Su1498 Inhibits Alveolarization in Newborn Mice.

Abstract

BACKGROUND: Bronchopulmonary dysplasia (BPD) in premature infants is characterized by inhibited alveolarization and vasculogenesis. Inhibitors of angiogenesis induce emphysema in newborn rats resulting in a phenotype similar to BPD in premature infants. Our goal was to generate a mouse model of inhibited alveolarization that could be employed to explore the mechanisms resulting in, and interventions for BPD. SU1498 is a commercially available compound that inhibits vascular endothelial growth factor receptors.METHODS: Three day old C3H/HeNHsd mice were injected with a single dose of SU1498 (30mg/kg, SC). Lungs of control (sham-injected) and treated mice were inflation fixed on postnatal day 21. Tissue sections were mounted and morphometric analysis was performed to determine the volume density (VD) of air space, tissue, large blood vessels, conducting airways, and alveolar surface area. Lungs were also harvested for electron microscopic analysis of alveolar structures.RESULTS: The VD of airspace (63.7±1.9% vs. 53.2±1.2%) and conducting airways (3.0±0.9% vs. 0.9±0.4%) were significantly greater in treated versus control mice (n=8, P<0.05). The VD of large blood vessels was not different between the two groups. The alveolar tissue VD (31.0±1.5% vs. 43.9±1.3%) and the alveolar surface area (318.6±31.6 cm2 vs. 238.1±22.8cm2) were significantly less in treated versus control mice (n=8, P<0.05). Electron microscopy demonstrated a decrease in alveolar wall thickness in the lungs of treated mice. Treatment also resulted in fewer but enlarged capillaries compared to controls.CONCLUSION: A single of dose of the VEGFR inhibitor, SU1498, to newborn mice results in inhibition of alveolar development at 21 days. This phenotype provides a model for the investigation of mechanisms resulting in inhibited alveolarization. Such investigation may lead to strategies for the prevention or treatment of BPD in prematurely born infants. Fig. 1 Figure. No Caption Available.