AAV9‐miR‐29b Treatment Decreases Expression of Matrix Proteins and Improves Alveolarization in Mice Exposed to Maternal Inflammation and Neonatal Hyperoxia

Abstract

BackgroundBronchopulmonary dysplasia (BPD) continues to be a significant pulmonary complication for preterm infants. Severe BPD is characterized by decreased alveolarization and obstructive and/or restrictive lung function due to increases in or dysregulation of extracellular matrix proteins. We have previously reported decreased pulmonary miR‐29b expression in our mouse model that mimics the pathophysiology observed in infants with severe BPD. The current studies tested the hypothesis that AAV9‐mediated restoration of miR‐29b in the developing lung will improve lung alveolarization and minimize the pulmonary fibrosis.MethodsPregnant C3H/HeN mice received an intraperitoneal LPS injection on E16 and newborn pups were exposed in 85% oxygen from birth to 14 days of life. On postnatal day 3, PBS containing adeno‐associated 9 (AAV9)‐mir‐29b or AAV9‐control was administered intranasally. On postnatal day 14 or 28, mouse lung tissues were analyzed for changes in miR‐29 expression, alveolarization, and matrix protein expression.ResultsDecreases in alveolarization and increases in septal thickness were observed at both 14 and 28 days after LPS/O2 exposure. Administration of AAV9‐miR29b modestly improved alveolarization at 28 days but completely prevented the increases in septal thickness observed at both 14 and 28 days. AAV9‐miR29b also prevented the increases in phospho‐SMAD2/3, aSMA, vimentin, and MMP‐9.ConclusionOur data suggest that miR‐29b restoration may represent a novel therapeutic strategy to treat or prevent severe BPD in prematurely born infants.