Inhibition of VEGF blocks TGF-₁ production through a PI3K/Akt signaling pathway

¹ Dept of Internal Medicine, Airway Remodeling Laboratory
² Dept of Biochemistry, Chonbuk National University Medical School, Jeonju, South Korea.
³ Dept of paediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

^* To whom correspondence should be addressed. E-mail: leeyc{at}chonbuk.ac.kr.

	Abstract

Vascular endothelial growth factor (VEGF) is a mediator of airway inflammation and remodeling in asthma. Transforming growth factor (TGF)-₁ plays pivotal roles in diverse biologic processes including tissue remodeling and repair in a number of chronic lung diseases. However, there are little studies elucidating the interactions between VEGF and TGF-₁ in allergic airway disease.

We used a murine model of allergic airway disease to define the mechanism by which VEGF induces subepithelial fibrosis and to investigate a potential relationship between VEGF and TGF-₁ and the mechanisms by which VEGF signaling regulates TGF-₁ expression in allergic airway disease.

This study with 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-₁. Administration of VEGF inhibitors reduced the pathophysiological signs of allergic airway disease and decreased the increased TGF-1 levels and peribronchial fibrosis, including phosphoinositide 3-kinase (PI3K) activity after OVA inhalation. In addition, the increased TGF-₁ levels and collagen deposition after OVA inhalation were decreased by administration of PI3K inhibitors.

These results suggest that inhibition of VEGF attenuates peribronchial fibrosis, at least mediated by regulation of TGF-₁ expression through PI3K/Akt pathway in a murine model of allergic airway disease.

Keywords:  Airway remodeling, phosphoinositide 3-kinase, subepithelial fibrosis, transforming growth factor-₁, vascular endothelial growth factor