Associate Professor Medical College of Wisconsin/Children's Wisconsin
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Introduction: Bronchopulmonary dysplasia (BPD) is a common sequela of preterm birth that persists throughout childhood. The mechanisms behind the high airway resistance that results from neonatal hyperoxia exposure are not well understood. We hypothesize that neonatal hyperoxia is associated with smooth muscle cell (SMC) hyperplasia and decreased beta 2 (B2) receptor density and activity, which contribute to an increase in airway resistance.
Methods: Newborn rat pups were randomized to a hyperoxic environment (FiO2 =0.90) or control normoxic environment (FiO2=0.21) for the first 15 days of life. At day 15, plethysmography was utilized to measure airway resistance. Rats were then anesthetized for lung harvest, tissue processing, and histology. Western Blot and PCR of lung lysate were used to quantify protein and mRNA expression of beta 2 receptors (ADBR2) and SMC actin (ACTA2). IHC staining identified SMCs and epithelial cells on histology slides. Qupath software was utilized to obtain bronchiole measurements and characterize SMC and epithelial layers of bronchioles.
Results: Hyperoxia exposed animals demonstrated higher airway resistance measured by Expiratory Flow at 50% Tidal Volume when compared to normoxia controls (p value < 0.005). ADRB2 mRNA expression was lower in hyperoxia exposed rats (p < 0.005) but there was no difference in expression of ACTA2 (p=0.83). Hyperoxia exposed rats had increased protein expression of ADRB2 (p= 0.008) and ACTA2 (p=0.001). Histologic analysis demonstrated an increase in the number of epithelial cells per bronchiolar area for hyperoxia exposed rats (p=0.065) but no difference in number of SMC cells (p=0.84). Both epithelial cell area and SMC cell area were greater in hyperoxia exposed rats when normalized to bronchiolar area (p=0.024 and p=0.044, respectively).
Conclusions: These preliminary studies suggest hyperoxia is associated with SMC hypertrophy, in addition to dysregulated epithelial cell anatomy. Epithelial layer overgrowth may contribute to the increase protein expression of ADRB2 and subsequent downregulation of ADRB2 mRNA expression. However, without a concomitant increase in number of SMCs, control of SMC dilation via the beta receptor pathway is likely impacted and may lead to the high airway resistance observed in hyperoxia-associated lung disease.
