Inhibition of VEGF blocks TGF-beta1 production through a PI3K/Akt signalling pathway.

Vascular endothelial growth factor (VEGF) is a mediator of airway inflammation and remodelling in asthma. Transforming growth factor (TGF)-beta(1) plays pivotal roles in diverse biological processes, including tissue remodelling and repair in a number of chronic lung diseases. However, there are few studies elucidating the interactions between VEGF and TGF-beta(1) in allergic airway disease. A murine model of allergic airway disease was used to define the mechanism by which VEGF induces subepithelial fibrosis and to investigate a potential relationship between VEGF and TGF-beta(1) and the mechanisms by which VEGF signalling regulates TGF-beta(1) expression in allergic airway disease. The ovalbumin (OVA)-inhaled murine model revealed the following typical pathophysiological features of allergic airway disease in the lungs: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased peribronchial fibrosis, and increased levels of VEGF and TGF-beta(1). Administration of VEGF inhibitors reduced the pathophysiological signs of allergic airway disease and decreased the increased TGF-beta(1) levels and peribronchial fibrosis, including phosphoinositide 3-kinase (PI3K) activity after OVA inhalation. In addition, the increased TGF-beta(1) levels and collagen deposition after OVA inhalation were decreased by administration of PI3K inhibitors. These results suggest that inhibition of vascular endothelial growth factor attenuates peribronchial fibrosis, at least when mediated by regulation of transforming growth factor-beta(1) expression through phosphoinositide 3-kinase/Akt pathway in a murine model of allergic airway disease.