RESUMEN
Rationale: The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications. Objectives: To conduct a screening of circulating proteins in childhood asthma and to study proteins that emerged from human studies in a mouse model of asthma. Methods: We included 2,264 children from eight birth cohorts from the Mechanisms of the Development of ALLergy project and the Tucson Children's Respiratory Study. In cross-sectional analyses, we tested 46 circulating proteins for association with asthma in the selection stage and carried significant signals forward to a validation and replication stage. As CK (creatine kinase) was the only protein consistently associated with asthma, we also compared whole blood CK gene expression between subjects with and without asthma (n = 249) and used a house dust mite (HDM)-challenged mouse model to gain insights into CK lung expression and its role in the resolution of asthma phenotypes. Measurements and Main Results: As compared with the lowest CK tertile, children in the highest tertile had significantly lower odds for asthma in selection (adjusted odds ratio, 95% confidence interval: 0.31; 0.15-0.65; P = 0.002), validation (0.63; 0.42-0.95; P = 0.03), and replication (0.40; 0.16-0.97; P = 0.04) stages. Both cytosolic CK forms (CKM and CKB) were underexpressed in blood from asthmatics compared with control subjects (P = 0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, Ckb expression was reduced, and after the HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness and reduction of airway mucin. Conclusions: Circulating concentrations and gene expression of CK are inversely associated with childhood asthma. Mouse models support a possible direct involvement of CK in asthma protection via inhibition of airway hyperresponsiveness and reduction of airway mucin.
Asunto(s)
Asma , Hipersensibilidad Respiratoria , Ratones , Animales , Niño , Humanos , Creatina Quinasa/metabolismo , Estudios Transversales , Asma/metabolismo , Pulmón/metabolismo , Hipersensibilidad Respiratoria/complicaciones , Pyroglyphidae , Mucinas/metabolismo , Modelos Animales de EnfermedadRESUMEN
Titanium dioxide nanoparticles (TiO2NPs) are widely used in industrial and medicinal fields and in various consumer products, and their increasing use has led to an increase in the number of toxicity studies; however, studies investigating the underlying toxicity mechanism have been rare. In this study, we evaluated potential toxic effects of TiO2NPs exposure on lungs as well as the development of asthma through the ovalbumin (OVA)-induced mouse model of asthma. Furthermore, we also investigated the associated toxic mechanism. TiO2NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number and level of inflammatory cells and mediators, respectively. OVA-induced asthma exposed mice to TiO2NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with those in non-exposed asthmatic mice. This was also accompanied by increased inflammatory cell infiltration and mucus production in the lung tissues. Additionally, TiO2NPs decreased the expression of B-cell lymphoma 2 (Bcl2) and the expressions of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 were escalated in the lungs of asthmatic mice compared with those in non-exposed asthmatic mice. These responses were consistent with in vitro results obtained using human airway epithelial cells. TiO2NPs treated cells exhibited an increase in the mRNA and protein expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO2NP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiO2NP exposure induced toxicological changes in the respiratory tract and exacerbated the development of asthma via activation of the TXNIP-apoptosis pathway. These results provide insights into the underlying mechanism of TiO2NP-mediated respiratory toxicity.
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Asma/patología , Proteínas Portadoras/genética , Hipersensibilidad/patología , Inflamación/patología , Pulmón/patología , Nanopartículas/toxicidad , Tiorredoxinas/genética , Titanio/toxicidad , Regulación hacia Arriba/genética , Animales , Apoptosis , Asma/sangre , Asma/complicaciones , Asma/genética , Líquido del Lavado Bronquioalveolar , Proteínas Portadoras/metabolismo , Caspasa 3/metabolismo , Recuento de Células , Línea Celular , Fenómenos Químicos , Citocinas/biosíntesis , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hipersensibilidad/sangre , Hipersensibilidad/complicaciones , Hipersensibilidad/genética , Inmunoglobulina E/sangre , Inflamación/sangre , Inflamación/genética , Mediadores de Inflamación/metabolismo , MAP Quinasa Quinasa Quinasa 5/metabolismo , Ratones , Moco/metabolismo , Nanopartículas/ultraestructura , Ovalbúmina , ARN Mensajero/genética , ARN Mensajero/metabolismo , Hipersensibilidad Respiratoria/complicaciones , Tiorredoxinas/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismoRESUMEN
In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from n-hexane extract from leaves of Nectandra leucantha and chemically prepared using oxidative coupling from eugenol, was evaluated in an experimental model of mixed-granulocytic asthma. Initially, in silico studies of biseugenol showed good predictions for drug-likeness, with adherence to Lipinski's rules of five (RO5), good Absorption, Distribution, Metabolism and Excretion (ADME) properties and no alerts for Pan-Assay Interference Compounds (PAINS), indicating adequate adherence to perform in vivo assays. Biseugenol (20 mg·kg-1) was thus administered intraperitoneally (four days of treatment) and resulted in a significant reduction in both eosinophils and neutrophils of bronchoalveolar lavage fluid in ovalbumin-sensitized mice with no statistical difference from dexamethasone (5 mg·kg-1). As for lung function parameters, biseugenol (20 mg·kg-1) significantly reduced airway and tissue damping in comparison to ovalbumin group, with similar efficacy to positive control dexamethasone. Airway hyperresponsiveness to intravenous methacholine was reduced with biseugenol but was inferior to dexamethasone in higher doses. In conclusion, biseugenol displayed antiasthmatic effects, as observed through the reduction of inflammation and airway hyperresponsiveness, with similar effects to dexamethasone, on mixed-granulocytic ovalbumin-sensitized mice.
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Antiasmáticos/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Granulocitos/patología , Éteres Fenílicos/farmacología , Animales , Antiasmáticos/química , Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Asma/complicaciones , Asma/fisiopatología , Disponibilidad Biológica , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , Simulación por Computador , Modelos Animales de Enfermedad , Granulocitos/efectos de los fármacos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Lignanos/química , Lignanos/farmacología , Lignanos/uso terapéutico , Modelos Lineales , Masculino , Ratones Endogámicos BALB C , Éteres Fenílicos/química , Éteres Fenílicos/uso terapéutico , Pruebas de Función Respiratoria , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/tratamiento farmacológico , Hipersensibilidad Respiratoria/fisiopatologíaRESUMEN
INTRODUCTION: Collagen colitis (CC) is a microscopic colitis diagnosed by mucosal biopsy and is extremely rare in children. PATIENT CONCERNS: We reported a child with severe persistent diarrhea that could not be relieved with traditional diarrheal treatment. No abnormalities were found after multiple colonoscopies. DIAGNOSES: A significant increase in total IgE levels was found in the patient's blood. He had a history of mild chronic allergic rhinitis and slightly intermittent wheezing. However, we found that the child had a hyperallergic reaction to multiple respiratory antigens and had mild pulmonary dysfunction. Finally, colonoscopy with biopsy identified the diagnosis of CC. INTERVENTION: Considering that a respiratory allergic reaction was one of the causes of diarrhea, anti-allergic treatment was given to the child, and his severe diarrhea was soon relieved. Corticosteroid treatment was suggested to the patient, but his parents firmly refused steroid therapy. According to the patient's specific allergic reaction to mites, desensitization treatment was finally chosen for him. OUTCOMES: After 1 year of desensitization for dust mites, the patient's respiratory symptoms improved, total IgE levels decreased, autoantibodies declined, and diarrhea did not reoccur. Colonoscopy with biopsy showed a significant improvement in pathology. CONCLUSION: CC in children is rare, and childhood CC induced by a respiratory allergic reaction has not been previously reported. Therefore, this is a special case of CC in a patient who was cured with anti-allergy treatments and desensitization instead of steroid therapy.
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Colitis Colagenosa/diagnóstico , Colitis Colagenosa/etiología , Diarrea/etiología , Hipersensibilidad Respiratoria/complicaciones , Antialérgicos/uso terapéutico , Biopsia , Niño , Enfermedad Crónica , Colitis Colagenosa/terapia , Colonoscopía , Desensibilización Inmunológica , Diarrea/terapia , Humanos , Masculino , Hipersensibilidad Respiratoria/terapiaRESUMEN
INTRODUCTION: Most children with eosinophilic esophagitis (EoE) are atopic, but the impact of atopy on the remission and development of EoE is still unclear. The aim of our study was to determine the impact of atopy on remission of EoE and to describe allergy tests and the choice of treatment for a cohort of EoE children in France. METHODS: All children diagnosed with EoE between January 2013 and June 2018 in the five pediatric centers in the northeast of France were included. Children were divided into two groups according to personal atopic disorders. Histological remission was defined on the basis of an eosinophilic count below 15 eosinophils per high-power field. RESULTS: Among the 49 children included, 38 (78%) were atopic. Allergy tests were performed for 45 children (92%). Rates of sensitization were similar in both groups: 64% had food sensitization and 64% had aeroallergen sensitization. The most commonly attempted first-line therapy was with proton pump inhibitors (63%), followed by swallowed topical steroids (STS) (18%). First-line therapy was not associated with atopic status (P=0.88). Atopic children had a nonsignificant tendency for a higher remission rate after STS (55% vs. 0%, P=0.24) and a higher global remission rate (54% vs. 33%, P=0.18) compared with non-atopic children. CONCLUSION: Allergy testing is relevant in the majority of children with EoE whether or not they have atopic disorders. Atopy seems to be associated with better response to STS. Further studies are needed to determine whether atopic status determines histological response.
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Esofagitis Eosinofílica/terapia , Hipersensibilidad a los Alimentos/complicaciones , Hipersensibilidad Respiratoria/complicaciones , Adolescente , Niño , Preescolar , Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/etiología , Femenino , Estudios de Seguimiento , Hipersensibilidad a los Alimentos/diagnóstico , Hipersensibilidad a los Alimentos/terapia , Francia , Humanos , Lactante , Masculino , Hipersensibilidad Respiratoria/diagnóstico , Hipersensibilidad Respiratoria/terapia , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Aspergilosis/diagnóstico , Quistes/diagnóstico , Laringitis/diagnóstico , Laringoestenosis/diagnóstico , Hipersensibilidad Respiratoria/diagnóstico , Aspergilosis/complicaciones , Aspergilosis/patología , Aspergilosis/cirugía , Aspergillus fumigatus , Niño , Fibrosis Quística/complicaciones , Quistes/patología , Quistes/cirugía , Humanos , Laringitis/complicaciones , Laringitis/patología , Laringitis/cirugía , Laringoscopía , Laringoestenosis/etiología , Laringoestenosis/cirugía , Terapia por Láser , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/patología , Hipersensibilidad Respiratoria/cirugía , Ruidos Respiratorios/etiologíaRESUMEN
Chronic cough is one of the most common complaints for which patients in China seek medical attention. However, there are no nationwide data on the prevalence and socioeconomic burden of chronic cough. Although approximately 50% of Chinese men smoke, the vast majority of patients presenting for evaluation of chronic cough are never smokers. An equal sex distribution and a middle-aged predominance have been observed in the Chinese chronic cough population, despite demonstration of a higher cough reflex sensitivity in females and older patients. The role of air pollution in the distinct age and sex distribution requires further study. In terms of the etiologies of chronic cough in China, cough-variant asthma, upper airway cough syndrome, nonasthmatic eosinophilic bronchitis, and atopic cough are the most common causes, comprising 75.2% to 87.6% of cases across different regions. Chinese Guidelines for Diagnosis and Treatment of Cough were initially published in 2005, and updated in 2009 and 2016. In addition, the China Cough Coalition was established in 2016. Great progress has been made in both cough-related clinical practice and research in recent years, however, there are still challenges ahead. To facilitate optimal management of chronic cough in China, efforts promoting the dissemination and application of published guidelines will be essential, especially in community-based healthcare and in rural regions. As chronic refractory cough has been identified as a huge challenge to clinicians worldwide, continued international cooperation will be essential in optimizing evaluation and management of chronic cough.
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Contaminación del Aire/estadística & datos numéricos , Tos/epidemiología , Fumar/epidemiología , Distribución por Edad , Asma/complicaciones , Bronquitis/complicaciones , China/epidemiología , Enfermedad Crónica , Tos/etiología , Tos/terapia , Eosinofilia/complicaciones , Reflujo Gastroesofágico/complicaciones , Humanos , Aceptación de la Atención de Salud , Guías de Práctica Clínica como Asunto , Prevalencia , Reflejo , Hipersensibilidad Respiratoria/complicaciones , Distribución por SexoRESUMEN
BACKGROUND: Healthcare workers are at risk for occupational chronic hand eczema (CHE) because of frequent handwashing and prolonged use of occlusive gloves. Prevention programs based on skin care education have been shown to be beneficial. We developed and assessed the efficacy of a skin care educational intervention for healthcare workers of our hospital. METHODS: The intervention consisted of two sessions, one week apart, each divided in a theoretical and a practical part, focusing on the skin barrier, types of eczema, risk factors for CHE, hand hygiene measures respectful of the skin, proper use of protective gloves and emollient creams. Its efficacy was assessed by a questionnaire, administered before and after the intervention, investigating the participants' knowledge of risk factors for CHE and risk behaviors. RESULTS: Twenty-three subjects, mostly (65.2%) nurses, took part in the intervention; 60.9% had a self-reported atopic background and 65.2% participants reported a history of CHE. The intervention improved significantly the participants' knowledge on CHE risk factors, i.e. frequent handwashing (P=0.023), surgical scrubbing (P=0.016) and prolonged glove wearing (P=0.022). The frequency of hand washing was significantly reduced (P=0.022). The participants gave a positive unanimous feedback. CONCLUSIONS: Our intervention was effective, by significantly improving the participants' knowledge and by inducing significant behavioral changes. Improving the formulation of alcoholic hand rubs may be a key factor to encourage their use. Coexisting nonoccupational risk behaviors are just as important in the prevention of CHE.
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Dermatitis Profesional/prevención & control , Eccema/prevención & control , Educación Continua , Dermatosis de la Mano/prevención & control , Personal de Salud , Alérgenos/efectos adversos , Dermatitis Atópica/complicaciones , Dermatitis Atópica/genética , Dermatitis Profesional/etiología , Susceptibilidad a Enfermedades , Eccema/etiología , Emolientes/uso terapéutico , Guantes Protectores , Dermatosis de la Mano/etiología , Desinfección de las Manos , Tareas del Hogar , Humanos , Irritantes/efectos adversos , Italia , Actividades Recreativas , Evaluación de Programas y Proyectos de Salud , Hipersensibilidad Respiratoria/complicaciones , Factores de Riesgo , Crema para la Piel , Encuestas y CuestionariosRESUMEN
BACKGROUND: Resveratrol (RSV) has attracted interest as an alternative drug for the treatment of acute lung injury (ALI) and other pulmonary diseases, but its poor oral bioavailability is a limitation. In this study, we employed drug delivery nanotechnology to improve the stability, lung localization and efficacy of orally administered resveratrol to control lung damage leading to ALI. METHODS AND MATERIALS: RSV-loaded lipid-core nanocapsules (RSV-LNCs), prepared by interfacial deposition of biodegradable polymers, were given orally to A/J mice prior to lipopolysaccharide (LPS) intranasal instillation. Inflammatory changes, oxidative stress and lung tissue elastance were assessed 24 h after LPS challenge. RESULTS: RSV-LNCs (5 mg/kg), given 1, 4, 6 or 12 h but not 24 h before provocation, inhibited LPS-induced leukocyte accumulation in the bronchoalveolar fluid (BALF), whereas unloaded nanocapsules (ULNCs) or free RSV (5 mg/kg) were ineffective. RSV-LNCs (2.5-10 mg/kg) but not ULNCs or RSV improved lung function and prevented total leukocyte and neutrophil accumulation equally in both BALF and lung tissue when given 4 h before LPS challenge. Similar findings were seen concerning the generation of a range of pro-inflammatory cytokines such as IL-6, KC, MIP-1α, MIP-2, MCP-1 and RANTES in lung tissue. In addition, only RSV-LNCs inhibited MDA levels and SOD activity in parallel with blockade of the ERK and PI3K/Akt pathways following LPS provocation. CONCLUSION: Nanoformulation of RSV in biodegradable oil-core polymers is an effective strategy to improve the anti-ALI activity of RSV, suggesting that the modified-release formulation of this plant polyphenol may be of great value in clinical conditions associated with ALI and respiratory failure.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/enzimología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Nanocápsulas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Resveratrol/administración & dosificación , Resveratrol/uso terapéutico , Transducción de Señal , Lesión Pulmonar Aguda/complicaciones , Administración Oral , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Pulmón/efectos de los fármacos , Masculino , Ratones Endogámicos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/patología , Resveratrol/farmacologíaRESUMEN
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.
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Asma/complicaciones , Asma/tratamiento farmacológico , Chalconas/uso terapéutico , Estrés Oxidativo , Sustancias Protectoras/uso terapéutico , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/tratamiento farmacológico , Animales , Especificidad de Anticuerpos , Asma/patología , Líquido del Lavado Bronquioalveolar/citología , Adhesión Celular/efectos de los fármacos , Chalconas/farmacología , Quimiocinas/metabolismo , Colágeno/metabolismo , Ciclooxigenasa 2/metabolismo , Daño del ADN , Modelos Animales de Enfermedad , Eosinófilos/efectos de los fármacos , Eosinófilos/patología , Femenino , Glutatión/metabolismo , Células Caliciformes/efectos de los fármacos , Células Caliciformes/patología , Humanos , Hiperplasia , Mediadores de Inflamación/metabolismo , Pulmón/metabolismo , Pulmón/patología , Malondialdehído/metabolismo , Ratones Endogámicos BALB C , Ovalbúmina , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismo , Células THP-1RESUMEN
We measured the effect of Rho-kinase on inflammation and mucus hypersecretion in the airways of mouse models of asthma. Additionally, we aimed to determine if these effects were the result of JNK 1/2-AP1 pathway inhibition.We sensitized and challenged female C57BL/6 mice using house dust mites (HDM) followed by treatment with an inhibitor of Rho-kinase. Lung tissue was harvested to evaluate inflammation and mucus secretion in the airways of asthma mice. Cytokine expression in broncho-alveolar lavage fluid (BALF) was established by ELISA and airway responsiveness, and was determined by the invasive lung function test. JNK1/2, p-JNK1/2, AP-1, and p-AP-1 protein expression was determined by Western blot analysis. Asthma model mice that were treated with Rho-kinase inhibitor showed a significantly decrease in inflammation score, inflammatory cells, and airway responsiveness. Additionally, we found that IL-13 expressions in BALF and mucus secretion were decreased in HDM-challenged mice treated with Rho-kinase inhibitor. Furthermore, Rho-kinase inhibitor treatment decreased the expression of JNK1/2 and AP-1 phosphorylation. Our findings indicated that the Rho-kinase inhibitor decreased HDM-induced mucus secretion as well as airway inflammation in asthma mice through regulation of the JNK1/2-AP-1 pathway.
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Regulación hacia Abajo , Inflamación/patología , Interleucina-13/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Moco/metabolismo , Transducción de Señal , Factor de Transcripción AP-1/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Asma/complicaciones , Asma/parasitología , Asma/patología , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Femenino , Ratones Endogámicos C57BL , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pyroglyphidae/fisiología , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/parasitología , Transducción de Señal/efectos de los fármacos , Quinasas Asociadas a rho/metabolismoRESUMEN
Importance: Rhinovirus infection in early life, particularly with allergic sensitization, is associated with higher risks of developing recurrent wheeze and asthma. While emerging evidence links different rhinovirus species (eg, rhinovirus C) to a higher severity of infection and asthma exacerbation, to our knowledge, little is known about longitudinal associations of rhinovirus C infection during infancy with subsequent morbidities. Objective: To examine the association of different viruses (respiratory syncytial virus [RSV], rhinovirus species) in bronchiolitis with risks of developing recurrent wheeze. Design, Setting, and Participants: This multicenter prospective cohort study of infants younger than 1 year who were hospitalized for bronchiolitis was conducted at 17 hospitals across 14 US states during 3 consecutive fall to winter seasons (2011-2014). Exposures: Major causative viruses of bronchiolitis, including RSV (reference group) and 3 rhinovirus species (rhinovirus A, B, and C). Main Outcomes and Measures: Development of recurrent wheeze (as defined in national asthma guidelines) by age 3 years. Results: This analytic cohort comprised 716 infants who were hospitalized for RSV-only or rhinovirus bronchiolitis. The median age was 2.9 months (interquartile range, 1.6-3.8 months), 541 (76%) had bronchiolitis with RSV only, 85 (12%) had rhinovirus A, 12 (2%) had rhinovirus B, and 78 (11%) had rhinovirus C infection. Overall, 231 (32%) developed recurrent wheeze by age 3 years. In the multivariable Cox model, compared with infants with RSV-only infection, the risk of recurrent wheeze was not significantly different in those with rhinovirus A or B (rhinovirus A: hazard ratio [HR], 1.27; 95% CI, 0.86-1.88; rhinovirus B: HR, 1.39; 95% CI, 0.51-3.77; both P > .10). By contrast, infants with rhinovirus C had a significantly higher risk (HR, 1.58; 95% CI, 1.08-2.32). There was a significant interaction between virus groups and IgE sensitization on the risk of recurrent wheeze (P for interaction < .01). Only infants with both rhinovirus C infection and IgE sensitization (to food or aeroallergens) during infancy had significantly higher risks of recurrent wheeze (HR, 3.03; 95% CI, 1.20-7.61). Furthermore, compared with RSV-only, rhinovirus C infection with IgE sensitization was associated with significantly higher risks of recurrent wheeze with subsequent development of asthma at age 4 years (HR, 4.06; 95% CI, 1.17-14.1). Conclusions and Relevance: This multicenter cohort study of infants hospitalized for bronchiolitis demonstrated between-virus differences in the risk of developing recurrent wheeze. Infants with rhinovirus C infection, along with IgE sensitization, had the highest risk. This finding was driven by the association with a subtype of recurrent wheeze: children with subsequent development of asthma.
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Bronquiolitis Viral/complicaciones , Infecciones por Coxsackievirus/complicaciones , Enterovirus/inmunología , Hipersensibilidad a los Alimentos/complicaciones , Inmunoglobulina E/sangre , Hipersensibilidad Respiratoria/complicaciones , Ruidos Respiratorios/etiología , Asma/etiología , Biomarcadores/sangre , Bronquiolitis Viral/inmunología , Preescolar , Infecciones por Coxsackievirus/inmunología , Femenino , Estudios de Seguimiento , Hipersensibilidad a los Alimentos/sangre , Hipersensibilidad a los Alimentos/diagnóstico , Hipersensibilidad a los Alimentos/inmunología , Humanos , Lactante , Masculino , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Recurrencia , Hipersensibilidad Respiratoria/sangre , Hipersensibilidad Respiratoria/diagnóstico , Hipersensibilidad Respiratoria/inmunología , Infecciones por Virus Sincitial Respiratorio/complicaciones , Infecciones por Virus Sincitial Respiratorio/inmunología , Factores de RiesgoRESUMEN
BACKGROUND: Environmental tobacco smoke (ETS) is a known risk factor for severe respiratory syncytial virus (RSV) infections, yet the mechanisms of ETS/RSV comorbidity are largely unknown. Cystathionine γ-lyase regulates important physiological functions of the respiratory tract. METHODS: We used mice genetically deficient in the cystathionine γ-lyase enzyme (CSE), the major H2S-generating enzyme in the lung to determine the contribution of H2S to airway disease in response to side-stream tobacco smoke (TS), and to TS/RSV co-exposure. RESULTS: Following a 2-week period of exposure to TS, CSE-deficient mice (KO) showed a dramatic increase in airway hyperresponsiveness (AHR) to methacholine challenge, and greater airway cellular inflammation, compared with wild-type (WT) mice. TS-exposed CSE KO mice that were subsequently infected with RSV exhibited a more severe clinical disease, airway obstruction and AHR, enhanced viral replication, and lung inflammation, compared with TS-exposed RSV-infected WT mice. TS-exposed RSV-infected CSE KO mice had also a significant increase in the number of neutrophils in bronchoalveolar lavage fluid and increased levels of inflammatory cytokines and chemokines. CONCLUSION: This study demonstrates the critical contribution of the H2S-generating pathway to airway reactivity and disease following exposure to ETS alone or in combination with RSV infection.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Cistationina gamma-Liasa/deficiencia , Pulmón/fisiopatología , Pulmón/virología , Hipersensibilidad Respiratoria/complicaciones , Infecciones por Virus Sincitial Respiratorio/complicaciones , Contaminación por Humo de Tabaco/efectos adversos , Animales , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Sulfuro de Hidrógeno/química , Inflamación/etiología , Masculino , Cloruro de Metacolina , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/citología , Hipersensibilidad Respiratoria/virología , Virus Sincitiales RespiratoriosRESUMEN
Platelets modulate asthma pathogenesis by forming the platelet-eosinophil aggregation (PEA), which facilitates the activation of eosinophils. Platelets exhibit the purinergic receptor (P2Y12R), which responds to cysteinyl leukotriene E4 (LTE4 ). We have suggested that the combination of an antiplatelet drug (clopidogrel, [Clo]) and montelukast (Mon) would synergistically suppress asthma. BALB/c mice were intraperitoneally sensitized with ovalbumin (OVA) on days 0 and 14 and subsequently challenged on days 28-30 and 42-44. Mice were administered with Clo (10 mg/kg), Mon (10 mg/kg) or both drugs (Clo/Mon) orally 30 minutes before the OVA (1%) challenge on days 42-44. Mice were assayed for airway hyper-responsiveness (AHR) to methacholine and airway inflammation. Clopidogrel and montelukast attenuated the increased AHR; the combined treatment was more effective than a single treatment for total and eosinophil counts (all P < 0.05). Levels of interleukin (IL)-4, IL-5, IL-13, platelet factor 4, eosinophil peroxidase and LTE4 increased in the bronchoalveolar lavage fluid of asthmatic mice, but these levels decreased in mice treated with Clo/Mon (all P < 0.05). Goblet cell hyperplasia decreased in response to Clo/Mon. Mouse platelets and eosinophils were isolated and co-cultured for an in vitro assay with 10 µmol/L adenosine diphosphate (ADP), LTE4 (200 nmol/L), Mon (1 µmol/L), Clo (1 µmol/L) and Clo/Mon (1 µmol/L). Flow cytometry revealed that the increased formation of the PEA (%) was fully mediated by ADP and partly mediated by LTE4 . Clo/Mon reduced ADP-induced PEA formation and P-selectin expression (P < 0.05). In conclusion, Clo/Mon synergistically relieved asthma by inhibiting ADP-mediated PEA formation.
Asunto(s)
Acetatos/uso terapéutico , Asma/tratamiento farmacológico , Clopidogrel/uso terapéutico , Quinolinas/uso terapéutico , Adenosina Difosfato/farmacología , Animales , Asma/sangre , Asma/fisiopatología , Biomarcadores/metabolismo , Líquido del Lavado Bronquioalveolar , Agregación Celular/efectos de los fármacos , Quimiocinas/metabolismo , Ciclopropanos , Citocinas/metabolismo , Sinergismo Farmacológico , Eosinófilos/metabolismo , Eosinófilos/patología , Femenino , Inflamación/patología , Mediadores de Inflamación/metabolismo , Recuento de Leucocitos , Leucotrieno E4/sangre , Leucotrieno E4/metabolismo , Pulmón/patología , Ratones Endogámicos BALB C , Moco/metabolismo , Activación Plaquetaria/efectos de los fármacos , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/fisiopatología , Sulfuros , Células Th2/metabolismoRESUMEN
Our previous study showed that neonatal S. pneumoniae infection aggravated airway inflammation and airway hyperresponsiveness (AHR) in an OVA-induced allergic asthma model. As airway smooth muscle (ASM) plays a pivotal role in AHR development, we aim to investigate the effects of neonatal S. pneumoniae pneumonia on ASM structure and AHR development. Non-lethal neonatal pneumonia was established by intranasally infecting 1-week-old BALB/C mice with the S. pneumoniae strain D39. Five weeks after infection, the lungs were collected to assess the levels of α-SMA and the contractile proteins of ASM. Our results indicate that neonatal S. pneumoniae pneumonia significantly increased adulthood lung α-SMA and SMMHC proteins production and aggravated airway inflammatory cells infiltration and cytokines release. In addition, the neonatal S. pneumoniae pneumonia group had significantly higher Penh values compared to the uninfected controls. These data suggest that neonatal S. pneumoniae pneumonia promoted an aberrant ASM phenotype and AHR development in mice model.
Asunto(s)
Pulmón/metabolismo , Músculo Liso/metabolismo , Neumonía/genética , Hipersensibilidad Respiratoria/genética , Actinas/genética , Animales , Animales Recién Nacidos , Líquido del Lavado Bronquioalveolar/microbiología , Modelos Animales de Enfermedad , Humanos , Pulmón/microbiología , Pulmón/patología , Ratones , Músculo Liso/microbiología , Músculo Liso/patología , Fenotipo , Neumonía/complicaciones , Neumonía/microbiología , Neumonía/patología , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/microbiología , Hipersensibilidad Respiratoria/patología , Streptococcus pneumoniae/patogenicidadRESUMEN
In the general population, particularly in individuals with asthma, cough is a common symptom, often reported after exertion, although regular exercise may be associated with a reduction in the prevalence of cough. In athletes, exercise-induced cough is also a particularly frequent symptom. The main etiologies of cough in athletes are somewhat similar to non-athletes, including asthma/airway hyperresponsiveness, upper airways disorders such as allergic or non-allergic rhinitis, and exercise-induced laryngeal obstruction, although these conditions are more frequently observed in athletes. In these last, this symptom can also be related to the high ventilation and heat exchange experienced during exercise, particularly during exposure to cold/dry air or pollutants. However, gastroesophageal reflux, a common cause of cough in the general population, despite being highly prevalent in athletes, has not been reported as a main cause of cough in athletes. Cough may impair quality of life, sleep and exercise performance in the general population and probably also in athletes, although there are few data on this. The causes of cough should be documented through a systematic evaluation, the treatment adapted according to identified or most probable cough etiology and pattern of presentation, while respecting sports anti-doping regulations. More research is needed on exercise-induced persistent cough in the athlete to determine its pathophysiology, optimal management and consequences.
Asunto(s)
Atletas , Tos/etiología , Ejercicio Físico , Obstrucción de las Vías Aéreas/complicaciones , Obstrucción de las Vías Aéreas/etiología , Asma Inducida por Ejercicio/complicaciones , Tos/fisiopatología , Humanos , Prevalencia , Calidad de Vida , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/etiologíaRESUMEN
BACKGROUND: Most patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD) suffer from recurrence of nasal polyps. However, little is known about the specific cellular and molecular mechanisms contributing to the pathogenesis of nasal polyp development in patients with NERD in particular, especially at baseline when cyclooxygenase 1 inhibitors are not present. The objectives of this study were to identify proteins involved in the pathogenesis of nasal polyps in patients with NERD. METHODS: We collected nasal polyp tissue from patients with NERD and from patients with aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP). Protein profiles were analyzed by 2-dimensional electrophoresis and identified several proteins, including L-plastin, as highly expressed. We examined L-plastin and tissue factor (TF) expression by immunohistochemical and immunofluorescence analyses. To examine the role of L-plastin in eosinophils, we knocked down L-plastin expression in Eol-1 cells by using siRNA transfection. RESULTS: L-plastin protein levels in nasal polyp tissue were increased in patients with NERD relative to those in patients with aspirin tolerant CRSwNP. Immunofluorescence analysis revealed that L-plastin was dominantly expressed in eosinophils and L-plastin and TF were co-expressed in eosinophils in NERD nasal polyp tissue. Knockdown of L-plastin in Eol-1 cells disrupted the cell surface distribution of TF by stimulation with granulocyte macrophage colony-stimulating factor. CONCLUSION: Increased expression of L-plastin by eosinophils may contribute to abnormal fibrin deposition through TF translocation to the eosinophil cell surface in NERD nasal polyp tissue, which in turn may contribute to the pathogenesis of NERD.
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Antiinflamatorios no Esteroideos/efectos adversos , Regulación de la Expresión Génica , Glicoproteínas de Membrana/genética , Proteínas de Microfilamentos/genética , Pólipos Nasales/complicaciones , Pólipos Nasales/genética , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/etiología , Endotelio/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Femenino , Fibrina/metabolismo , Humanos , Inmunohistoquímica , Masculino , Glicoproteínas de Membrana/metabolismo , Proteínas de Microfilamentos/metabolismo , Pólipos Nasales/inmunología , ARN Interferente Pequeño/genética , Tromboplastina/metabolismoRESUMEN
Interleukin (IL)-37 has been described as a negative regulator of immune responses and is critical for asthma pathogenesis, but the mechanisms behind the protective role of IL-37 against allergic asthma are less well understood. We show here that IL-37 administered intranasally inhibited house dust mite (HDM)-induced chronic airway eosinophilic inflammation, goblet cell hyperplasia, peribronchial collagen deposition and airway hyperresponsiveness (AHR) to methacholine. In contrast to a weakened Th2 response in the lung that was characterized by the downregulation of Th2-associated cytokines and chemokines in IL-37-treated mice, IL-37 has no effect on relevant markers of systemic Th2 immune including serum immunoglobulins expression and in vitro production of Th2-associated cytokines by splenocytes on HDM recall. We demonstrated that the production of thymic stromal lymphopoietin (TSLP) in the lung tissue was associated with IL-37. Importantly, compared with IL-37 alone, TSLP coadministration with IL-37 restored HDM-induced airway inflammation and structural alterations, increased AHR to methacholine and promoted Th2-associated cytokine production. We further found that IL-37 inhibited the induction of TSLP expression by the main antigen of house dust mite, Der p1, by suppressing NF-κB and extracellular signal regulated kinase 1/2 (ERK1/2) activation in human bronchial epithelial (16-HBE) cells in vitro. These data highlight the importance of TSLP in IL-37-mediated protective role in asthma. IL-37 might represent a useful innovative and alternative therapy to control TSLP production in the airway.
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Asma/tratamiento farmacológico , Citocinas/metabolismo , Hipersensibilidad/dietoterapia , Interleucina-1/uso terapéutico , Sistema de Señalización de MAP Quinasas , FN-kappa B/metabolismo , Pyroglyphidae/fisiología , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Animales , Asma/complicaciones , Asma/inmunología , Asma/fisiopatología , Línea Celular , Enfermedad Crónica , Citocinas/administración & dosificación , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/parasitología , Femenino , Humanos , Hipersensibilidad/complicaciones , Hipersensibilidad/inmunología , Hipersensibilidad/fisiopatología , Interleucina-1/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos BALB C , Pyroglyphidae/efectos de los fármacos , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/fisiopatología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Linfopoyetina del Estroma TímicoRESUMEN
In asthma, airway nerve dysfunction leads to excessive bronchoconstriction and cough. It is well established that eosinophils alter nerve function and that airway eosinophilia is present in 50 to 60% of asthmatics. However, the effects of eosinophils on airway nerve structure have not been established. We tested whether eosinophils alter airway nerve structure and measured the physiological consequences of those changes. Our results in humans with and without eosinophilic asthma showed that airway innervation and substance P expression were increased in moderate persistent asthmatics compared to mild intermittent asthmatics and healthy subjects. Increased innervation was associated with a lack of bronchodilator responsiveness and increased irritant sensitivity. In a mouse model of eosinophilic airway inflammation, the increase in nerve density and airway hyperresponsiveness were mediated by eosinophils. Our results implicate airway nerve remodeling as a key mechanism for increased irritant sensitivity and exaggerated airway responsiveness in eosinophilic asthma.
Asunto(s)
Asma/patología , Eosinófilos/patología , Pulmón/inervación , Adulto , Anciano , Animales , Asma/sangre , Asma/complicaciones , Asma/fisiopatología , Broncoconstricción/efectos de los fármacos , Broncodilatadores/farmacología , Eosinófilos/efectos de los fármacos , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neuronas/efectos de los fármacos , Calidad de Vida , Reflejo/efectos de los fármacos , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/patología , Hipersensibilidad Respiratoria/fisiopatología , Sustancia P/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Various allergenic proteins are produced by house dust mites (HDM). However, the allergenicity and clinical implications of these allergens are unknown. OBJECTIVE: The purpose of this study was to identify allergens in Dermatophagoides farinae and elucidate the sensitization profiles to these in Korean patients suffering from respiratory (allergic rhinitis and/or asthma) and atopic dermatitis symptoms. METHODS: IgE reactivities in sera from 160 HDM allergy patients were analysed by one- and two-dimensional gel electrophoresis and immunoblotting. IgE-reactive components were identified by liquid chromatography-coupled electrospray ionization-tandem mass spectrometry. Nine recombinant mite allergens (Der f 1, Der f 2, Der f 10, Der f 11, Der f 13, Der f 14, Der f 30, Der f 32 and Der f Alt a 10) were produced, and the IgE reactivity in sera to each was determined by ELISAs. RESULTS: Der f 1 and Der f 2 were recognized by IgE in serum samples from 88.1% and 78.1% of all patients, respectively. Patients with respiratory allergies were mainly sensitized to these major allergens, whereas patients with atopic dermatitis symptoms showed polysensitization to major and minor allergen components (including Der f 11, Der f 13, Der f 14, Der f 32 and Der f Alt a 10). CONCLUSIONS: Patients with respiratory allergic disease sensitize to major allergen components of HDM. Those with atopic dermatitis were sensitized to a broader range of minor allergen components of HDM (Der f 11, Der f 13, Der f 14, Der f 32 and Der f Alt a 10).