Involvement of PTEN in airway hyperresponsiveness and inflammation in bronchial asthma

Abstract

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.

Genome-Wide Profiling of Antigen-Induced Time Course Expression Using Murine Models for Acute and Chronic Asthma

“…Ribbons of three to four sections cut at 8 µm were stained with hematoxylin and eosin (HE) for assessment of inflammatory changes, and with periodic acid-Schiff (PAS) for visualization of mucin-secreting cells in the intrapulmonary conducting airways. To quantitatively assess peribronchial and perivascular inflammation, the HE slides (n = 6) were evaluated by two independent investigators using microscopy and scored on a subjective scale from 0 to 3 as previously described [17]: A value of ‘0’ was assigned when no inflammation was detectable, a value of ‘1’ when occasional cuffing of bronchi or vessels with inflammatory cells was observed, a value of ‘2’ when most bronchi or vessels were surrounded by thin layers (1–5 cells) of inflammatory cells and a value of ‘3’ when most bronchi or vessels were surrounded by thick layers (>5 cells) of inflammatory cells. Total lung inflammation of each animal group (fig.…”

Lovastatin inhibits antigen-induced airway eosinophilia without affecting the production of inflammatory mediators in mice

“…Inflammation was scored by three independent blinded investigators. The degree of inflammation was evaluated on a subjective scale of 0-3, as described elsewhere [15].…”

Geldanamycin treatment reduces neovascularization in a mouse model of retinopathy of prematurity

“…Applied in a micro dispersed form, this dose was non-toxic in mice and showed a wide tissue distribution, including the brain and a nearly 100% bioavailability. The chosen Wortmannin concentration of 100 μg/kg per day has been shown to be quite effective in a mouse model for asthma in which the effect of PI3K inhibitors was determined on allergeninduced bronchial inflammation and airway hyperresponsiveness [18]. Room temperature was maintained at 20°C, and the mice were kept in a 12-h day and night shift by an automatic illumination system.…”