Brooke Dir, Raveena Mishra, Nicole Hennen, Emily Mooers, Ru-jeng Teng, Ganesh Konduri, Jeffrey L. Segar, Justin Grobe, Matthew R. Hodges, Gary C. Mouradian
Medical College of Wisconsin.
United States
American Journal of Respiratory Cell and Molecular Biology
Am J Respir Cell Mol Biol 2026;
DOI: 10.1093/ajrcmb/aanag031
Abstract
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 CSO limited to the saccular stage of lung development in neonatal mice underlies 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, though 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, expanding the widespread impact CSO has 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.
Category
Class III. Pulmonary Hypertension Associated with Lung Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes