RESUMEN
The aim of this study was to evaluate the presence of type-II secretory phospholipase A2 (sPLA2-IIA) in alveolar space and its possible role in the destruction of surfactant in three rat models of acute lung injury. Alveolar instillation of either lipopolysaccaride or live Pseudomonas aeruginosa resulted in a significant increase in lung oedema and in a decrease in static compliance of the respiratory system together with alveolar-neutrophil influx as compared with healthy control rats. The upregulation of messenger ribonucleic acid and sPLA2-IIA by the lung was evident. This was associated with surfactant degradation and a decrease in large:small ratio of surfactant aggregates in bacteria-instilled rats. A negative correlation between compliance and sPLA2-IIA activity in bronchoalveolar lavage fluid was shown. By contrast, during alpha naphthylthiourea-induced injury, neither alveolar-neutrophil influx nor increase in sPLA2-IIA activity was observed. Additional experiments in rats treated with a specific inhibitor of type-II secretory phospholipase A2 activity (3 acetamine-1-benzyl-2 ethylindolyl-5 oxy; propane phosphonic acid (LY311727)) demonstrated no improvement in physiological parameters despite a biochemical effect, suggesting that its activity is only one of the multiple factors involved in the pathophysiology of lung injury.
Asunto(s)
Rendimiento Pulmonar/fisiología , Fosfolipasas A/análisis , Fosfolipasas A/fisiología , Neumonía/complicaciones , Neumonía/fisiopatología , Alveolos Pulmonares/química , Edema Pulmonar/complicaciones , Edema Pulmonar/fisiopatología , Surfactantes Pulmonares/química , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/fisiopatología , Animales , Líquido del Lavado Bronquioalveolar/química , Modelos Animales de Enfermedad , Fosfolipasas A2 Grupo II , Masculino , Fosfolipasas A2 , Alveolos Pulmonares/fisiopatología , Ratas , Ratas Sprague-Dawley , Índice de Severidad de la EnfermedadRESUMEN
Cell-mediated immunity plays a key role in containing the growth of Mycobacterium tuberculosis in the host. The induction of an antibody response or a mixed cell-mediated and humoral response is frequently associated with tuberculosis disease or a decrease in the ability to control M. tuberculosis load. We recently reported the induction of similar immune responses and protection by rectal, subcutaneous (SC) or intradermal administration of Mycobacterium bovis BCG in adult mice, guinea pigs and macaques. The rectal immunization, which did not induce the side-effects associated with parenteral routes (axillary adenitis) and which could be used to reduce the risks of viral transmission associated with unsafe injections in the developing world, was analysed and compared in newborn and adult BALB/c mice. The rectal and SC immunization induced, in mice immunized as newborns or as adults, a mixed T helper 1/T helper 2 (Th1/Th2) immune response; however, particularly in adult mice, after SC administration of BCG, the level of Th2 immune response is significantly higher than it is by the rectal route. Six months after immunization with BCG, rectal and SC delivery induced similar levels of protective immunity against a virulent challenge with M. tuberculosis strain (H37Rv) in mice immunized as adults, but the rectal BCG delivery triggered stronger protection than the SC delivery if mice were immunized as newborns.
Asunto(s)
Vacuna BCG/administración & dosificación , Mycobacterium tuberculosis/inmunología , Células TH1/inmunología , Células Th2/inmunología , Administración Rectal , Animales , Animales Recién Nacidos , Recuento de Colonia Microbiana , Femenino , Inyecciones Subcutáneas , Interferón gamma/biosíntesis , Ratones , Ratones Endogámicos BALB C , Mycobacterium bovis/aislamiento & purificaciónRESUMEN
Asthma may result from excessive Th-2 response in children not previously exposed to Th-1-inducing infections. We tested the hypothesis that BCG vaccination in Th-2-susceptible newborn BP2 mice blocks allergic inflammation and bronchial hyperreactivity (BHR). Ten day-old BP2 mice received 10(5) CFU of BCG 1173P2 intranasally (IN), and 6, 10 or 14 weeks thereafter were sensitized with 100 microg ovalbumin (OVA) in aluminium hydroxide twice subcutaneously (SC) at 1 week interval, and challenged 1 week after the second sensitization with 10 microg OVA IN. Compared to OVA-challenged unvaccinated mice, those that received BCG 8 weeks before challenge developed intense bronchial inflammation, BHR, and high IgE titers. Inflammation involved T cells, macrophages, dendritic cells and was accompanied by increased levels of Interleukin-5 (IL-5) in the bronchoalveolar lavages (BAL). However, animals challenged 16 weeks after BCG vaccination did not develop BHR nor bronchial hypereosinophilia, and showed reduced IgE levels. Bronchial infiltration by immunocompetent cells was also significantly reduced. Increased levels of gamma-interferon (IFN-gamma) after in vitro stimulation of tracheo-bronchial lymph node cells accompanied this blockage, but levels of IL-5 remained high. We demonstrate that 16 weeks after vaccination with BCG in newborn BP2 mice which have a high Th-2 background, allergic inflammation and BHR were blocked, even though a clear Th-1 shift was not achieved.
Asunto(s)
Vacuna BCG/farmacología , Hiperreactividad Bronquial/prevención & control , Hipersensibilidad/prevención & control , Inflamación/prevención & control , Animales , Animales Recién Nacidos , Asma/prevención & control , Vacuna BCG/administración & dosificación , Niño , Citocinas/biosíntesis , Relación Dosis-Respuesta Inmunológica , Humanos , Hipersensibilidad Tardía , Hipersensibilidad Inmediata , Síndrome de Job/inmunología , Síndrome de Job/terapia , Pulmón/citología , Pulmón/inmunología , Masculino , Ratones , Mycobacterium bovis/aislamiento & purificación , Ovalbúmina/inmunología , Fenotipo , Células TH1/inmunología , Células Th2/inmunología , Factores de TiempoRESUMEN
The virulence of the mycobacteria that cause tuberculosis depends on their ability to multiply in mammalian hosts. Disruption of the bacterial erp gene, which encodes the exported repetitive protein, impaired multiplication of M. tuberculosis and M. bovis Bacille Calmette-Guérin in cultured macrophages and mice. Reintroduction of erp into the mutants restored their ability to multiply. These results indicate that erp contributes to the virulence of M. tuberculosis.