Background and objective
Proinflammatory mediators released into the systemic circulation of ventilated adults can initiate lung and liver dysfunction, and the lung immune landscape is mediated by hepatic signals during systemic inflammation. These interactions, however, remain enigmatic in ventilated preterm neonates. The objective of this study is to elucidate the lung-liver axis in a preterm lamb model where lung-injury interactions have been described, using proteomics and bioinformatics to profile ventilator-induced changes in lung, liver, and plasma.
Methods
123-127d (term 145d) preterm lambs received 15-min respiratory support (initial dynamic PEEP manoeuvre) with either no tidal inflations (ΔP) (n=8) [DynPEEP] or increasing tidal inflations at 20 cmH2O ΔP (n=5) [Dyn20], or 30 cmH2O ΔP (n=5) [Dyn30], allowing 30-min of apnoea for injury marker expression. Tissue (lung and liver) samples were TMT-labelled and analysed using LC-MS/MS in data-dependent acquisition mode while plasma samples were label-free and analysed in data-independent acquisition mode. Protein alterations in tissues and plasma were compared between DynPEEP and Dyn20 or Dyn30 with bioinformatic analysis performed to identify biological processes underlying proteome changes.
Results
Across sample types, principal component analysis revealed distinct clustering of Dyn20 and Dyn30 proteome from DynPEEP. In the lung, both Dyn20 and Dyn30 exhibited enrichment of proteins associated with immune regulation, coagulation, tissue remodelling, and metabolism. Alterations observed in the liver included increased inflammation, angiogenesis, and energy metabolism. Indicators of organ damage were significantly increased in Dyn30 plasma compared to DynPEEP and Dyn20, including antioxidative and anti-inflammatory proteins.
Conclusion
Extrapulmonary proteome changes were identified in the preterm liver and plasma following ventilation. Inflammatory, angiogenic, and metabolic processes upregulated in the liver indicate potential mechanisms driving hepatic dysfunction, and protein mediators of injury identified in plasma highlight their role in interorgan crosstalk.