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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #332842
Title: Metabolic perturbations of postnatal growth restriction and hyperoxia-induced pulmonary hypertension in a bronchopulmonary dysplasia model

Author
item LA FRANO, MICHAEL - National Institutes Of Health (NIH)
item FAHRMANN, JOHANNES - National Institutes Of Health (NIH)
item GRAPOV, DMITRY - Cds - Creative Data Solutions
item FIEHN, OLIVER - National Institutes Of Health (NIH)
item Pedersen, Theresa
item Newman, John
item UNDERWOOD, MARK - University Of California
item STEINHORN, ROBIN - Northwestern College
item WEDGWOOD, STEPHEN - University Of California

Submitted to: Metabolomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/20/2017
Publication Date: 2/13/2017
Citation: La Frano, M.R., Fahrmann, J.F., Grapov, D., Fiehn, O., Pedersen, T.L., Newman, J.W., Underwood, M.A., Steinhorn, R.H., Wedgwood, S. 2017. Metabolic perturbations of postnatal growth restriction and hyperoxia-induced pulmonary hypertension in a bronchopulmonary dysplasia model. Metabolomics. 32:13.

Interpretive Summary: Pulmonary hypertension (PH) in newborn infants is a common result of bronchopulmonary dysplasia (BPD) and contributes to increased morbidity and mortality of preterm birth. Growth restriction from poor nutrition and excess oxygen exposure (i.e. hyperoxia) can independently contribute to PH development in newborns. In this study, we explored the metabolic consequences of PH induced by either hyperoxia (75% oxygen exposure), post-natal under nutrition, or a combination of these two insults using newborn Sprague-Dawley rats (n=4/group). Primary metabolism, complex lipids, and lipid mediators were characterized in plasma and lung tissue using GC- and LC-MS technologies. Hyperoxia produced multiple changes to primary metabolism in the lung that indicated elevated oxidative stress, including activation of anti-oxidant pathways, and reduction in reactive oxygen-sensitive membrane lipids. Unlike lung tissue, plasma metabolite changes were induction mode-specific or additive in the combined modes. For example growth-restriction reduced plasma phospholipids, hyperoxia increased oxygenated lipids and TMAO concentrations, and the combined insult elevated 3-hydroxybutyric acid and arginine, suggesting direct and negative impacts on energy metabolism and possibly an adaptive nitric oxide response attempting to reduce the vascular tone. Therefore, the present study highlights a variety of metabolic changes that occur due to postnatal growth-restriction and hyperoxia-induced PH, identifying numerous metabolites and pathways influenced by treatment-specific or combined effects. The rat model used in this study may be robust means of uncovering the mechanisms that contribute to the pathology of PH.

Technical Abstract: 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 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 PH- induction with hyperoxia and post-natal growth restriction in a rat model of BPD. Methods: Sprague-Dawley neonates (n=4/group) underwent three modes of PH induction: 1) growth-restriction-induced by larger litter sizes; 2) hyperoxia-induced by 75% oxygen exposure; 3) combined growth restriction and hyperoxia. Primary metabolism, complex lipids, 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 ß 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 TMAO; 3) additive effects on 3 hydroxybutyric acid and arginine). Conclusion: The present study highlights the variety of metabolic changes that occur due to postnatal growth-restriction and hyperoxia-induced PH, identifying numerous metabolites and pathways influenced by treatment-specific or combined effects. The rat model used in this study may be robust means of uncovering the mechanisms that contribute to the pathology of PH.