Inhibition of VEGF receptors causes lung cell apoptosis and emphysema

TLDR

Pulmonary emphysema is a major global health issue marked by loss of alveolar structures. The study hypothesizes that chronic VEGF receptor blockade will trigger alveolar cell apoptosis and emphysema. Chronic VEGF receptor inhibition with SU5416 caused emphysema and alveolar septal apoptosis, reduced VEGFR‑2 signaling, and pruning of pulmonary arteries, while a caspase inhibitor prevented these effects, demonstrating that VEGF signaling protects alveolar structure and that apoptosis drives emphysema.

Abstract

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 lung, we hypothesized that chronic blockade of VEGF receptors could induce alveolar cell apoptosis and emphysema. Chronic treatment of rats with the VEGF receptor blocker SU5416 led to enlargement of the air spaces, indicative of emphysema. The VEGF receptor inhibitor SU5416 induced alveolar septal cell apoptosis but did not inhibit lung cell proliferation. Viewed by angiography, SU5416-treated rat lungs showed a pruning of the pulmonary arterial tree, although we observed no lung infiltration by inflammatory cells or fibrosis. SU5416 treatment led to a decrease in lung expression of VEGF receptor 2 (VEGFR-2), phosphorylated VEGFR-2, and Akt-1 in the complex with VEGFR-2. Treatment with the caspase inhibitor Z-Asp-CH2-DCB prevented SU5416-induced septal cell apoptosis and emphysema development. These findings suggest that VEGF receptor signaling is required for maintenance of the alveolar structures and, further, that alveolar septal cell apoptosis contributes to the pathogenesis of emphysema.