Respiratory distress and
bronchopulmonary dysplasia (BPD) are major problems in preterm infants that are often addressed by
glucocorticoid treatment and increased
oxygen supply, causing catabolic and injurious side effects. Recombinant human
keratinocyte growth factor (rhKGF) is noncatabolic and antiapoptotic and increases
surfactant pools in immature lungs. Despite its usefulness in injured neonatal lungs, the mechanisms of improved
surfactant homeostasis in vivo and systemic effects on
lipid homeostasis are unknown. We therefore exposed newborn rats to 85% vs. 21%
oxygen and treated them systemically with rhKGF for 48 h before death at 7 days. We determined type II pneumocyte (PN-II) proliferation,
surfactant protein (SP)
mRNA expression, and the pulmonary metabolism of individual
phosphatidylcholine (PC) species using [D(9)-methyl]
choline and tandem mass spectrometry. In addition, we assessed liver and plasma lipid metabolism, addressing PC synthesis de novo, the liver-specific
phosphatidylethanolamine methyl
transferase (PEMT) pathway, and
triglyceride concentrations. rhKGF was found to maintain PN-II proliferation and increased SP-B/C expression and
surfactant PC in both normoxic and hyperoxic lungs. We found increased total PC together with decreased [D(9)-methyl]
choline enrichment, suggesting decreased turnover rather than increased secretion and synthesis as the underlying mechanism. In the liver, rhKGF increased PC synthesis, both de novo and via PEMT, underlining the organotypic differences of rhKGF actions on lipid metabolism. rhKGF increased the hepatic secretion of newly synthesized polyunsaturated PC, indicating improved systemic supply with
choline and
essential fatty acids. We suggest that rhKGF has potential as a therapeutic agent in neonates by improving pulmonary and systemic PC homeostasis.