Hyperoxia‐Induced Bronchopulmonary Dysplasia in Neonatal Rats Acutely and Chronically Alters the Control of Breathing

Abstract

Infants born prematurely have immature lungs, and the neural mechanisms that control breathing are still developing. Premature infants often require supplemental oxygen therapy (hyperoxia) which acutely improves oxygen saturation but consequently leads to bronchopulmonary dysplasia (BPD; chronic lung disease in infants). Whether hyperoxia‐induced BPD also exacerbates the control of breathing is unknown. Thus, the major objective of this study was to elucidate the short and long‐term effects of hyperoxia‐induced BPD on the control of breathing. Sprague Dawley rat pups were exposed to room air (21% O2/Bal. N2) or hyperoxia (90% O2/Bal. N2) from postnatal day 0–10 (P0–10) and ventilation measured during room air (20 min) and hypoxic (10 min; 12% O2/Bal. N2) conditions at P10, 12, 14, 17, 21, 43, and 60 using plethysmography to test the hypothesis that hyperoxia‐induced BPD would decrease breathing stability and impair development of key brainstem respiratory nuclei. By P20, hyperoxic treated pups had significantly (p<0.05) reduced inspiratory (33%) and expiratory flow rates (24%) compared to control (normoxic‐reared) pups, consistent with BPD and pulmonary histologic data from prior publications. Minute ventilation in hyperoxia‐treated pups was significantly decreased (−20% of control) at P10 but increased thereafter while breathing room air (+50% of control; P12–14), and increased ~25% under hypoxic conditions (P12–14, 60, p<0.05). These changes were initially driven by significant increases in breathing frequency (P12–17; +20–46%) and later by increased tidal volume (P43–60; 50%). Room air and hypoxia breathing frequency variability was significantly lower by 20–35% from P10–21 and elevated by 70% at P60, respectively. Moreover, the cumulative histograms of breathing frequencies binned every 10 breaths/min were significantly different in room air and hypoxia conditions across all ages in hyperoxic pups compared to control pups. Preliminary analyses indicated tidal volume variability across room air and hypoxia is also significantly elevated acutely (P10) by 100% and chronically (P60) by 250% in hyperoxic pups compared to control pups. Additional preliminary data indicate increased expression of an astrocytic marker (GFAP) throughout brainstem respiratory nuclei in P60 rats perinatally treated with hyperoxia, consistent with astrogliosis. These data demonstrate significant and lasting anatomical and physiological changes to the brainstem and the neural control of breathing in a rat model of BPD, suggesting additional potential pathologies in human BPD patients.Support or Funding InformationChildren's Hospital of Wisconsin Research InstituteThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.