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Title: Dynamic surfactant metabolism in preterm infants
Author: Goss, Kevin Colin William
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2012
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Exogenous surfactant therapy has dramatically improved survival in extremely preterm infants, however the turnover of exogenous and synthesis of endogenous surfactant components are still poorly understood in this group. Additionally there is evidence for this patient group that improving nutrition improves long-term outcomes in respiratory function, growth and neurodevelopment. Phosphatidylcholine (PC) is the dominant phospholipid in both surfactant and in plasma and can be synthesised from choline by one of two pathways: the CDPcholine pathway, which is present in all nucleated cells, or by three sequential methylations of phosphatidylethanolamine in the PEMT pathway, which is localised to hepatocytes and is the primary source of polyunsaturated PC species and de novo synthesis of choline. This study quantified choline phospholipid metabolism and pulmonary surfactant kinetics in preterm infants in vivo. Children aged between 23 and 28 weeks gestation and in receipt of exogenous surfactant were intravenously infused with [methyl-D9]choline chloride within 48 hours of birth. Lipid extracts from sequential plasma and endotracheal aspirate samples were then analysed by electrospray ionisation tandem mass spectrometry (ESIMS/ MS). Fractional incorporation into newly synthesised PC species is demonstrated rapidly in plasma samples at a higher rate than previously reported in adults, indicating a high level of hepatic activity for CDP-choline. Analysis of the PC species derived from the PEMT pathway shows significantly lower flux in this pathway than reported in adults. Finally incorporation into surfactant PC species is very low initially before rising slowly over several days and with the rapid changes in other acidic phospholipids suggests a rapid recycling of components of the exogenous surfactant not equilibrating with the CDP-choline pathway thereby providing evidence for the first time of differing rates of exogenous surfactant recycling versus de novo synthesis in the human preterm infant. This study proves that the technique works in the clinical environment, is sensitive and rapid enough to provide data in a clinically relevant timeframe, opening the possibility for translational use to identify biomarkers for disease progression.
Supervisor: Clark, Howard ; Postle, Anthony Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology ; RJ Pediatrics ; RM Therapeutics. Pharmacology