Peroxisome proliferator activated receptor-gamma modulates reactive oxygen species generation and activation of nuclear factor-kappaB and hypoxia-inducible factor 1alpha in allergic airway disease of mice.

摘要

BACKGROUND: Reactive oxygen species (ROSs) play a crucial role in the pathogenesis of airway inflammation. Peroxisome proliferator activated receptor (PPAR)-gamma is also involved in airway inflammation. We have demonstrated that the administration of PPARgamma agonists or adenovirus carrying PPARgamma cDNA (AdPPARgamma) reduced bronchial inflammation and airway hyperresponsiveness. However, the effects of PPARgamma on ROS generation in conditions associated with airway inflammation have not been clarified. OBJECTIVE: This study aimed to investigate the effects of the PPARgamma on ROS generation in allergic airway disease of mice. METHODS: We have used a female C57BL/6 mouse model for allergic airway disease to determine the role of PPARgamma. RESULTS: In this study with an ovalbumin-induced murine model of allergic airway disease, the increased ROS generation and the increased expression of T(H)2 cell cytokines, adhesion molecules, chemokines, and vascular endothelial growth factor in lungs after ovalbumin inhalation were significantly reduced by the administration of PPARgamma agonists or AdPPARgamma. We also showed that the increased nuclear factor-kappaB and hypoxia-inducible factor 1alpha levels in nuclear protein extracts of lung tissues after ovalbumin inhalation were decreased by the administration of PPARgamma agonists or AdPPARgamma. CONCLUSION: These results indicate that the effects of PPARgamma are mediated by the modulation of ROS generation and activation of redox-sensitive transcription factor nuclear factor-kappaB and HIF-1alpha in allergic airway disease of mice. CLINICAL IMPLICATIONS: Thus, these findings provide a pivotal molecular mechanism for the use of PPARgamma agonists to prevent and/or treat asthma and other airway inflammatory disorders.