Toward Endotype-Based Bronchopulmonary Dysplasia: Evolving Definitions and the Role of Translational Models

Bronchopulmonary dysplasia (BPD) remains one of the most frequent and clinically relevant chronic respiratory complications of extreme prematurity. Although successive definitions have improved disease classification, most are still based on oxygen requirement and respiratory support assessed at 36 weeks postmenstrual age (PMA), an approach that fails to capture the biological heterogeneity, dynamic clinical trajectories and long-term consequences of the disease. This narrative review analyzes the evolution of BPD definitions, from early time-based criteria to contemporary classifications based on severity and respiratory support, highlighting their strengths and limitations for predicting outcomes and translational research. We argue for the need to move beyond BPD as a single clinical entity toward a framework based on phenotypes and endotypes, including the parenchymal, airway, vascular, inflammatory, and mechanical components of the disease. Although non-animal alternatives are rapidly evolving, animal models remain the primary tools for analyzing specific developmental windows, injurious exposures, and molecular pathways involved in impaired alveolarization, abnormal vascular growth, inflammation, and ventilator-induced lung injury. We propose an endotype-based approach to guide the selection of preclinical models, supported by standardized injury protocols, longitudinal multimodal measurements, and the integration of emerging technologies such as organoids, lung-on-a-chip platforms, multi-omics, and predictive modeling. Redefining BPD through a translational and mechanism-based framework may improve risk stratification and support precision neonatal therapies.