Metabolic perturbations of postnatal growth restriction and hyperoxia-induced pulmonary hypertension in a bronchopulmonary dysplasia model

Introduction: Neonatal pulmonary hypertension (PH) is a common manifestation of bronchopulmonary dysplasia (BPD) and contributes to increased morbidity and mortality of preterm birth. Postnatal growth restriction (PNGR) and hyperoxia are independent contributors to PH development, as indicated by our previous work in a rat model of BPD. Objective: To explore the metabolic consequences of induction of PH with hyperoxia and PNGR in a rat model of BPD. Methods: Sprague–Dawley rat pups (n = 4/group) underwent three modes of PH induction: (1) growth restriction-induced by larger litter size; (2) hyperoxia-induced by 75% oxygen exposure; (3) combined growth restriction and hyperoxia. Primary metabolism, complex lipids, biogenic amines, and lipid mediators were characterized in plasma and lung tissue using GC- and LC-MS technologies. Results: Specific to hyperoxic induction, pulmonary metabolomics suggested increased reactive oxygen species (ROS) generation as indicated by: (1) increased indicators of β-oxidation and mitochondrial respiration; (2) changes in ROS-sensitive pathway activity and metabolites including the polyol pathway and xanthine oxidase pathways, and reduced glutathione; (3) decreased plasmalogens. Unlike the lung, circulating metabolite changes were induction mode-specific or additive in the combined modes (e.g. 1) growth-restriction reduced phosphatidylcholine; (2) hyperoxia increased oxylipins and trimethylamine-N-oxide (TMAO); (3) additive effects on 3-hydroxybutyric acid and arginine. Conclusion: The present study highlights the variety of metabolic changes that occur due to PNGR- and hyperoxia-induced PH, identifying numerous metabolites and pathways influenced by treatment-specific or combined effects. The rat model used in this study presents a robust means of uncovering the mechanisms that contribute to the pathology of PH.