Vascular endothelial growth factor in developing ovine lung: endogenous expression and effects of exogenous administration on respiratory syncytial virus infection

Abstract

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis in children with nearly all children infected by two years of age. Preterm infants and infants with cardiopulmonary compromise or immunodeficiency are at increased risk for severe RSV disease. However, a high percentage of hospitalizations due to severe RSV disease occur in otherwise healthy infants. Severe RSV disease is characterized by bronchiolitis and airway obstruction secondary to sloughed epithelial cells, cellular debris and inflammatory cells that can partially occlude the airway lumen. There is currently no licensed vaccine to prevent RSV infection. The purpose of this study was to develop a model of RSV infection in the newborn lamb using a human strain of RSV, strain A2. The pulmonary pathology and cellular localization of antigen was determined, in addition to the viral effect on the expression of epithelial innate immune genes, surfactant proteins A and D (SP-A and SPD respectively) and sheep beta-defensin-1 (SBD-1). Pulmonary lesions were characterized by suppurative bronchiolitis with multifocal alveolar consolidation and peak pulmonary lesions at day 6 post-infection. RSV infection increased expression of SP-A and SBD-1, which demonstrates alteration of innate immune responses caused by RSV A2. Using this model, lambs were pretreated with exogenous human recombinant vascular endothelial growth factor (rhVEGF) prior to RSV infection. VEGF is a known endothelial mitogen, but also plays an important pulmonary role in surfactant protein production, epithelial cell proliferation, and epithelial cell survival. VEGF administration prior to RSV infection decreased both viral load and pulmonary pathology at peak