RESUMEN
Phosphatase and tensin homologue deleted on chromosome ten (PTEN) is part of a complex signaling system that affects a variety of important cell functions. PTEN blocks the action of PI3K by dephosphorylating the signaling lipid phosphatidylinositol 3,4,5-triphosphate. We have used a mouse model for asthma to determine the effect of PI3K inhibitors and PTEN on allergen-induced bronchial inflammation and airway hyperresponsiveness. PI3K activity increased significantly after allergen challenge. PTEN protein expression and PTEN activity were decreased in OVA-induced asthma. Immunoreactive PTEN localized in epithelial layers around the bronchioles in control mice. However, this immunoreactive PTEN dramatically disappeared in allergen-induced asthmatic lungs. The increased IL-4, IL-5, and eosinophil cationic protein levels in bronchoalveolar lavage fluids after OVA inhalation were significantly reduced by the intratracheal administration of PI3K inhibitors or adenoviruses carrying PTEN cDNA (AdPTEN). Intratracheal administration of PI3K inhibitors or AdPTEN remarkably reduced bronchial inflammation and airway hyperresponsiveness. These findings indicate that PTEN may play a pivotal role in the pathogenesis of the asthma phenotype.
Asunto(s)
Asma/inmunología , Inflamación , Fosfatidilinositol 3-Quinasas/metabolismo , Monoéster Fosfórico Hidrolasas/inmunología , Monoéster Fosfórico Hidrolasas/fisiología , Ribonucleasas , Proteínas Supresoras de Tumor/inmunología , Proteínas Supresoras de Tumor/fisiología , Alérgenos/farmacología , Androstadienos/farmacología , Animales , Proteínas Sanguíneas/biosíntesis , Western Blotting , Líquido del Lavado Bronquioalveolar , Cationes , Células Cultivadas , Cromonas/farmacología , ADN Complementario/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Proteínas en los Gránulos del Eosinófilo , Femenino , Vectores Genéticos , Inmunohistoquímica , Interleucina-4/biosíntesis , Interleucina-5/biosíntesis , Operón Lac , Pulmón/inmunología , Cloruro de Metacolina/farmacología , Ratones , Ratones Endogámicos BALB C , Morfolinas/farmacología , Fosfohidrolasa PTEN , Fenotipo , Fosforilación , Factores de Tiempo , WortmaninaRESUMEN
The ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to regulate cell activation, differentiation, proliferation, and/or apoptosis. PPARgamma is also associated with anti-inflammatory responses. However, the signaling mechanism remains elusive. We have used a mouse model for asthma to determine the effect of PPARgamma agonists, rosiglitazone or pioglitazone, and PPARgamma on allergen-induced bronchial inflammation and airway hyperresponsiveness. Administration of PPARgamma agonists or adenovirus carrying PPARgamma cDNA (AdPPARgamma) reduced bronchial inflammation and airway hyperresponsiveness. Expression of PPARgamma was increased by ovalbumin (OVA) inhalation, and the increase was further enhanced by the administration of the PPARgamma agonists or AdPPARgamma. Levels of IL-4, IL-5, IL-13, and eosinophil cationic protein were increased after OVA inhalation, and the increased levels were significantly reduced by the administration of PPARgamma agonists or AdPPARgamma. The results also showed that the administration of PPARgamma agonists or AdPPARgamma up-regulated phosphatase and tensin homologue deleted on chromosome ten (PTEN) expression in allergen-induced asthmatic lungs. This up-regulation correlated with decreased phosphatidylinositol 3-kinase activity as measured by reduced phosphorylation of Akt. These findings demonstrate a protective role of PPARgamma in the pathogenesis of the asthma phenotype through regulation of PTEN expression.
Asunto(s)
Asma/prevención & control , Regulación de la Expresión Génica/efectos de los fármacos , PPAR gamma/fisiología , Fosfohidrolasa PTEN/genética , Animales , Asma/etiología , Asma/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Eosinófilos/química , Femenino , Expresión Génica/efectos de los fármacos , Interleucina-13/análisis , Interleucina-4/análisis , Interleucina-5/análisis , Pulmón/química , Cloruro de Metacolina/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/administración & dosificación , PPAR gamma/agonistas , PPAR gamma/genética , Fosfohidrolasa PTEN/análisis , Fosfohidrolasa PTEN/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Pioglitazona , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rosiglitazona , Tiazolidinedionas/farmacología , Tráquea/química , TransfecciónRESUMEN
Isocyanate chemicals, including toluene diisocyanate (TDI), are currently the most common causes of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is characterized by hyperresponsiveness and inflammation of the airways. One of the histological hallmarks of inflammation is angiogenesis, but the possible role of vascular endothelial growth factor (VEGF), a potent angiogenic cytokine, in TDI-induced asthma is unknown. We developed a murine model to investigate TDI-induced asthma by performing two courses of sensitization with 3% TDI and one challenge with 1% TDI using ultrasonic nebulization to examine the potential involvement of VEGF in that disease. These mice develop the following typical pathophysiological features: airway hyperresponsiveness, airway inflammation, and increased VEGF levels in the airway. Administration of VEGFR inhibitors reduced all these pathophysiological symptoms. These results suggest that VEGF is one of the major determinants of TDI-induced asthma and that the inhibition of VEGF may be a good therapeutic strategy.