Abstract 1904 Neonatal Pulmonology I: Mechanical Influences on Lung Development Platform, Tuesday, 5/4

During lung development, fluid distension (∼3mm Hg) gently stretches acinar epithelial and mesenchymal cells and stimulates maturation in preparation for birth. Stretch coordinates Parathyroid Hormone-related Protein (PTHrP) expression by Type II epithelial cells (TII) and PTHrP Receptor by adjacent lipid interstitial cells (LIC). Receptor-mediated PTHrP action on LICs regulates adipocyte differentiation related protein (ADRP) expression. ADRP mediates lipid processing by LICs and lipid trafficking to TIIs as substrate for surfactant phospholipid production. Mechanical deformation (5-10%) comparable to liquid distension during intra-uterine development up-regulates the expression of PTHrP (30%) by TIIs, as well as PTHrP receptor activity (130%) by LICs. Stretching TIIs 15-20% decreases PTHrP mRNA. Mechanical deformation of pulmonary cells ex utero reflects molecular mechanisms underlying pulmonary overdistension or volutrauma which occurs in respiratory distress syndrome. To test this hypothesis, we examined the preterm baboon model of Bronchopulmonary Dysplasia. Baboon fetuses were prematurely delivered (125 days gestation) and mechanically ventilated. Pulmonary distension decreased pulmonary PTHrP and increased ADRP, consistent with the uncoupling of the surfactant precursor lipid metabolic pathway which we observed in vitro. Treatment of preterm animals with a specific monoclonal antibody to Bombesin-Like Peptide (Sunday, et al, JCI 1998), which reduces lung injury in the preterm baboon model, reverses the deleterious effects of overdistension (volutrauma) on PTHrP and ADRP expression. These findings suggest that restoration of specific intercellular signaling pathways in the developing alveolus may prevent or lessen mechanically-induced lung injury.

Funded by NIH grant HL55268 [to JST and LPR].