106: Clinical interventions abrogate lethal structural and functional pulmonary defects in neonatal Erk3-/-knockout mice

Neonatal respiratory distress syndrome (NRDS) is associated with PTB and is the leading cause of death among neonates. Rates of infant mortality due to pulmonary insufficiency have improved with the introduction of antenatal glucocorticoid treatment and surfactant replacement. However, the mechanism by which glucocorticoids promote fetal lung maturation remains poorly understood despite decades of clinical use. We have developed an Erk3-/- murine model of neonatal respiratory distress syndrome, in which pups expire shortly after birth due to pulmonary immaturity without immediate intervention. We have previously found alterations in expression of genes critical to lung function associated with ERK3 loss as well as histological changes in response to glucocorticoid therapy. Here we have sought to further characterize the structural changes associated with neonatal lethality due to respiratory distress using high resolution micro-CT analysis of murine fetal lungs. Dexamethasone (0.4 mg/kg) or saline was administered to dams on days E16.5 and E17.5 of gestation, during the saccular stage of development, and fetal lungs were extracted at E18.5. Lungs were fixed in paraformaldehyde and embedded in stabilizing gel to preserve pulmonary structure. After overnight staining in 1% iodine, tissues were imaged on the SkyScan 1272 MicroCT at 70 kV, 142 uA, and 0.2° step angle, for a voxel size of 3 micrometers and 3K resolution. Images were analyzed using CTAn by Bruker and ImageJ. Relative to wild-type littermates, Erk3-/- mice exhibited smaller lung tissue volume, with decreased porosity and saccular space (Figure 1) as well as areas of atelectasis (Figure 2). These pulmonary defects are partially reversed by glucocorticoid treatment, yet neonatal lethality is not prevented. Using a murine model of NRDS and high resolution tomography, we have observed gross morphological alterations in lung structure associated with ERK3 loss which is abrogated by standard clinical treatments in neonatal care. Additional characterization of structural alterations in pulmonary development and architecture associated with NRDS are underway to determine the effect of perinatal clinical interventions (i.e., surfactant administration) on postnatal lung structure and function.View Large Image Figure ViewerDownload Hi-res image Download (PPT)