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1 Division of Physiology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
* To whom correspondence should be addressed. E-mail: ebreen{at}ucsd.edu.
To test the hypothesis that VEGF is important for the maintenance of alveolar structure and elastic properties in adult mice, lung-targeted ablation of the VEGF gene was accomplished through intratracheal delivery of an adeno-associated cre recombinase virus (AAV/Cre) to VEGFloxP transgenic mice and the effects were followed for 8 weeks. Control mice were similarly treated with AAV/Cre. Pulmonary VEGF levels were reduced by 86 % at 5 weeks post-infection but returned to normal levels by 8 weeks. VEGFR-2 levels were also reduced at five weeks (by 51 %) and returned to control values by 8 weeks. However, alveolar septal wall destruction (increased mean linear intercept) and loss of lung elastic recoil (increased compliance) persisted for eight weeks. No decrease in alveolar cell proliferation was detected by western blot or immunohistochemical analysis of proliferating cell nuclear antigen. Increased alveolar septal cell and bronchial epithelial cell apoptosis was detected by TUNEL analysis at five weeks. Total lung caspase-3 levels and enzyme activity were also increased at five weeks. No obvious accumulation of inflammatory cells was observed at any time after tracheal instillation of AAV/Cre. Thus, a transient decrease in pulmonary VEGF leads to increased alveolar and bronchial cell apoptosis, alveolar septal wall destruction and changes in lung elastic recoil (processes that are characteristic of emphysema) that persist for at least 8 weeks.
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