Limited postnatal feeding reduces the PPARy-Setd8-H4K20me-1_WNT pathway in the lung of chronically ventilated preterm lambs

Preterm neonates supported by invasive intermittent mechanical ventilation (IMV) often experience poor postnatal growth characterized by feeding intolerance and failure to thrive. One consequence of poor postnatal nutrition is reduced substrate availability such as essential fatty acids, and reduced alveolar formation, all resulting in poor lung outcomes and risk for chronic lung disease. Our group showed that preterm lambs supported by IMV have feeding intolerance, poor growth, and impaired alveolar formation. In contrast, preterm lambs supported by high-frequency nasal ventilation (HFNV) feed and grow, and have normal alveolar formation. When preterm lambs supported by HFNV have feeding volumes restricted, they experience poor postnatal growth, and have arrested alveolar formation. One pathway involved in alveolar formation is the essential fatty acid docosahexanoic acid (DHA) activated PPARγ-Setd8- H4K20me1-Wnt pathway. We hypothesized that restricted feeding of preterm lambs supported by HFNV reduces available serum DHA, as well as components of the PPARγ- Setd8-H4K20me1-Wnt pathway. To test this hypothesis, we used the preterm lamb model of chronic lung disease. Two groups of preterm lambs were supported by noninvasive HFNV for 21 days. One group (restricted) had feedings restricted to 75% (mL/kg/day) of that received by the control group (matched for feeding tolerated during IMV). iv The other group (control) received feedings as tolerated, progressing to ad libitum. Both groups were fed ewe's colostrum for three days, proceeding to mature ewe milk. We measured plasma and lung DHA, as well as components of the PPARγ-Setd8-H4K20me1-Wnt pathway. Restricted feeding of preterm lambs reduced serum and lung DHA levels relative to control. Restricted feeding of preterm lambs also significantly decreased lung PPARγ, Setd8, and Wnt signaling components β-catenin, and Wnt11 compared to control. Restricted feeding also reduced Wnt output gene MMP9 mRNA transcript level compared to control. In conclusion, restricted feeding of preterm lambs managed by HFNV reduces serum DHA and components of the PPARγ-Setd8-H4K20me1-Wnt pathway in the lung. We speculate that restoration of serum DHA levels in preterm lambs managed by restricted feeding during HFNV will restore PPARγ- Setd8-H4K20me1-Wnt pathway activation and alveolar formation.