Targeting IL-6 and Endothelin Signaling to Protect Lung Development in Mechanically Ventilated Newborns

Mechanical ventilation (MV) is a life-saving intervention for preterm infants but often contributes to bronchopulmonary dysplasia (BPD) by disrupting normal lung development. Building on previous findings of reduced alveolar epithelial cells in BPD, this study uncovers the mechanistic link between MV, inflammation, and arrested alveolarization.

Using a neonatal mouse model of ventilation-induced lung injury (nVILI), Il6-deficient mice, pharmacological inhibitors, precision-cut lung slices, and human BPD lung samples, the researchers demonstrate that MV induces IL-6–dependent activation of endothelin-1 (Edn1) signaling. This cascade triggers nuclear sequestration of the anti-proliferative transcription factor FoxO1 in alveolar type 2 (AT2) cells, leading to AT2 depletion and impaired alveolar growth.

Importantly, blocking IL-6 or endothelin receptors (ET(A) and ET(B)) prevented FoxO1 nuclear sequestration and restored alveolar development in newborn mice.

Clinical relevance:
These findings identify an IL-6–Edn1–FoxO1 axis as a key pathway driving MV-induced lung growth arrest, suggesting that targeting IL-6 and endothelin signaling could offer novel therapeutic strategies to protect the developing lungs of preterm infants at risk for BPD.

Find the full article here: https://pubmed.ncbi.nlm.nih.gov/41067869/