Establishment of a neonatal rat model of sequential hyperoxic hypoxia to recapitulate clinical progression of bronchopulmonary dysplasia-associated pulmonary hypertension.

BACKGROUND: Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) seriously threatens the lives of preterm infants. The absence of animal models that can simulate its progression from early hyperoxic lung injury to late hypoxic vascular remodeling has hindered related research. OBJECTIVE: To establish a neonatal rat BPD-PH model by simulating exposure to sequential hyperoxic hypoxia experienced by human preterm infants. METHODS: Newborn SD rats were randomized into two control groups (C1 exposed to 21% O₂ for 2 weeks; C2 exposed to 21% O₂ for 3 weeks), and three exposure groups (H1 exposed to 75% O₂ for 2 weeks; H2 exposed to 75% O₂ for 2 weeks and then to 10% O₂ for a week; H3 exposed to 75% O₂ for 2 weeks and then to normoxia for a week). Cardiopulmonary parameters were evaluated by echocardiography, right ventricular systolic pressure measurement, histology, and α-SMA immunofluorescence. RESULTS: H1 and H2 groups exhibited distinct phenotypes, with those in the H2 group showing more severe phenotypes. The H2 group exhibited a 142% increase in RVSP relative to those in the C2 group. The right-heart index (RI) was 0.43 ± 0.01 in the H2 group, 0.36 ± 0.02 in the H3 group, and 0.22 ± 0.03 in the C2 group. Pulmonary vascular remodeling was significantly increased in the H2 group compared to the control and H3 groups. The H2 group uniquely replicated the disease process, with alveolar simplification preceding hypoxia-induced vascular thickening. CONCLUSION: The sequential hyperoxic hypoxia model dynamically mimicked the clinical progression of BPD-PH, which may provide a powerful platform for stage-specific mechanism research and development of novel therapeutic strategies.