Reduced parenteral glucose supply in preterm neonatal infection ameliorates the pulmonary damage

Abstract

Preterm infants are acutely susceptible to neonatal sepsis, a syndrome characterized by systemic pro-inflammatory activity and life-threatening multi-organ dysfunction. However, the specific pulmonary pathological response to sepsis and the potential for metabolic interventions to mitigate lung injury remain poorly characterized. Herein, we evaluated the impact of varying parenteral glucose regimens on pulmonary outcomes during severe infection using a preterm piglet model. Genome-wide gene expression analysis was used to characterize lung transcriptome profiles. The relationships between gene expression and circulating biochemical and immune profiles were also investigated. Our findings demonstrate that significant pulmonary tissue damage is a hallmark of neonatal sepsis. A reduced-glucose regimen markedly attenuated pulmonary tissue damage while simultaneously alleviating systemic metabolic acidosis and hyperlactatemia. Mechanistically, lung transcriptome profiling revealed a profound activation of pathways associated with inflammatory signaling, programmed cell death, and the dysregulation of glucose, amino acid, and lipid metabolism. The low-glucose intervention effectively mitigated these widespread molecular and metabolic disturbances, suggesting a restorative effect on the pulmonary transcriptome landscape. To facilitate further mechanistic exploration and the identification of novel therapeutic targets, we developed the NeoSepPulmoExplorer (https://pharmaco-omicslab.shinyapps.io/NeoSepPulmoExplorer/), an interactive web-based toolkit for better mechanistic understanding and the identification of potential treatment targets. These results collectively underscore the importance of metabolic modulation in preserving organ function, though further translational studies are requisite to improve clinical outcomes in septic neonates.