RESUMEN
BACKGROUND: Inhalation of particulate matter, as part of air pollution, is associated with increased morbidity and mortality. Nanoparticles (< 100 nm) are likely candidates for triggering inflammatory responses and activation of coagulation pathways because of their ability to enter lung cells and pass bronchial mucosa. We tested the hypothesis that bronchial segmental instillation of carbon nanoparticles causes inflammation and activation of coagulation pathways in healthy humans in vivo. METHODS: This was an investigator-initiated, randomized controlled, dose-escalation study in 26 healthy males. Participants received saline (control) in one lung segment and saline (placebo) or carbon nanoparticles 10 µg, 50 µg, or 100 µg in the contra-lateral lung. Six hours later, blood and bronchoalveolar lavage fluid (BALF) was collected for inflammation and coagulation parameters. RESULTS: There was a significant dose-dependent increase in blood neutrophils (p = 0.046) after challenge with carbon nanoparticles. The individual top-dose of 100 µg showed a significant (p = 0.05) increase in terms of percentage neutrophils in blood as compared to placebo. CONCLUSIONS: This study shows a dose-dependent effect of bronchial segmental challenge with carbon nanoparticles on circulating neutrophils of healthy volunteers. This suggests that nanoparticles in the respiratory tract induce systemic inflammation. TRIAL REGISTRATION: Dutch Trial Register no. 2976. 11 July 2011. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2976.
Asunto(s)
Contaminación del Aire/efectos adversos , Exposición por Inhalación/efectos adversos , Nanopartículas/administración & dosificación , Nanotubos de Carbono/efectos adversos , Neutrófilos/citología , Administración por Inhalación , Adulto , Pruebas de Provocación Bronquial , Líquido del Lavado Bronquioalveolar/química , Voluntarios Sanos , Humanos , Inflamación/inducido químicamente , Pulmón/metabolismo , Masculino , Tamaño de la Partícula , Material Particulado , Adulto JovenRESUMEN
Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation, and data suggest that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed dabigatran (10 mg/g) or placebo chow during a 3-wk HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with dabigatran levels reported in human trials. Surprisingly, dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology (P < 0.05) and decreased IL-4 levels (P < 0.01), without influencing other HDM-induced responses. Considering the limited effects of dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of dabigatran in patients with asthma.
Asunto(s)
Alérgenos/administración & dosificación , Antígenos Dermatofagoides/administración & dosificación , Asma/tratamiento farmacológico , Dabigatrán/administración & dosificación , Administración Oral , Animales , Antitrombina III/metabolismo , Antitrombinas/administración & dosificación , Asma/sangre , Asma/patología , Coagulación Sanguínea/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/inmunología , Dermatophagoides pteronyssinus/inmunología , Modelos Animales de Enfermedad , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Péptido Hidrolasas/metabolismoRESUMEN
BACKGROUND: Esophagectomy is frequently accompanied by substantial complications with secondary disturbance of the immune system. After esophagectomy for adenocarcinoma of the distal esophagus and/or gastroesophageal junction, the majority of patients develops an early recurrence and dies within 2 years. The aim of this study was to determine the relevance of perioperative complications on the timing of death due to recurrence. METHODS: A consecutive series of 351 patients who underwent esophagectomy for adenocarcinoma of the esophagus and gastroesophageal junction was reviewed. RESULTS: Of the 351 included patients, 191 patients (54%) died due to recurrence of esophageal adenocarcinoma. Of these 191 patients, 77 (40%), 138 (72%), and 186 patients (97%) died before 12, 24, and 60 months, respectively. Multivariate Cox regression analysis demonstrated that T-stage, lymph node ratio >0.20, the presence of extracapsular lymph node involvement, but not complications were significant factors for the prediction of death due to cancer recurrence. However, in the patients who died, multivariate Cox regression analysis demonstrated that not only the presence of extracapsular lymph node involvement but also the occurrence of complications were significantly related with a shorter time interval until death due to recurrence. CONCLUSION: The relation between perioperative complications and cancer recurrence per se is not causal. However, postoperative complications are independently associated with the early timing of death due to cancer recurrence. A possible explanation for this phenomenon is that immunologic host factors enhance microscopic residual disease to develop more rapidly into clinically manifest recurrence.