(885) Hyperoxia-Induced Airway Resistance and Renin-Angiotensin System Expression in a Mouse Model of BPD

Introduction: Bronchopulmonary dysplasia is a chronic pediatric lung disease characterized by high airway resistance that results from neonatal hyperoxia exposure. Mechanisms underlying this hyperoxia-induced airway resistance are unclear. The Renin-Angiotensin System is a hormonal system active in the lungs that is initiated by angiotensin converting enzyme (ACE) and comprised of two pathways: the pro-developmental pathway consisting of angiotensin converting enzyme 2 (ACE2) and angiotensin II receptor type 2 (AT2) and the pro-fibrotic pathway mediated by angiotensin II receptor type 1 (AT1). The Renin-Angiotensin System is implicated in multiple pathologic pulmonary processes but its role in the pathophysiology of hyperoxia-induced airway resistance is unknown.

Methods: C57 mouse pups were randomized to normoxic (FiO2 = 0.21) or hyperoxic (FiO2=0.75) conditions for the first 15 days of life with data collection on days 15, 20, and 30. Airway resistance parameters measured via plethysmography included peak expiratory flow (PEF), expiratory flow at 50% tidal volume (EF50), expiratory time (Te), peak inspiratory flow (PIF). Polymerase chain reaction and Western blot respectively measured mRNA and protein expression of ACE, ACE2, AT1, and AT2.

Results: On day 15, hyperoxia animals demonstrated lower PIF and prolonged Te and, by day 20, significantly lower EF50 and PEF, indicating increased airway resistance. Day 15 Renin-Angiotensin System evaluation revealed lower ACE, ACE2, and AT2 mRNA expression in hyperoxia animals, accompanied by less ACE and AT2 protein and more AT1 protein. Hyperoxia animals continued to demonstrate less ACE and ACE2 mRNA and ACE2 protein on day 20, but there were no differences between groups in respiratory parameters or of any Renin-Angiotensin System mRNA or protein expression by day 30, with the exception of persistently low ACE mRNA and protein.

Conclusions: Hyperoxia exposure resulted in abnormal Renin-Angiotensin System mRNA and protein expression that favored its pro-fibrotic pathway in our mouse model of Bronchopulmonary Dysplasia. This change was associated with increased airway resistance, suggesting the Renin-Angiotensin System may have a causative role in the pathologic airway resistance of Bronchopulmonary Dysplasia.