Titrating cumulative neonatal hyperoxia in mice to model bronchopulmonary dysplasia severities

The severity of bronchopulmonary dysplasia (BPD) is defined by the type or amount of respiratory support needed at 36 weeks' postmenstrual age, reflecting varying degrees of impairment in the supply and demand systems regulating arterial oxygenation. However, existing preclinical BPD models fail to account for the comprehensive nature of arterial oxygen regulation (lungs, control mechanisms, and metabolism). Here, based on the predictive power of cumulative supplemental oxygen and BPD severity, we demonstrate that dose-dependent increases of cumulative supplemental oxygen (CSO) limited to the saccular stage of lung development in neonatal mice underlie distinct pathophysiologic features associated with varying degrees of BPD-like phenotypes. Specifically, greater saccular-stage CSO levels elicited pathological features commonly associated with severe BPD, including worse alveolar simplification, risk for pulmonary hypertension, hypoventilation, changes in body growth, greater work of breathing, and metabolic acidosis. However, low levels of saccular-stage CSO elicited features associated with mild BPD, including mild but significant alveolar simplification and pulmonary vascular medial wall thickening, with a compensatory ventilatory hyperpnea driven by an increased neural drive to breathe. Thus, we show that different levels of CSO can elicit clinically relevant mild or severe BPD-like phenotypes, underscoring the widespread impact of CSO on physiological systems regulating arterial oxygenation. This paradigm enables preclinical testing of therapeutic efficacy across BPD severities, albeit without other common complicating factors. However, this paradigm is amenable to additional insults to align with the more complex clinical course of BPD.