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Published on: May 4, 2020
Effects of recombinant human keratinocyte growth factor on surfactant, plasma, and liver phospholipid homeostasis in
Marco Raith1, Katharina Schaal, Roland Koslowski
1Department of Neonatology, Faculty of Medicine, Eberhard-Karls-University, Calwer Strasse 7, Tübingen, Germany.
Insights
Recombinant human keratinocyte growth factor (rhKGF) improves lung surfactant and systemic lipid metabolism in newborn rats, offering potential therapeutic benefits for preterm infants with respiratory distress and bronchopulmonary dysplasia (BPD).
Area of Science:
- Neonatal physiology and respiratory medicine
- Lipid metabolism and pulmonary surfactant homeostasis
Background:
- Respiratory distress and bronchopulmonary dysplasia (BPD) in preterm infants pose significant clinical challenges.
- Current treatments like glucocorticoids and oxygen therapy have detrimental side effects.
- Recombinant human keratinocyte growth factor (rhKGF) shows promise for immature lungs but its mechanisms and systemic effects are unclear.
Purpose of the Study:
- To investigate the mechanisms by which rhKGF improves pulmonary surfactant homeostasis in vivo.
- To assess the systemic effects of rhKGF on lipid metabolism in neonatal rats.
- To evaluate rhKGF's potential as a therapeutic agent for neonatal respiratory conditions.
Main Methods:
- Newborn rats were exposed to hyperoxia (85% O2) or normoxia (21% O2) and treated with rhKGF.
- Pulmonary type II pneumocyte (PN-II) proliferation, surfactant protein (SP) mRNA, and phosphatidylcholine (PC) metabolism were analyzed.
- Liver and plasma lipid metabolism, including PC synthesis pathways (de novo, PEMT) and triglyceride levels, were assessed.
Main Results:
- rhKGF maintained PN-II proliferation and increased SP-B/C expression and surfactant PC in both normoxic and hyperoxic lungs.
- Pulmonary PC metabolism showed decreased turnover, not increased synthesis or secretion, as the mechanism for increased PC.
- rhKGF enhanced hepatic PC synthesis (de novo and PEMT pathways) and increased secretion of newly synthesized polyunsaturated PC.
Conclusions:
- rhKGF effectively improves pulmonary surfactant homeostasis and positively modulates systemic lipid metabolism in neonatal rats.
- The findings suggest rhKGF enhances pulmonary and systemic phosphatidylcholine (PC) balance.
- rhKGF demonstrates potential as a therapeutic agent for improving outcomes in neonates with respiratory challenges.
Abstract:
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.
