Establishment of a rat model of bronchopulmonary dysplasia complicated with pulmonary hypertension and its potential applications

Objective Bronchopulmonary dysplasia (BPD), a common chronic lung disease in premature infants, is frequently complicated by pulmonary hypertension (PH), a dangerous condition characterized by elevated pulmonary vascular pressure. At present, the most classic and commonly used animal model for BPD involves exposure to high oxygen concentrations, but existing studies based on this model have seldom addressed whether it recapitulates the pathological features of PH. Methods In the present study, we established a rat model of BPD complicated with PH (BPD-PH). Histological hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), flowcytometry, reverse transcription–quantitative PCR (RT-qPCR), wound healing assay, transwell migration and invasion assays, transcriptome RNA-sequencing and GO analysis were performed to evaluate this BPD-PH model. Results Our study demonstrated that rats with BPD-PH exhibited characteristic alveolar simplification and features of pulmonary hypertension, including increased mRVP, RV/LV + S and RV/WT. BPD-PH rats had enhanced inflammatory response and increased accumulation of immune cells in lung. Moreover, differentially expressed genes in the BPD-PH rat model were depicted and we found Leucine-rich alpha-2-glycoprotein 1 ( Lrg1 ) was significantly upregulated by 19.32 fold ( p < 0.001). LRG1 affected migration, invasion and transforming growth factor-β (TGF-β) signaling activation in primary alveolar epithelial cells and pulmonary endothelial cells. Finally, our BPD-PH model was used for the evaluation of two commonly used drugs for BPD and PH, Dexamethasone and Sildenafil. These two drugs were effective in alleviating lung injury, inflammatory response and hypoxia-induced PH in the rat model of BPD-PH. Conclusion Our data indicate that we established a novel BPD-PH model in rats, and it provided a new choice for the future research for BPD complicated with PH.