Cargando…

Inhibiting AKT Phosphorylation Employing Non-Cytotoxic Anthraquinones Ameliorates T(H)2 Mediated Allergic Airways Disease and Rhinovirus Exacerbation

BACKGROUND: Severe asthma is associated with T helper (T(H)) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have be...

Descripción completa

Detalles Bibliográficos
Autores principales: Cesar de Souza Alves, Caio, Collison, Adam, Hatchwell, Luke, Plank, Maximilian, Morten, Matthew, Foster, Paul S., Johnston, Sebastian L., França da Costa, Cristiane, Vieira de Almeida, Mauro, Couto Teixeira, Henrique, Paula Ferreira, Ana, Mattes, Joerg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818233/
https://www.ncbi.nlm.nih.gov/pubmed/24223970
http://dx.doi.org/10.1371/journal.pone.0079565
Descripción
Sumario:BACKGROUND: Severe asthma is associated with T helper (T(H)) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro. OBJECTIVE: To determine the anti-inflammatory potential of anthraquinones in-vivo. METHODS: BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation. RESULTS: Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of T(H)2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung. CONCLUSION: Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.