Neonatal ventilatory changes in the control of breathing in a hyperoxia‐induced mouse model of bronchopulmonary dysplasia

Abstract

While hyperoxia is needed for survival of very premature infants (<28 weeks gestation) due to immature lungs and immature neural control of breathing, it contributes to bronchopulmonary dysplasia (BPD), a chronic lung disease associated with heighted pediatric morbidity and mortality. Given the plasticity of the neural control of breathing, this study seeks to address whether the neural control of breathing adapts to lung disease and the roles of clusters of pulmonary neuroendocrine cells called neuroepithelial bodies (NEBs) in mediating breathing adaptations (or maladaptations). NEBs line the airways, are O2 and CO2 sensitive, are hypertrophied/hyperplastic in human BPD, and are innervated by vagal fibers that inhibit breathing when activated. Herein, we test the hypotheses that chronic neonatal hyperoxia causes age‐dependent changes to cardiorespiratory control and these changes are in part mediated by NEBs. Mice expressing eGFP in all NEBs were exposed to hyperoxia (FIO2: 0.7 from 0‐14 days of life; P0‐14) had reduced alveolar density (P<0.001) and fewer alveoli (P<0.001) compared with normoxic controls (n=4) at P22 (by 2‐tailed t‐Test), consistent with clinical BPD. Whole‐body flow through plethysmography did not reveal baseline breathing differences between normoxic (n=10) and hyperoxic (n=10) mice at any of the ages studied (P14‐22), though there is a trend (n=3/group) for a greater respiratory exchange ratio (RER) measured by respirometry in hyperoxic mice. There was also a significant main effect of hyperoxia (n=7) reducing the hypoxic and hypercapnic ventilatory responses compared to normoxic mice (n=10; two‐way mixed effect model with Sidak post‐hoc test). Ongoing studies aim to lesion NEBs using Saporin toxin conjugated to an NEB specific membrane protein in a subset of mice to address the functional role of NEBs in breathing in normoxic and hyperoxic treated mice.