition, the promoting effect of ESI-09 on ASMCs proliferation was inhibited by store-operated Ca2+ channel blocker, SKF-96365. CONCLUSIONS: Our results suggest that Epac has a protecting effect on asthmatic airway inflammation and airway remodeling, and Epac reduces ASMCs proliferation by inhibiting SOCE in part.


Assuntos
Remodelação das Vias Aéreas , Asma/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Hipersensibilidade Respiratória/metabolismo , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Apoptose , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/fisiopatologia , Sinalização do Cálcio , Proliferação de Células , Células Cultivadas , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , Modelos Animais de Doenças , Feminino , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Fatores de Troca do Nucleotídeo Guanina/genética , Hidrazonas/farmacologia , Mediadores da Inflamação/metabolismo , Isoxazóis/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos Endogâmicos BALB C , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ovalbumina , Pneumonia/induzido quimicamente , Pneumonia/fisiopatologia , Pneumonia/prevenção & controle , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/fisiopatologia
7.
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
8.
Exp Lung Res ; 45(9-10): 275-287, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31608695

RESUMO

Background: Obesity is one of the factors associated with severe, uncontrolled asthma. The effect of pravastatin on asthmatic airway inflammation in obesity has not been evaluated. Methods: C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity with or without ovalbumin (OVA) sensitization and challenge. Pravastatin was administered intraperitoneally during the OVA treatment. Airway inflammation and airway hyper-responsiveness (AHR) were analyzed and lung tissues were examined. The changes in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were measured in the lung tissues. Results: HFD with OVA sensitization and challenge exacerbated eosinophilic and neutrophilic airway inflammation and increased AHR compared to lean asthma mice. The levels of cytokines examined in bronchoalveolar lavage fluid (BALF) revealed that the expressions of IL-4, 5, and 17 were elevated in the obese asthmatic group and decreased after pravastatin treatment, indicating that both the Th2 and Th17 pathways were stimulated by HFD-induced obesity and OVA challenge and suppressed by pravastatin treatment. Moreover, the serum leptin and adiponectin ratio was elevated only in obese asthmatic mice and decreased with pravastatin administration. Pravastatin successfully alleviated the airway inflammation of lung tissues and AHR in both obese and lean asthmatic mice, however, treatment with pravastatin had no effects on BALF cell counts and cytokines in lean asthma mice. In lung tissues, the phosphorylation of p38 MAPK was significantly decreased in lean as well as obese asthmatic mice. Conclusions: Pravastatin treatment in obese asthmatic mice suppressed allergic airway infiltration and AHR by inhibition of Th2 and Th17-associated signaling pathways, decreasing the leptin expression and downstream p38 MAPK signaling pathways. The effect on lean asthmatic mice was different, independent of airway cell counts and cytokines.


Assuntos
Asma/tratamento farmacológico , Asma/etiologia , Inflamação/tratamento farmacológico , Obesidade/complicações , Pravastatina/farmacologia , Hipersensibilidade Respiratória/tratamento farmacológico , Animais , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Ovalbumina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Hipersensibilidade Respiratória/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
9.
Cells ; 8(10)2019 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-31569343

RESUMO

Elevated levels of immunoglobulin E (IgE) are associated with allergies and other immunological disorders. Sensitization with alum adjuvant favours IgE production while CpG-ODN adjuvant, a synthetic toll-like receptor 9 (TLR9) agonist, inhibits it. The cellular mechanisms underlying in vivo TLR regulation of immunoglobulin production, specially IgE, are still controversial. Specifically, TLR-mediated IgE regulation in vivo is not yet known. In this study we showed that augmented levels of IgE induced by sensitizations to OVA with or without alum adjuvant or with OVA-pulsed dendritic cells (DCs) were inhibited by co-administration of CpG. Notably, CpG-mediated suppression of IgE production required MyD88-expression on DCs but not on B-cells. This finding contrasts with previous in vitro studies reporting regulation of IgE by a direct action of CpG on B cells via MyD88 pathway. In addition, we showed that CpG also inhibited IgE production in a MyD88-dependent manner when sensitization was performed with OVA-pulsed DCs. Finally, CpG signalling through MyD88 pathway was also necessary and sufficient to prevent anaphylactic antibody production involved in active cutaneous anaphylaxis.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Células Dendríticas/imunologia , Imunoglobulina E/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Oligodesoxirribonucleotídeos/administração & dosagem , Ovalbumina/efeitos adversos , Hipersensibilidade Respiratória/tratamento farmacológico , Adjuvantes Imunológicos/farmacologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoglobulina E/efeitos dos fármacos , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Oligodesoxirribonucleotídeos/farmacologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Int J Mol Sci ; 20(19)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581442

RESUMO

Garlic (Allium sativum L.) has been used extensively as a food ingredient and medicinally, but the effect on asthmatic airway inflammation has not been studied in detail. We accordingly explored the protective effects exerted by various garlic fraction extracts against airway inflammation with Dermatophagoides pteronyssinus (Der p)-induced allergic asthma in vivo and in vitro. Garlic extraction was realized using n-hexane, dichloromethane, ethylacetate, n-butanol, and water in sequence to obtain different fraction extracts. Mice were orally administered different fractions (80 mg/kg) daily for four weeks. The histological results showed that the water fraction could ameliorate lung-based goblet cell hyperplasia, inflammatory cell infiltration, and mucus hypersecretion. The water fraction extracts decreased IgE and IgG1, and they decreased inflammatory cells as quantified in bronchoalveolar lavage fluid (BALF); however, they increased IgG2a in serum. Moreover, the water fraction extracts increased IFN-γ and IL-12 (both constituting Th1 cytokines) in BALF, but they reduced IL-13, -4, and -5 (all constituting Th2 cytokines), and also inhibited the expression of IL-1ß, IL-6, and TNF-α. The water fraction also inhibited the PI3K/Akt/NF-κB signal pathways in A549 cells. These findings suggest that water fraction extracts of garlic have a clear anti-inflammatory effect on Der p-induced allergic asthma.


Assuntos
Antiasmáticos/farmacologia , Antígenos de Dermatophagoides/imunologia , Alho/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Hipersensibilidade Respiratória/imunologia , Animais , Antiasmáticos/química , Antiasmáticos/isolamento & purificação , Líquido da Lavagem Broncoalveolar , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Modelos Animais de Doenças , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Camundongos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Hipersensibilidade Respiratória/diagnóstico , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/metabolismo , Transdução de Sinais
11.
Eur Rev Med Pharmacol Sci ; 23(18): 8124-8129, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31599440

RESUMO

OBJECTIVE: Samter's triad is the combination of asthma, aspirin sensitization, and nasal polyposis. Few data are available on the use of omalizumab in this disease. The study aimed to describe the impact of omalizumab on clinical and functional parameters and the quality of life of a series of patients with Samter's triad. Moreover, we aimed to provide a review of the literature on this topic. PATIENTS AND METHODS: We retrospectively described four patients with Samter's triad undergoing omalizumab therapy. Clinical, functional, and immunological data of these patients were collected at baseline and follow-up. RESULTS: Reduction of asthma exacerbations and salbutamol rescue therapy were observed in all patients after anti-IgE treatment together with an improvement in the quality of life. A significant improvement in FEV1, FVC, and FEF25-75 was observed. No major side-effects were observed. A total of 14 studies regarding omalizumab in aspirin-exacerbated respiratory diseases were included in the review, comprising 78 patients. All studies reported a good efficacy in improving asthma control; restoration of aspirin tolerance was repeatedly reported. CONCLUSIONS: The results of our case series and review of the literature suggest that omalizumab effectively improves asthma control, lung function tests, and quality of life in patients with Samter's triad.


Assuntos
Antiasmáticos/uso terapêutico , Asma Induzida por Aspirina/tratamento farmacológico , Pólipos Nasais/tratamento farmacológico , Omalizumab/uso terapêutico , Adulto , Idoso , Asma/tratamento farmacológico , Asma/fisiopatologia , Asma Induzida por Aspirina/fisiopatologia , Intervalo Livre de Doença , Hipersensibilidade a Drogas/tratamento farmacológico , Hipersensibilidade a Drogas/fisiopatologia , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Fluxo Máximo Médio Expiratório , Pessoa de Meia-Idade , Pólipos Nasais/fisiopatologia , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/fisiopatologia , Teste de Desfecho Sinonasal , Terapêutica , Capacidade Vital
12.
BMC Pharmacol Toxicol ; 20(1): 57, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511086

RESUMO

BACKGROUND: Poncirin is flavanone derivative (isolated from Poncirus trifoliata) with known pharmacological activities such as anti-tumor, anti-osteoporotic, anti-inflammatory and anti-colitic. The present study aimed to explore the anti-allodynic and anti-hyperalgesic potentials of poncirin in murine models of inflammatory pain. METHODS: The analgesic potential of poncirin was evaluated in formalin-, acetic acid-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced inflammatory pain models in mice. Anti-allodynic and anti-hyperalgesic activities were measured using Von Frey filaments, Randall Selitto, hotplate and cold acetone tests. The serum nitrite levels were determined using Griess reagent. The Quantitative Real-time PCR (qRT-PCR) was performed to assess the effect of poncirin on mRNA expression levels of inflammatory cytokines and anti-oxidant enzymes. RESULTS: Intraperitoneal administration of poncirin (30 mg/kg) markedly reduced the pain behavior in both acetic acid-induced visceral pain and formalin-induced tonic pain models used as preliminary screening tools. The poncirin (30 mg/kg) treatment considerably inhibited the mechanical hyperalgesia and allodynia as well as thermal hyperalgesia and cold allodynia. The qRT-PCR analysis showed noticeable inhibition of pro-inflammatory cytokines (mRNA expression levels of TNF-α, IL-1ß and IL-6) (p < 0.05) in poncirin treated group. Similarly, poncirin treatment also enhanced the mRNA expressions levels of anti-oxidant enzymes such as transcription factor such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) (p < 0.05), heme oxygenase (HO-1) (p < 0.05) and superoxide dismutase (SOD2) (p < 0.05). Chronic treatment of poncirin for 6 days did not confer any significant hepatic and renal toxicity. Furthermore, poncirin treatment did not altered the motor coordination and muscle strength in CFA-induced chronic inflammatory pain model. CONCLUSION: The present study demonstrated that poncirin treatment significantly reduced pain behaviors in all experimental models of inflammatory pain, suggesting the promising analgesic potential of poncirin in inflammatory pain conditions.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Dor Crônica/tratamento farmacológico , Flavonoides/uso terapêutico , Hiperalgesia/tratamento farmacológico , Ácido Acético/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Carragenina/antagonistas & inibidores , Dor Crônica/induzido quimicamente , Modelos Animais de Doenças , Flavonoides/toxicidade , Formaldeído/efeitos adversos , Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade Respiratória/tratamento farmacológico
14.
JCI Insight ; 52019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31184998

RESUMO

Airway neutrophilia occurs in approximately 50% of patients with asthma and is associated with particularly severe disease. Unfortunately, this form of asthma is usually refractory to corticosteroid treatment, and there is an unmet need for new therapies. Pulmonary neutrophilic inflammation is associated with Th17 cells, whose differentiation is controlled by the nuclear receptor, RORγt. Here, we tested whether VTP-938, a selective inverse agonist of this receptor, can reduce disease parameters in animal models of neutrophilic asthma. When administered prior to allergic sensitization through the airway, the RORγt inverse agonist blunted allergen-specific Th17 cell development in lung-draining lymph nodes and attenuated allergen-induced production of IL-17. VTP-938 also reduced pulmonary production of IL-17 and airway neutrophilia when given during the allergen challenge of the model. Finally, in an environmentally relevant model of allergic responses to house dust extracts, VTP-938 suppressed production of IL-17 and neutrophilic inflammation, and also markedly diminished airway hyperresponsiveness. Together, these findings suggest that orally available inverse agonists of RORγt might provide an effective therapy to treat glucocorticoid-resistant neutrophilic asthma.


Assuntos
Asma/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/uso terapêutico , Hipersensibilidade Respiratória/tratamento farmacológico , Animais , Modelos Animais de Doenças , Poeira , Hipersensibilidade/imunologia , Inflamação , Interleucina-17 , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Pneumonia , Células Th17/imunologia
15.
Int Immunopharmacol ; 74: 105706, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31254955

RESUMO

Linalool is a natural product present in fruits and aromatic plants with biological activities. Researchers have reported that the inhalation of linalool exerts anti-inflammatory activities. In this study, we examined the therapeutic effects of linalool on airway inflammation and mucus overproduction in mice with allergic asthma. Oral administration of linalool significantly inhibited the levels of eosinophil numbers, Th2 cytokines and immunoglobulin E (IgE) caused by ovalbumin (OVA) exposure. Linalool exerted preventive effects against the influx of inflammatory cells and mucus hypersecretion in the lung tissues. Linalool also dose-dependently decreased the levels of inducible nitric oxide synthase (iNOS) expression and protein kinase B (AKT) activation in the lung tissues. Linalool effectively downregulated the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) caused by OVA exposure. Furthermore, linalool exerted inhibitory effect on OVA-induced airway hyperresponsiveness (AHR). In the in vitro study, the increased secretion of MCP-1 was attenuated with linalool treatment in lipopolysaccharide (LPS)-stimulated H292 airway epithelial cells. In conclusion, linalool effectively exerts a protective role in OVA-induced airway inflammation and mucus hypersecretion, and its protective effects are closely related to the downregulation of inflammatory mediators and MAPKs/NF-κB signaling.


Assuntos
Monoterpenos Acíclicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Pulmão/metabolismo , Hipersensibilidade Respiratória/tratamento farmacológico , Células Th2/imunologia , Administração Oral , Alérgenos/imunologia , Animais , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulina E/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ovalbumina/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia
16.
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
17.
JCI Insight ; 4(9)2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31045581

RESUMO

Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl ß-muricholic acid (AßM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AßM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.


Assuntos
Alérgenos/imunologia , Asma/imunologia , Inflamação/imunologia , Hipersensibilidade Respiratória/imunologia , Resposta a Proteínas não Dobradas/imunologia , Animais , Ácidos e Sais Biliares/efeitos adversos , Quimiocinas , Citocinas/metabolismo , Feminino , Humanos , Hipersensibilidade , Pulmão/imunologia , Pulmão/metabolismo , Metaplasia/imunologia , Metaplasia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Deficiências na Proteostase , Pyroglyphidae/imunologia , Receptores Acoplados a Proteínas-G/metabolismo , Hipersensibilidade Respiratória/tratamento farmacológico , Ácido Tauroquenodesoxicólico/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos
18.
Toxicol Sci ; 170(2): 462-475, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31070765

RESUMO

Multiple studies have addressed the vital role of Nod-like receptor protein 3(NLRP3)/caspase-1/IL-1ß signaling in asthma. Yet, the role of NLRP3/caspase-1 in toluene diisocyanate (TDI)-induced asthma is still obscure. The aim of this study is to investigate the role of the NLRP3/caspase-1 axis in TDI-induced asthma. Using an established murine model of TDI-induced asthma as described previously, we gave the asthmatic mice a highly selective NLRP3 inhibitor, MCC950, as well as the specific caspase-1 inhibitors VX-765 and Ac-YVAD-CHO for therapeutic purposes. Airway resistance was measured and bronchoalveolar lavage fluid was analyzed. Lungs were examined by histology, immunohistochemistry, Western blotting, and flow cytometry. TDI exposure elevated the expression of NLRP3 and caspase-1 that was coupled with increased airway hyperresponsiveness (AHR), neutrophil-dominated cell infiltration, pronounced goblet cell metaplasia, extensive collagen deposition, and increased TH2/TH17 responses. Both VX-765 and Ac-YVAD-CHO effectively inhibited the activation of caspase-1 in TDI-asthmatic mice that was accompanied by dramatic attenuation of AHR, airway inflammation, and airway remodeling, in addition to a decreased TH2 response and lower levels of IL-18 and IL-1ß. MCC950 blocked the activation of NLRP3 and downregulated protein expression of caspase-1, IL-1ß, and IL-18 in TDI-exposed mice. Furthermore, MCC950 remarkably alleviated AHR, airway inflammation, airway remodeling, and significantly suppressed TH2/TH17 responses. These findings suggested that blockade of the NLRP3/caspase-1 axis effectively prevents the progression of TDI-induced asthma and could be used as therapeutic targets for asthmatics.


Assuntos
Asma/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Serpinas/uso terapêutico , Sulfonas/uso terapêutico , Tolueno 2,4-Di-Isocianato/toxicidade , Proteínas Virais/uso terapêutico , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Asma/induzido quimicamente , Asma/imunologia , Caspase 1/fisiologia , Modelos Animais de Doenças , Interleucina-18/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/fisiologia , Hipersensibilidade Respiratória/tratamento farmacológico , Células Th17/imunologia , Células Th2/imunologia
19.
Am J Physiol Lung Cell Mol Physiol ; 317(3): L305-L316, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31116579

RESUMO

Inhalation of organic dust (OD) from swine confinement facilities leads to pulmonary inflammation, airway hyperresponsiveness, and oxidative stress. In mice, pretreatment with a hydroxyl radical scavenger prevents airway inflammation and airway hyperresponsiveness (AHR) induced by OD exposure. We sought to determine a mechanism by which OD could induce oxidative stress in bronchial epithelial cells. Human bronchial epithelial cells (BEAS-2B or NHBE) were treated with various concentrations of OD, followed by evaluation of intracellular oxidative stress using 2',7'-dichlorofluorescein diacetate (DCFDA). After stimulation with OD, gene expression of antioxidant genes was assessed by real-time quantitative PCR followed by quantification of Nrf2 nuclear translocation using a luciferase reporter assay. Phagocytic markers (CD36 and CD68) were analyzed by FACS. Cells were treated with an actin inhibitor, cytochalasin D, before OD exposure and evaluated for Nrf2 nuclear translocation and DCFDA. Mice were pretreated with sulforaphane, the Nrf2 activator, before OD exposure and evaluated for pulmonary inflammation and airway reactivity. OD induced a time- and concentration-dependent increase in DCFDA. mRNA expression levels of Nrf2-dependent genes and Nrf2 nuclear translocation were increased after OD exposure. OD exposure increased the expression of CD68 and CD36. Cytochalasin D prevented oxidative stress and Nrf2 nuclear translocation after OD. Pretreatment with sulforaphane prevented OD-induced inflammation and AHR while increasing the uptake of OD in bronchial epithelial cells. Bronchial epithelial cells can phagocytose OD, resulting in an increase in endogenous oxidative stress. Nrf2-dependent mechanisms mediate the antioxidant response to OD.


Assuntos
Brônquios/metabolismo , Poeira , Células Epiteliais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Células Epiteliais/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Isotiocianatos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Fagócitos , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/metabolismo
20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA