RESUMEN
BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.
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Dieta Alta en Grasa , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Ratones Endogámicos C57BL , Ratones Transgénicos , Obesidad , Fibrosis Pulmonar , Animales , Masculino , Dieta Alta en Grasa/efectos adversos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Fibrosis Pulmonar/prevención & control , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Inhibidores de PCSK9 , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Ratones Obesos , Proproteína Convertasa 9/metabolismo , Proproteína Convertasa 9/genética , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Hiperreactividad Bronquial/prevención & control , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/fisiopatología , Anticuerpos Monoclonales HumanizadosRESUMEN
Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2>95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 mikroM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor - Nomega-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p<0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p<0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-alpha and IL-1beta in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia, Hyperoxia, Airway hyperreactivity, Resveratrol, Pro-inflammatory cytokines.
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Animales Recién Nacidos , Displasia Broncopulmonar , Modelos Animales de Enfermedad , Estrés Oxidativo , Neumonía , Resveratrol , Animales , Resveratrol/farmacología , Estrés Oxidativo/efectos de los fármacos , Displasia Broncopulmonar/prevención & control , Displasia Broncopulmonar/metabolismo , Neumonía/prevención & control , Neumonía/metabolismo , Neumonía/inducido químicamente , Ratas , Hiperoxia/complicaciones , Hiperoxia/metabolismo , Estilbenos/farmacología , Estilbenos/uso terapéutico , Antioxidantes/farmacología , Hiperreactividad Bronquial/prevención & control , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/fisiopatología , Hiperreactividad Bronquial/inducido químicamente , Ratas Sprague-Dawley , MasculinoRESUMEN
This study was conducted to investigate whether a transient receptor potential ankyrin 1 (TRPA1) antagonist (HC-030031) can reduce airway inflammation and hyperresponsiveness in a murine allergic rhinitis (AR) model. BALB/c mice were sensitized and challenged by ovalbumin (OVA) to induce AR. HC-030031 or vehicle was administrated to mice via intraperitoneal injection prior to OVA challenges. Nose-scratching events, histopathologic alterations of the airways, and bronchial hyperresponsiveness (BHR) were assessed. Differential cells and proinflammatory cytokines in the nasal lavage (NAL) and bronchoalveolar lavage (BAL) fluid were measured. Expressions of TRPA1 in nasal mucosa were examined by immunohistochemistry. TRPA1-expressing vagal neurons were labeled by immunofluorescent staining. HC-030031-treated AR mice had markedly reduced type-2 inflammation in nasal mucosa and ameliorated-nose-scratching events than AR mice received vehicle. HC-030031 treatment also dramatically reduced leucocyte numbers and IL-8 level in the BAL fluid, inhibited lower airway remodeling and fibrosis, and nearly abolished BHR. HC-0300031 treatment significantly inhibited the upregulated number of TRPA1 expressing nasal epithelial cells and TRPA1 expressing sensory neurons, leading to downregulation of SP in both upper and lower airways. Targeting TRPA1 may represent a promising strategy for treating AR and AR-related asthma.
Asunto(s)
Asma/prevención & control , Hiperreactividad Bronquial/prevención & control , Modelos Animales de Enfermedad , Inflamación/prevención & control , Rinitis Alérgica/complicaciones , Canal Catiónico TRPA1/antagonistas & inhibidores , Remodelación de las Vías Aéreas (Respiratorias) , Animales , Asma/etiología , Asma/patología , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/patología , Femenino , Inflamación/etiología , Inflamación/patología , Ratones , Ratones Endogámicos BALB CRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Callicarpa japonica Thunb., as an herbal medicine has been used for the treatment of inflammatory diseases in China and Korea. MATERIALS AND METHODS: Ultra performance liquid chromatography-photodiode array-quadrupole time-of-flight mass spectrometer (UPLC-PDA-QTof MS) was used to detect the major phenylethanoid glycosides in the C. japonica extract. BALB/c mice were intraperitoneally sensitized by ovalbumin (OVA) (on days 0 and 7) and challenged by OVA aerosol (on days 11-13) to induce airway inflammatory response. The mice were also administered with C. japonica Thunb. (CJT) (20 and 40 mg/kg Per oral) on days 9-13. CJT pretreatment was conducted in lipopolysaccharide (LPS)-stimulated RAW264.7 or phorbol 12-myristate 13-acetate (PMA)-stimulated A549 cells. RESULTS: CJT administration significantly reduced the secretion of Th2 cytokines, TNF-α, IL-6, immunoglobulin E (IgE) and histamine, and the recruitment of eosinophils in an OVA-exposed mice. In histological analyses, the amelioration of inflammatory cell influx and mucus secretion were observed with CJT. The OVA-induced airway hyperresponsiveness (AHR), iNOS expression and NF-κB activation were effectively suppressed by CJT administration. In addition, CJT led to the upregulation of HO-1 expression. In an in vitro study, CJT pretreatment suppressed the LPS-induced TNF-α secretion in RAW264.7 cells and attenuated the PMA-induced IL-6, IL-8 and MCP-1 secretion in A549 cells. These effects were accompanied by downregulated NF-κB phosphorylation and by upregulated HO-1 expression. CONCLUSION: These results suggested that CJT has protective activity against OVA-induced airway inflammation via downregulation of NF-κB activation and upregulation of HO-1, suggesting that CJT has preventive potential for the development of allergic asthma.
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Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Asma/prevención & control , Hiperreactividad Bronquial/prevención & control , Callicarpa , Hemo-Oxigenasa 1/metabolismo , Pulmón/efectos de los fármacos , Proteínas de la Membrana/metabolismo , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Células A549 , Animales , Antiasmáticos/aislamiento & purificación , Antiinflamatorios/aislamiento & purificación , Asma/inducido químicamente , Asma/enzimología , Asma/fisiopatología , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/enzimología , Hiperreactividad Bronquial/fisiopatología , Broncoconstricción/efectos de los fármacos , Callicarpa/química , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Pulmón/enzimología , Pulmón/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina , Extractos Vegetales/aislamiento & purificación , Células RAW 264.7 , Transducción de Señal , Regulación hacia ArribaAsunto(s)
Asma , Hiperreactividad Bronquial , Trastornos Respiratorios , Hipersensibilidad Respiratoria , Asma/tratamiento farmacológico , Asma/etiología , Asma/prevención & control , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/prevención & control , Cisteamina/uso terapéutico , HumanosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Myxopyrum serratulum A. W. Hill. (Oleaceae) is a traditionally used Indian medicinal plant for the treatment of cough, asthma and many other inflammatory diseases. AIM OF THE STUDY: In this study, the protective effects of M. serratulum on airway inflammation was investigated in ovalbumin (OVA)-induced murine model of allergic asthma and lipopolysaccharide (LPS)-stimulated inflammation in RAW 264.7 murine macrophages, and the possible mechanisms were elucidated. MATERIALS AND METHODS: The phytochemicals present in the methanolic leaf extract of M. serratulum (MEMS) were identified by reverse phase high performance liquid chromatography (RP-HPLC) analysis. In vitro anti-inflammatory activity of MEMS were evaluated by estimating the levels of nitric oxide (NO), reactive oxygen species (ROS) and cytokines (IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17A, IFN-γ, TNF-α, G-CSF and GM-CSF) in LPS-stimulated RAW 264.7 macrophages. In vivo anti-asthmatic activity of MEMS was studied using OVA-induced murine model. Airway hyperresponsiveness (AHR), was measured; total and differential cell counts, eosinophil peroxidase (EPO), prostaglandin E2 (PGE2), NO, ROS, and cytokines (IL-4, IL-5 and IL-13), were estimated in bronchoalveolar lavage fluid (BALF). Serum total IgE level was measured; and the histopathological changes of lung tissues were observed. The expressions of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in lung tissue homogenates were detected by Western blot. RESULTS: The chromatographic analysis of MEMS identified the presence of gallic acid, protocatechuic acid, catechin, ellagic acid, rutin, p-coumaric acid, quercetin, naringenin and apigenin. MEMS (125 and 250⯵g/mL) dose-dependently reduced the levels of NO, ROS and pro-inflammatory cytokines in LPS-stimulated RAW 264.7 macrophages. MEMS (200 and 400â¯mg/kg, p.o.) significantly (pâ¯<â¯0.05) alleviated AHR; number of inflammatory cells, EPO, PGE2, NO, ROS, and cytokines (IL-4, IL-5 and IL-13) in BALF; serum total IgE and the histopathological changes associated with lung inflammation. Western blot studies showed that MEMS substantially suppressed COX-2 and iNOS protein expressions in the lung tissues of OVA-sensitized/challenged mice. CONCLUSIONS: The present study corroborates for the first time the ameliorative effects of MEMS on airway inflammation by reducing the levels of oxidative stress, pro-inflammatory cytokines and inhibiting COX-2, iNOS protein expressions, thereby validating the ethnopharmacological uses of M. serratulum.
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Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Asma/prevención & control , Hiperreactividad Bronquial/prevención & control , Broncoconstricción/efectos de los fármacos , Pulmón/efectos de los fármacos , Macrófagos/efectos de los fármacos , Oleaceae , Extractos Vegetales/farmacología , Animales , Antiasmáticos/aislamiento & purificación , Antiinflamatorios/aislamiento & purificación , Asma/inmunología , Asma/metabolismo , Asma/fisiopatología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/fisiopatología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/farmacología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/fisiopatología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Oleaceae/química , Ovalbúmina , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Asthma is a common chronic inflammatory disease, which is characterized by airway hyperresponsiveness (AHR), high serum levels of immunoglobulin (Ig)E, and recruitment of various inflammatory cells such as eosinophils and lymphocytes. Korean traditional fermented foods have been reported to exert beneficial effects against allergic diseases such as asthma and atopic dermatitis. In this study, we investigated whether Staphylococcus succinus strain 14BME20 (14BME20) isolated from doenjang, a traditional high-salt-fermented soybean food of Korea, exerts suppressive effects on allergic airway inflammation in a murine model. Mice were orally administered with 14BME20, then sensitized and challenged with ovalbumin as an allergen. Administration of the 14BME20 significantly suppressed AHR and influx of inflammatory cells into the lungs and reduced serum IgE levels. Moreover, the proportion of T helper type 2 (Th2) cells and the production of Th2 cytokines were decreased in 14BME20-treated mice, whereas dendritic cells (DCs) with tolerogenic characteristics were increased. In contrast, oral administration of 14BME20 increased the proportion of CD4+CD25+Foxp3+ regulatory T (Treg) cells and the level of interleukin (IL)-10 in 14BME20-treated mice. Furthermore, 14BME20 induced maturation of tolerogenic DCs, and 14BME20-treated DCs increased Treg cell population in a co-culture system of DCs and CD4+ T cells. The addition of a neutralizing anti-IL-10 mAb to the culture of cells that had been treated with 14BME20 decreased the enhanced Treg cell population, thereby indicating that 14BME20-treated DCs increase Treg cell population via DC-derived IL-10. These results demonstrate that oral administration of 14BME20 suppresses airway inflammation by enhancing Treg responses and suggest that the 14BME20 isolated from doenjang may be a therapeutic agent for allergic asthma.
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Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Microbiología de Alimentos , Interleucina-10/metabolismo , Staphylococcus/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Asma/inmunología , Asma/metabolismo , Asma/patología , Asma/prevención & control , Hiperreactividad Bronquial/patología , Hiperreactividad Bronquial/prevención & control , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Tolerancia Inmunológica , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Mediadores de Inflamación/metabolismo , RatonesRESUMEN
Asthma is a chronic inflammatory disease that involves a variety of cytokines and cells. Interleukin-16 (IL-16) is highly expressed during allergic airway inflammation and is involved in its development. However, its specific mechanism of action remains unclear. In the present study, we used an animal model of ovalbumin (OVA)-induced allergic asthma with mice harboring an IL-16 gene deletion to investigate the role of this cytokine in asthma, in addition to its underlying mechanism. Increased IL-16 expression was observed during OVA-induced asthma in C57BL/6J mice. However, when OVA was used to induce asthma in IL-16-/- mice, a diminished inflammatory reaction, decreased bronchoalveolar lavage fluid (BALF) eosinophil numbers, and the suppression of OVA-specific IgE levels in the serum and BALF were observed. The results also demonstrated decreased levels of T helper type 2 (Th2) and Th17 cytokines upon OVA-induced asthma in IL-16-/- mice. Hence, we confirmed that IL-16 enhances the lung allergic inflammatory response and suggest a mechanism possibly associated with the up-regulation of IgE and the promotion of Th2 and Th17 cytokine production. This work explored the mechanism underlying the regulation of IL-16 in asthma and provides a new target for the clinical treatment of asthma.
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Asma/metabolismo , Hiperreactividad Bronquial/metabolismo , Interleucina-16/metabolismo , Pulmón/metabolismo , Ovalbúmina , Células Th17/metabolismo , Células Th2/metabolismo , Animales , Asma/inmunología , Asma/fisiopatología , Asma/prevención & control , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/fisiopatología , Hiperreactividad Bronquial/prevención & control , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Broncoconstricción , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Interleucina-16/deficiencia , Interleucina-16/genética , Pulmón/inmunología , Pulmón/fisiopatología , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Bazo/inmunología , Bazo/metabolismo , Células Th17/inmunología , Células Th2/inmunologíaRESUMEN
Glucagon has been shown to be beneficial as a treatment for bronchospasm in asthmatics. Here, we investigate if glucagon would prevent airway hyperreactivity (AHR), lung inflammation, and remodeling in a murine model of asthma. Glucagon (10 and 100 µg/Kg, i.n.) significantly prevented AHR and eosinophilia in BAL and peribronchiolar region induced by ovalbumin (OVA) challenge, while only the dose of 100 µg/Kg of glucagon inhibited subepithelial fibrosis and T lymphocytes accumulation in BAL and lung. The inhibitory action of glucagon occurred in parallel with reduction of OVA-induced generation of IL-4, IL-5, IL-13, TNF-α, eotaxin-1/CCL11, and eotaxin-2/CCL24 but not MDC/CCL22 and TARC/CCL17. The inhibitory effect of glucagon (100 µg/Kg, i.n.) on OVA-induced AHR and collagen deposition was reversed by pre-treatment with indomethacin (10 mg/Kg, i.p.). Glucagon increased intracellular cAMP levels and inhibits anti-CD3 plus anti-CD28-induced proliferation and production of IL-2, IL-4, IL-10, and TNF- α from TCD4+ cells in vitro. These findings suggest that glucagon reduces crucial features of asthma, including AHR, lung inflammation, and remodeling, in a mechanism probably associated with inhibition of eosinophils accumulation and TCD4+ cell proliferation and function. Glucagon should be further investigated as an option for asthma therapy.
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Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Hiperreactividad Bronquial/prevención & control , Glucagón/farmacología , Ovalbúmina/farmacología , Neumonía/prevención & control , Animales , Asma/prevención & control , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular/efectos de los fármacos , Quimiocina CCL24/metabolismo , Citocinas/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones Endogámicos , Receptores de Glucagón/metabolismoRESUMEN
Fine particulate matter (PM2.5) can penetrate into alveolar spaces and induce airway inflammation. Recent evidence suggests that the activation of Toll-like receptor 4 (TLR4) signaling may participate in PM2.5-induced acute lung injury. We investigated the effect of VGX-1027, a TLR4 blocker, on PM2.5-induced airway inflammation and bronchial hyperresponsiveness (BHR) in a murine model in vivo and on inflammatory mechanisms in vitro in human airway epithelial cells. Mice were injected intraperitoneally with vehicle (PBS) or VGX-1027 (25â¯mg/kg) one hour before intranasal instillation of vehicle (PBS) or PM2.5 (7.8â¯mg/kg) for two consecutive days and inflammatory events and BHR studied 24â¯h later. Human airway epithelial Beas-2b cells were pretreated with vehicle or VGX-1027 (50⯵M) in vitro one hour before incubation with vehicle or PM2.5 (150â¯ng/ml) for 24â¯h and effects on inflammatory mediators and mechanisms studied. VGX-1027 pretreatment attenuated PM2.5-induced BHR and elevated total and neutrophils, macrophages, lymphocytes and eosinophils numbers in bronchoalveolar lavage (BAL) fluid in vivo. PM2.5-induced BAL fluid inflammatory mediator levels including TNF-α, chemokine (C-X-C motif) ligand1, IL-1ß, IL-6 and IL-18 were reduced by VGX-1027. PM2.5-induced increases in TNF-α, IL-1ß, IL-6 and IL-18 mRNA levels in Beas-2b cells were also reduced by VGX-1027. Mechanistically, VGX-1027 inhibited PM2.5-induced activation of the TLR4-NF-κB-p38 MAPK and NLRP3-caspase-1 pathways as well as the dysregulation of mitochondrial fusion/fission proteins in vivo and in vitro. VGX-1027 may be a potential prophylactic treatment for PM2.5-induced acute lung injury that has airway inflammation, BHR and mitochondrial damage.
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Acetatos/farmacología , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/prevención & control , Oxazoles/farmacología , Material Particulado/farmacología , Animales , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/patología , Caspasa 1/metabolismo , Línea Celular , Citocinas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamasomas/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Inflamación/prevención & control , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismoRESUMEN
Particulate matter (PM) is one of the most important environmental issues in China. This study aimed to explore the correlation between PM2.5 and airway inflammation in healthy rats. The PM2.5 group was given an intranasal instillation of PM2.5 suspension on 15 consecutive days, and each received oral saline from day 16 to 90. The BV intervention group was treated as the PM2.5 exposure group, except that BV instead of saline was given daily. A histopathologic examination was performed to evaluate the airway inflammation. The prevalence and function of Th1/Th2/Treg/Th17 cells were detected by flow cytometry and ELISA. The expression of AhR was detected by western blot and real-time PCR. We found that epithelial damage and increased infiltration of inflammatory cell were present in the airways after PM2.5 exposure; there was an immune imbalance of Th cells in the PM2.5 group; the expression of AhR was increased in the airways after PM2.5 exposure. In the PM2.5 + BV group, we demonstrated alleviated immune imbalance and reduced inflammatory cell infiltration in the airways. Our study showed that exposure to PM2.5 induced airway inflammation. The imbalance of Th1/Th2/Treg/Th17 in PM2.5-induced airway inflammation might be associated with activation of the AhR pathway. Oral BV reduces PM2.5-induced airway inflammation and regulates systemic immune responses in rats.
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Adyuvantes Inmunológicos/farmacología , Contaminantes Atmosféricos/efectos adversos , Hiperreactividad Bronquial/prevención & control , Extractos Celulares/farmacología , Material Particulado/efectos adversos , Neumonía/prevención & control , Células Th17/inmunología , Animales , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/patología , Neumonía/etiología , Neumonía/patología , RatasRESUMEN
Progranulin (PGRN) is a growth factor with multiple biological functions and has been suggested as an endogenous inhibitor of Tumor necrosis factor-α (TNF-α)-mediated signaling. TNF-α is believed to be one of the important mediators of the pathogenesis of asthma, including airway hyperresponsiveness (AHR). In the present study, effects of recombinant PGRN on TNF-α-mediated signaling and antigen-induced hypercontractility were examined in bronchial smooth muscles (BSMs) both in vitro and in vivo. Cultured human BSM cells (hBSMCs) and male BALB/c mice were used. The mice were sensitized and repeatedly challenged with ovalbumin antigen. Animals also received intranasal administrations of recombinant PGRN into the airways 1 h before each antigen inhalation. In hBSMCs, PGRN inhibited both the degradation of IκB-α (an index of NF-κB activation) and the upregulation of RhoA (a contractile machinery-associated protein that contributes to the BSM hyperresponsiveness) induced by TNF-α, indicating that PGRN has an ability to inhibit TNF-α-mediated signaling also in the BSM cells. In BSMs of the repeatedly antigen-challenged mice, an augmented contractile responsiveness to acetylcholine with an upregulation of RhoA was observed: both the events were ameliorated by pretreatments with PGRN intranasally. Interestingly, a significant decrease in PGRN expression was found in the airways of the repeatedly antigen-challenged mice rather than those of control animals. In conclusion, exogenously applied PGRN into the airways ameliorated the antigen-induced BSM hyperresponsiveness, probably by blocking TNF-α-mediated response. Increasing PGRN levels might be a promising therapeutic for AHR in allergic asthma.
Asunto(s)
Asma/fisiopatología , Bronquios/fisiopatología , Hiperreactividad Bronquial/prevención & control , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Músculo Liso/patología , Proteínas Recombinantes/administración & dosificación , Hipersensibilidad Respiratoria/prevención & control , Administración Intranasal , Animales , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/metabolismo , Células Cultivadas , Granulinas , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Músculo Liso/metabolismo , Progranulinas , Hipersensibilidad Respiratoria/etiología , Hipersensibilidad Respiratoria/metabolismo , Transducción de SeñalRESUMEN
Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c-/- ) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c-/- mice with AAD also had reduced numbers of α-smooth muscle actin-positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)-5, IL-13, IL-33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL-5, IL-33 and TNF levels in lung-draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3-positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 from co-cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls. Our data show that Fbln1c may be a therapeutic target in chronic asthma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma/metabolismo , Hiperreactividad Bronquial/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Inflamación/metabolismo , Pulmón/metabolismo , Actinas/metabolismo , Animales , Asma/inmunología , Asma/fisiopatología , Asma/prevención & control , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/fisiopatología , Hiperreactividad Bronquial/prevención & control , Broncoconstricción , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , Células Cultivadas , Técnicas de Cocultivo , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/deficiencia , Proteínas de la Matriz Extracelular/genética , Femenino , Genotipo , Humanos , Inflamación/inmunología , Inflamación/fisiopatología , Inflamación/prevención & control , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/fisiopatología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Interferencia de ARN , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factores de Tiempo , TransfecciónRESUMEN
Levosimendan has a calcium-sensitizing effect in the myocardium and opens ATP-sensitive potassium channels (KATP) in vascular smooth muscle. Because airway smooth muscle also expresses KATP, we characterized the protective potential of levosimendan against increased airway and respiratory tissue resistances. Animals were administered levosimendan alone (group L), levosimendan after pretreatment with a KATP channel blocker (glibenclamide, group LG), glibenclamide only (group G), or solvent alone (dextrose, group C). Airway resistance (Raw), tissue damping, and elastance were determined by forced oscillations under baseline conditions and following provocation tests with intravenous methacholine (MCh). Cardiac output (CO) was assessed by transpulmonary thermodilution. The same sequence of measurements was then repeated during intravenous infusion of levosimendan in groups L and LG or glucose in groups G and C Sham treatments in groups C and G had no effect on lung responsiveness. However, levosimendan treatment in group L elevated CO and inhibited the MCh-induced airway responses [Raw changes of 87.8 ± 83% (SD) vs. 24.4 ± 16% at 4 µg·kg-1·min-1 MCh, P < 0.001], and in G (35.2 ± 12.7 vs. 25.2 ± 12.9%, P < 0.05). The preventive affect of levosimendan against lung constriction vanished in the LG group. Levosimendan exerts a KATP-mediated potential to prevent bronchoconstriction and may prohibit adverse lung peripheral changes both in the small bronchi and the pulmonary parenchyma. The identification of a further pleiotropic property of levosimendan that is related to the pulmonary system is of particular importance for patients with decreased cardiorespiratory reserves for which simultaneous circulatory support is complemented with prevention of adverse respiratory events.
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Broncoconstricción/efectos de los fármacos , Hidrazonas/farmacología , Piridazinas/farmacología , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/prevención & control , Gasto Cardíaco/efectos de los fármacos , Modelos Animales de Enfermedad , Gliburida/farmacología , Hidrazonas/toxicidad , Canales KATP/metabolismo , Pulmón/efectos de los fármacos , Masculino , Cloruro de Metacolina/farmacología , Piridazinas/toxicidad , Conejos , SimendánRESUMEN
We have investigated the effects of slow (GYY4137) and rapid (NaHS) hydrogen sulfide (H2S) releasing donors in lipopolysaccharide (LPS)-induced airway inflammation in mice. LPS (0.1 mg/ml) in 60 µl PBS was administered by the intranasal (i.n.) route and control group received vehicle, whereas the subgroups of mice were treated with i.n. GYY4137 or NaHS. The tracheal reactivity, inflammatory cell count in bronchoalveolar lavage (BAL) fluid and lung histopathology were evaluated in all groups 48 h after LPS/PBS applications. 5-Hydroxytryptamine (5-HT)-induced contraction response in isolated tracheas was enhanced after LPS treatment but carbachol response was not altered. Incubation with atropine (10-6 M), 5-HT2A receptor antagonist ketanserin (10-9-10-7 M) and 5-HT3 receptor antagonist alosetron (10-8 and 10-7 M) prevented 5-HT-induced hyperreactivity whereas 5-HT4 receptor antagonist GR113808 (10-7 M, 10-6 M) did not have any effect in LPS-treated group. Electrical field stimulation (EFS) of isolated tracheas elicited frequency-dependent contractile response, which was not altered by LPS treatment alone but was enhanced in the presence of 5-HT (10-9-10-4 M). This data indicated that 5-HT2A and 5-HT3 receptors, and acetylcholine released from cholinergic nerves were contributing to 5-HT-induced hyperreactivity in the present experiments. The increase in neutrophil count along with cytokine (IL-1ß, TNF-α) levels in bronchoalveolar lavage (BAL) fluid and histopathological changes like paranchymal inflammation and interalveolar thickening were determined in LPS-treated mice. H2S production in lung homogenates were determined by the methylene blue assay, and found to be similar in both LPS and control groups. The experiments conducted after i.n. treatment with H2S donors has shown that only GYY4137 (1 mg/kg) inhibited 5-HT-induced hyperreactivity, and both GYY4137 and NaHS (1 mg/kg) prevented the neutrophil increase in BAL fluid in LPS-induced airway inflammation. IL-1ß increase in BAL fluid was abolished by both GYY4137 and NaHS treatments whereas TNF-α levels remained unchanged. Furthermore, GYY4137 treatment did not have any effect in LPS-induced changes of lung pathology whereas NaHS prevented the paranchymal inflammation. The different H2S releasing pattern of these donors may explain the difference of their effects in this model. Compounds that provide stable H2S levels via local application may be a new therapeutic approach in airway inflammation.
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Sulfuro de Hidrógeno/farmacología , Inflamación/prevención & control , Morfolinas/administración & dosificación , Compuestos Organotiofosforados/administración & dosificación , Sulfuros/administración & dosificación , Administración Intranasal , Animales , Hiperreactividad Bronquial/prevención & control , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Femenino , Inflamación/patología , Interleucina-1beta/metabolismo , Lipopolisacáridos/toxicidad , Pulmón/patología , Ratones , Morfolinas/farmacología , Neutrófilos/metabolismo , Compuestos Organotiofosforados/farmacología , Serotonina/administración & dosificación , Serotonina/metabolismo , Sulfuros/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The Toll-like receptor (TLR) adaptor proteins myeloid differentiating factor 88 (MyD88) and Toll, interleukin-1 receptor and resistance protein (TIR) domain-containing adaptor inducing interferon-ß (TRIF) comprise the two principal limbs of the TLR signalling network. We studied the role of these adaptors in the TLR4-dependent inhibition of allergic airway disease and induction of CD4+ ICOS+ T cells by nasal application of Protollin™, a mucosal adjuvant composed of TLR2 and TLR4 agonists. Wild-type (WT), Trif-/- or Myd88-/- mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges. Protollin's protection against allergic airway disease was TRIF-dependent and MyD88-independent. TRIF deficiency diminished the CD4+ ICOS+ T-cell subsets in the lymph nodes draining the nasal mucosa, as well as their recruitment to the lungs. Overall, TRIF deficiency reduced the proportion of cervical lymph node and lung CD4+ ICOS+ Foxp3- cells, in particular. Adoptive transfer of cervical lymph node cells supported a role for Protollin-induced CD4+ ICOS+ cells in the TRIF-dependent inhibition of airway hyper-responsiveness. Hence, our data demonstrate that stimulation of the TLR4-TRIF pathway can protect against the development of allergic airway disease and that a TRIF-dependent adjuvant effect on CD4+ ICOS+ T-cell responses may be a contributing mechanism.
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Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Asma/prevención & control , Linfocitos T CD4-Positivos/metabolismo , Pulmón/metabolismo , Rinitis Alérgica Estacional/prevención & control , Receptor Toll-Like 4/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/inmunología , Traslado Adoptivo , Animales , Antígenos de Plantas/inmunología , Asma/inmunología , Asma/metabolismo , Asma/fisiopatología , Betula/inmunología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/fisiopatología , Hiperreactividad Bronquial/prevención & control , Broncoconstricción , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Proliferación Celular , Quimiotaxis de Leucocito , Cisteína Endopeptidasas/inmunología , Modelos Animales de Enfermedad , Combinación de Medicamentos , Femenino , Predisposición Genética a la Enfermedad , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Lipopolisacáridos/inmunología , Pulmón/inmunología , Pulmón/fisiopatología , Activación de Linfocitos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Fenotipo , Polen/inmunología , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/metabolismo , Rinitis Alérgica Estacional/fisiopatología , Transducción de Señal , Factores de Tiempo , Receptor Toll-Like 4/inmunologíaRESUMEN
Recent studies have indicated that Thymic stromal lymphopoietin (TSLP) plays an important role in the prevention and treatment of asthma. However the role of TSLP in dysfunction of airway epithelial adherens junctions E-cadherin in house dust mite (HDM)-induced asthma has not been addressed. We hypothesized that TSLP contributed to HDM-induced E-cadherin dysfunction in asthmatic BALB/c mice and 16HBE cells. In vivo, a HDM-induced asthma mouse model was set up for 8weeks. Mice inhaled an anti-TSLP monoclonal antibody (mAb) before HDM. The mice treated with the anti-TSLP mAb ameliorated airway inflammation, the decreasing and aberrant distribution of E-cadherin and ß-catenin as well as phosphorylation(p)-AKT induced by HDM. In vitro, HDM increased the expression of TSLP and E-cadherin dysfunction by PI3K/Akt signaling pathway. The exposure of 16HBE to TSLP resulted in redistribution of E-cadherin. These results indicate that TSLP may be an important contributor in E-cadherin dysfunction of HDM-induced asthma. TSLP signaling blocking shows a protective effect in mice and that the PI3K/Akt pathway may play a role in this process.
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Anticuerpos Monoclonales/uso terapéutico , Asma/inmunología , Cadherinas/metabolismo , Citocinas/fisiología , Pyroglyphidae/inmunología , Administración por Inhalación , Animales , Anticuerpos Monoclonales/administración & dosificación , Asma/terapia , Bronquios/citología , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/prevención & control , Línea Celular , Cromonas/farmacología , Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Citocinas/inmunología , Modelos Animales de Enfermedad , Células Epiteliales , Humanos , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Morfolinas/farmacología , Proteína Oncogénica v-akt/fisiología , Fosfatidilinositol 3-Quinasas/fisiología , Fosforilación , Procesamiento Proteico-Postraduccional , Distribución Aleatoria , Transducción de Señal/inmunología , Organismos Libres de Patógenos Específicos , beta Catenina/análisis , Linfopoyetina del Estroma TímicoRESUMEN
The upper and lower airways behave as a physiological and pathophysiological unit. Subclinical lower airways abnormalities have been described in patients with rhinitis without asthma. These are expressed as bronchial hyperreactivity, abnormalities in lung function and bronchial inflammation, likely as a result of the same phenomenon with systemic inflammatory impact that reaches both the nose and the lungs, which for unknown reasons does not always have a full clinical expression. Patients with rhinitis are at increased risk of developing asthma; therefore, most authors suggest a careful clinical evaluation and monitoring of these patients, especially if symptoms related to inflammation in the lower airways are observed. Although current treatments, such as H1-antihistamines, intranasal steroids and allergen immunotherapy, are quite effective for the management of rhinitis, it is difficult to prove their capacity to prevent asthma among subjects with rhinitis. Evidence showing that the treatment of rhinitis has a favourable impact on indicators of bronchial hyperreactivity and inflammation among subjects that have no symptoms of asthma is more frequently described. In this review, we address the frequency and characteristics of lower airway abnormalities in subjects with rhinitis, both in paediatric and adult populations, their likely predictive value for the development of asthma and the possibilities for therapeutic intervention that could modify the risk of subjects with rhinitis towards presenting asthma.
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Alérgenos/uso terapéutico , Hiperreactividad Bronquial/prevención & control , Desensibilización Inmunológica/métodos , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Pulmón/inmunología , Rinitis Alérgica/terapia , Animales , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Humanos , Pulmón/patología , Rinitis Alérgica/complicaciones , Rinitis Alérgica/inmunología , Rinitis Alérgica/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Selaginella uncinata (Desv.) Spring, known as "Cuiyuncao", is a perennial herb widely distributed in the Southeast Asian countries. In the folk medicine, the local minority commonly use it to treat cough and asthma for centuries. AIM OF THE STUDY: This study was carried out to investigate the protective mechanisms of total flavonoids from S. uncinata (SUF) on airway hyperresponsiveness, cytokine release and bitter taste receptors (T2Rs) signaling with emphasis on inflammatory responses in a rat model of ovalbumin (OVA)-induced asthma. MATERIALS AND METHODS: Rats were sensitized and challenged with OVA to induce typical asthmatic reactions. Pathological changes of lung tissue were examined by HE staining. The serum levels of T cell-associated cytokines (IFN-γ, IL-4, IL-5 and IL-13), total IgE and OVA-specific IgE were determined by enzyme-linked immunosorbent assay (ELISA). Gene expressions of T2R10, IP3R1 and Orai1 in lung tissue were assayed by fluorescence quantitative real-time polymerase chain reaction (FQ-PCR) while protein expressions of NFAT1 and c-Myc were assayed by western blot analysis. The activation of SUF was investigated on tansgentic T2R10-GFP HEK293 cells. RESULTS: SUF treatment attenuated airway hyperresponsiveness and goblet cell hyperplasia compared with OVA-challenged asthmatic rats. The serum levels of IL-4, IL-5 and IL-13 as well as total and OVA-specific IgE were decreased while serum IFN-γ was increased in SUF-treated rats. SUF treatment significantly up-regulated T2R10 gene expression, down-regulated IP3R1 and Orai1 gene expression. SUF further suppressed eotaxin, NFAT1 and c-Myc protein expression in lung tissues of OVA-challenged rats. CONCLUSIONS: These results imply that SUF exerts anti-inflammatory function through the T2R10/IP3R1/NFAT1 dependent signaling pathway, and may warrant further evaluation as a possible agent for the treatment of asthma.
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Antiinflamatorios/farmacología , Asma/prevención & control , Hiperreactividad Bronquial/prevención & control , Broncodilatadores/farmacología , Flavonoides/farmacología , Pulmón/efectos de los fármacos , Ovalbúmina , Extractos Vegetales/farmacología , Selaginellaceae/química , Animales , Antiinflamatorios/aislamiento & purificación , Asma/sangre , Asma/inducido químicamente , Asma/fisiopatología , Hiperreactividad Bronquial/sangre , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/fisiopatología , Broncoconstricción/efectos de los fármacos , Broncodilatadores/aislamiento & purificación , Citocinas/sangre , Modelos Animales de Enfermedad , Flavonoides/aislamiento & purificación , Células HEK293 , Humanos , Inmunoglobulina E/sangre , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Factores de Transcripción NFATC/metabolismo , Proteína ORAI1/metabolismo , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , TransfecciónRESUMEN
Compelling evidences point out a crucial role for extracellular nucleotides such as adenosine triphosphate (ATP) during inflammatory conditions. Once released into the extracellular space, ATP modulates migration, maturation and function of various inflammatory cells via activating of purinergic receptors of the P2Y- and P2X- family. P2RX4 is an ATP-guided ion channel expressed on structural cells such as alveolar epithelial and smooth muscle cells as well as inflammatory cells including macrophages, dendritic cells (DCs) and T cells. P2RX4 has been shown to interact with P2RX7 and promote NLRP3 inflammasome activation. Although P2RX7 has already been implicated in allergic asthma, the role of P2RX4 in airway inflammation has not been elucidated yet. Therefore, we used a selective pharmacological antagonist and genetic ablation to investigate the role of P2RX4 in an ovalbumin (OVA) driven model of allergen-induced airway inflammation (AAI). Both, P2RX4 antagonist 5-BDBD treatment and P2rx4 deficiency resulted in an alleviated broncho alveolar lavage fluid eosinophilia, peribronchial inflammation, Th2 cytokine production and bronchial hyperresponsiveness. Furthermore, P2rx4-deficient bone marrow derived DCs (BMDCs) showed a reduced IL-1ß production in response to ATP accompanied by a decreased P2rx7 expression and attenuated Th2 priming capacity compared to wild type (WT) BMDCs in vitro. Moreover, mice adoptively transferred with P2rx4-deficient BMDCs exhibit a diminished AAI in vivo. In conclusion our data suggests that P2RX4-signaling contributes to AAI pathogenesis by regulating DC mediated Th2 cell priming via modulating IL-1ß secretion and selective P2RX4-antagonists might be a new therapeutic option for allergic asthma.