RESUMEN
RATIONALE: Traffic-related air pollution has been shown to augment allergy and airway disease. However, the enhancement of allergenic effects by diesel exhaust in particular is unproven in vivo in the human lung, and underlying details of this apparent synergy are poorly understood. OBJECTIVE: To test the hypothesis that a 2â h inhalation of diesel exhaust augments lower airway inflammation and immune cell activation following segmental allergen challenge in atopic subjects. METHODS: 18 blinded atopic volunteers were exposed to filtered air or 300â µg PM(2.5)/m(3) of diesel exhaust in random fashion. 1â h post-exposure, diluent-controlled segmental allergen challenge was performed; 2â days later, samples from the challenged segments were obtained by bronchoscopic lavage. Samples were analysed for markers and modifiers of allergic inflammation (eosinophils, Th2 cytokines) and adaptive immune cell activation. Mixed effects models with ordinal contrasts compared effects of single and combined exposures on these end points. RESULTS: Diesel exhaust augmented the allergen-induced increase in airway eosinophils, interleukin 5 (IL-5) and eosinophil cationic protein (ECP) and the GSTT1 null genotype was significantly associated with the augmented IL-5 response. Diesel exhaust alone also augmented markers of non-allergic inflammation and monocyte chemotactic protein (MCP)-1 and suppressed activity of macrophages and myeloid dendritic cells. CONCLUSION: Inhalation of diesel exhaust at environmentally relevant concentrations augments allergen-induced allergic inflammation in the lower airways of atopic individuals and the GSTT1 genotype enhances this response. Allergic individuals are a susceptible population to the deleterious airway effects of diesel exhaust. TRIAL REGISTRATION NUMBER: NCT01792232.
Asunto(s)
Alérgenos/toxicidad , Gasolina/toxicidad , Hipersensibilidad/inmunología , Exposición por Inhalación/efectos adversos , Hipersensibilidad Respiratoria/inmunología , Emisiones de Vehículos/toxicidad , Adulto , Biomarcadores/análisis , Lavado Broncoalveolar , Broncoscopía , Quimiocina CCL2/inmunología , Proteína Catiónica del Eosinófilo/inmunología , Eosinófilos/inmunología , Femenino , Genotipo , Glutatión Transferasa/genética , Glutatión Transferasa/inmunología , Humanos , Inmunoglobulina E/inmunología , Inflamación/inmunología , Interleucina-5/inmunología , Interleucina-8/inmunología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Hipersensibilidad Respiratoria/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: Airway epithelial cells represent the first line of defence against inhaled insults, including air pollution. Air pollution can activate innate immune signalling in airway epithelial cells leading to the production of soluble mediators that can influence downstream inflammatory cells. Our objective was to develop and validate a model of dendritic cell exposure to airway epithelial cell-conditioned media. After establishing the model, we explored how soluble mediators released from airway epithelial cells in response to air pollution influenced the phenotype of dendritic cells. METHODS: Human airway epithelial cells were cultured under control and urban particulate matter (PM10) exposure conditions with or without pharmacological inhibitors of the uric acid pathway. Culture supernatants were collected for conditioned media experiments with peripheral blood mononuclear cell-derived dendritic cells analysed by flow cytometry. RESULTS: Monocytes derived from peripheral blood mononuclear cells cultured in interleukin-4 and granulocyte macrophage colony stimulating factor differentiated into immature dendritic cells that phenotypically differentiated into mature dendritic cells in response to conditioned media from phorbol myristate acetate-activated THP-1 monocytes. Exposure of immature dendritic cells to conditioned media from airway epithelial cells exposed to PM10 resulted in dendritic cell maturation that was independent of uric acid. CONCLUSIONS: We present a conditioned media model useful for interrogating the contribution of soluble mediators produced by airway epithelial cells to dendritic cell phenotype and function. Furthermore, we demonstrate that PM10 exposure induces airway epithelial cell production of soluble mediators that induce maturation of dendritic cells independent of uric acid.
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Medios de Cultivo Condicionados/farmacología , Células Dendríticas/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Modelos Biológicos , Material Particulado/farmacología , Sistema Respiratorio/efectos de los fármacos , Ácido Úrico/metabolismo , Adulto , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Células Dendríticas/patología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Técnicas In Vitro , Interleucina-4/farmacología , Masculino , Fenotipo , Reproducibilidad de los Resultados , Sistema Respiratorio/metabolismo , Sistema Respiratorio/patologíaAsunto(s)
Adiponectina/inmunología , Antígenos de Plantas/inmunología , Asma/inmunología , Enfermedades Profesionales/inmunología , Esputo/inmunología , Thuja/inmunología , Adulto , Asma/fisiopatología , Índice de Masa Corporal , Pruebas de Provocación Bronquial , Polvo/inmunología , Eosinofilia/inmunología , Eosinofilia/fisiopatología , Volumen Espiratorio Forzado , Humanos , Lignanos/administración & dosificación , Masculino , Cloruro de Metacolina/administración & dosificación , Persona de Mediana Edad , Naftoles/administración & dosificación , Enfermedades Profesionales/fisiopatología , Exposición Profesional/efectos adversos , Esputo/citología , Adulto JovenRESUMEN
PURPOSE: To identify exposure-related knowledge, attitudes and behaviors of individuals occupationally exposed to diesel exhaust (DE); to reveal strengths, knowledge gaps and misperceptions therein. METHODS: A Mental Models approach was used to gather information about current scientific understanding of DE exposure hazards and the ways in which exposure can be reduced. Thirty individuals in British Columbia who were regularly exposed to occupational DE were interviewed. The audio was recorded and transcribed. Data was grouped together and examined to draw out themes around DE awareness, hazard assessment and risk reduction behaviors. These themes were then compared and contrasted with existing grey and research literature in order to reveal strengths, gaps and misperceptions regarding DE exposure. RESULTS: Study participants were aware and concerned about their exposure to DE but had incomplete and sometimes incorrect understanding of exposure pathways, health effects, and effective strategies to reduce their exposures. The perceived likelihood of exposure to DE was significantly greater compared to that of other work hazards (p<0.01), whereas the difference for their perceived severity of consequences was not significant. There was no universally perceived main source of information regarding DE, and participants generally distrusted sources of information based on their past experience with the source. Most of the actions that were taken to address DE exposure fell into the area of administrative controls such as being aware of sources of DE and avoiding these sources. CONCLUSIONS: This study of the knowledge, attitude, and behavior of those occupationally exposed to DE found, most notably, that more education and training and the creation of a health effects inventory regarding DE exposure were desired.
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Gasolina , Conocimientos, Actitudes y Práctica en Salud , Exposición Profesional , Emisiones de Vehículos/toxicidad , Adulto , Colombia Británica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Salud LaboralRESUMEN
Patient- and stakeholder-oriented research is vital to improving the relevance of research. The authors aimed to identify the 10 most important research priorities of patients, caregivers, and healthcare providers (family physicians, nurses, nurse practitioners, pharmacists, and dietitians) for hypertension management. Using the James Lind Alliance approach, a national web-based survey asked patients, caregivers, and care providers to submit their unanswered questions on hypertension management. Questions already answered from randomized controlled trial evidence were removed. A priority setting process of patient, caregiver, and healthcare providers then ranked the final top 10 research priorities in an in-person meeting. There were 386 respondents who submitted 598 questions after exclusions. Of the respondents, 78% were patients or caregivers, 29% lived in rural areas, 78% were aged 50 to 80 years, and 75% were women. The 598 questions were distilled to 42 unique questions and from this list, the top 10 research questions prioritized included determining the combinations of healthy lifestyle modifications to reduce the need for antihypertensive medications, stress management interventions, evaluating treatment strategies based on out-of-office blood pressure compared with conventional (office) blood pressure, education tools and technologies to improve patient motivation and health behavior change, management strategies for ethnic groups, evaluating natural and alternative treatments, and the optimal role of different healthcare providers and caregivers in supporting patients with hypertension. These priorities can be used to guide clinicians, researchers, and funding bodies on areas that are a high priority for hypertension management research for patients, caregivers, and healthcare providers. This also highlights priority areas for improved knowledge translation and delivering patient-centered care.
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Cuidadores , Personal de Salud , Hipertensión , Manejo de Atención al Paciente/métodos , Investigación Biomédica/organización & administración , Canadá/epidemiología , Cuidadores/psicología , Conocimientos, Actitudes y Práctica en Salud , Personal de Salud/psicología , Personal de Salud/estadística & datos numéricos , Prioridades en Salud , Humanos , Hipertensión/epidemiología , Hipertensión/terapiaRESUMEN
BACKGROUND: Inhalation of diesel exhaust (DE) at moderate concentrations causes increased airway responsiveness in asthmatics and increased airway resistance in both healthy and asthmatic subjects, but the effect of baseline airway responsiveness and anti-oxidant supplementation on this dynamic is unknown. OBJECTIVES: We aimed to determine if changes in airway responsiveness due to DE are attenuated by thiol anti-oxidant supplementation, particularly in those with underlying airway hyper-responsiveness. METHODS: Participants took N-acetylcysteine (600 mg) or placebo capsules three times daily for 6 days. On the last of these 6 days, participants were exposed for 2 h to either filtered air (FA) or DE (300 µg/m(3) of particulate matter smaller than 2.5 microns). Twenty-six non-smokers were studied under each of three experimental conditions (filtered air with placebo, diesel exhaust with placebo, and diesel exhaust with N-acetylcysteine) using a randomized, double-blind, crossover design, with a 2-week washout between conditions. Methacholine challenge was performed pre-exposure (baseline airway responsiveness) and post-exposure (effect of exposure). RESULTS: Anti-oxidant supplementation reduced baseline airway responsiveness in hyper-responsive individuals by 20% (p = 0.001). In hyper-responsive individuals, airway responsiveness increased 42% following DE compared with FA (p = 0.03) and this increase was abrogated with anti-oxidant supplementation (diesel exhaust with N-acetylcysteine vs. filtered air with placebo, p = 0.85). CONCLUSIONS: Anti-oxidant (N-acetylcysteine) supplementation protects against increased airway responsiveness associated with DE inhalation and reduces need for supplement bronchodilators in those with baseline airway hyper-responsiveness. Individuals with variants in genes of oxidative stress metabolism when exposed to DE are protected from increases in airway responsiveness if taking anti-oxidant supplementation.
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Acetilcisteína/uso terapéutico , Antioxidantes/uso terapéutico , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/prevención & control , Emisiones de Vehículos/toxicidad , Acetilcisteína/administración & dosificación , Adulto , Antioxidantes/administración & dosificación , Broncoconstrictores/farmacología , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Cloruro de Metacolina/farmacología , Persona de Mediana Edad , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
BACKGROUND: Prior research has shown that removing occupational asthmatics from exposure does not routinely lead to significant improvements in respiratory impairment. These studies were of limited duration and factors determining recovery remain obscure. Our objective was to evaluate residual respiratory impairment and associated sputum and blood biomarkers in subjects with Western red cedar asthma after exposure cessation. METHODS: Subjects previously diagnosed with cedar asthma, and removed from exposure to cedar dust for at least one year, were recruited. Subjects completed a questionnaire and spirometry. PC20 (methacholine concentration that produces 20% fall in FEV1 (forced expiratory volume at 1 second)) sputum cellularity and select Th1/Th2 (T helper cells 1 and 2) cytokine concentrations in peripheral blood were determined. The asthma impairment class was determined and multivariate analyses were performed to determine its relationship with sputum cell counts and serum cytokines. RESULTS: 40 non-smoking males (mean age 62) were examined at a mean interval of 25 years from cedar asthma diagnosis and 17 years from last cedar exposure. 40% were in impairment class 2/3. On average, the PC20 had increased by 2.0 mg/ml; the FEV1 decreased by 1.5 L, with greater decrease in those with greater impairment. Higher impairment was associated with serum interferon-gamma (meanâ=â1.3 pg/ml in class 2/3 versus 0.62 pg/ml in class 0/1, pâ=â0.04), mainly due to the FEV1 component (correlation with interferon-gammaâ=â-0.46, pâ=â0.005). CONCLUSION: Years after exposure cessation, patients with Western red cedar asthma have persistent airflow obstruction and respiratory impairment, associated with systemic inflammation.
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Asma/metabolismo , Asma/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Alérgenos/inmunología , Asma/inmunología , Asma Ocupacional , Cedrus/efectos adversos , Citocinas/sangre , Citocinas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Exposición Profesional , Pruebas de Función Respiratoria , Esputo/citología , Esputo/inmunologíaRESUMEN
BACKGROUND: Adverse health effects associated with diesel exhaust (DE) are thought to be mediated in part by oxidative stress, but the detailed mechanisms are largely unknown. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and may respond to exposures such as DE. OBJECTIVES: We profiled peripheral blood cellular miRNAs in participants with mild asthma who were exposed to controlled DE with and without antioxidant supplementation. METHODS: Thirteen participants with asthma underwent controlled inhalation of filtered air and DE in a double-blinded, randomized crossover study of three conditions: a) DE plus placebo (DEP), b) filtered air plus placebo (FAP), or c) DE with N-acetylcysteine supplementation (DEN). Total cellular RNA was extracted from blood drawn before exposure and 6 hr after exposure for miRNA profiling by the NanoString nCounter assay. MiRNAs significantly associated with DEP exposure and a predicted target [nuclear factor (erythroid-derived 2)-like 2 (NRF2)] as well as antioxidant enzyme genes were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for validation, and we also assessed the ability of N-acetylcysteine supplementation to block the effect of DE on these specific miRNAs. 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured in plasma as a systemic oxidative stress marker. RESULTS: Expression of miR-21, miR-30e, miR-215, and miR-144 was significantly associated with DEP. The change in miR-144 was validated by RT-qPCR. NRF2 and its downstream antioxidant genes [glutamate cysteine ligase catalytic subunit (GCLC) and NAD(P)H:quinone oxidoreductase 1 (NQO1)] were negatively associated with miR-144 levels. Increases in miR-144 and miR-21 were associated with plasma 8-hydroxydeoxyguanosine 8-OHdG level and were blunted by antioxidant (i.e, DEN). CONCLUSIONS: Systemic miRNAs with plausible biological function are altered by acute moderate-dose DE exposure. Oxidative stress appears to mediate DE-associated changes in miR-144.