Inhibition of VEGF receptors causes lung cell apoptosis and emphysema

Pulmonary emphysema, a significant global health problem, is characterized by a loss of alveolar structures. Because VEGF is a trophic factor required for the survival of endothelial cells and is abundantly expressed in the l ung, we hypothesized that chronic blockade of VEGF receptors could induce a lveolar cell apoptosis and emphysema. Chronic treatment of rats with the VE GF receptor blocker SU5416 led to enlargement of the air spaces, indicative of emphysema. The VEGF receptor inhibitor SU5416 induced alveolar septal c ell apoptosis but did not inhibit lung cell proliferation. Viewed by angiog raphy, SU5416-treated rat lungs showed a pruning of the pulmonary arterial tree, although we observed no lung infiltration by inflammatory cells or fi brosis. SU5416 treatment led to a decrease in lung expression of VEGF recep tor 2 (VEGFR-2), phosphorylated VEGFR-2, and Akt-1 in the complex with VEGF R-2. Treatment with the caspase inhibitor Z-Asp-CH2-DCB prevented SU5416-in duced septal cell apoptosis and emphysema development. These findings sugge st that VEGF receptor signaling is required for maintenance of the alveolar structures and, further, that alveolar septal cell apoptosis contributes t o the pathogenesis of emphysema.