Targeting IL6-Edn1-FoxO1 axis enables lung growth in mechanically ventilated newborn mice.

RATIONALE: Mechanical ventilation is a life-saving treatment for preterm infants that often leads to bronchopulmonary dysplasia (BPD). We previously demonstrated a reduced number of alveolar epithelial cells with a depletion of alveolar epithelial type 2 cells (AT2) in lungs of infants with BPD.

OBJECTIVE: To investigate and target the mechanisms by which mechanical ventilation causes an arrest of alveolarisation.

METHODS: Experimental mouse model of neonatal ventilation-induced lung injury (VILI) in wild-type mice, Il6-null mice, and pharmacological inhibition of interleukin (IL)-6 and endothelin receptors. Complementary, precision-cut lung slices (PCLS) and primary cells were analysed. Moreover, lungs of infants with BPD were studied.

RESULTS: Mechanical ventilation leads to an AT2 depletion and arrest of alveolar growth. Transcriptomic profiling, measurement of gene and protein expression, immunofluorescent staining as well as cell culture studies identified an IL-6-mediated expression of Endothelin-1 (Edn1) and a nuclear sequestration of the antiproliferative transcription factor FoxO1 in AT2. These findings were confirmed using murine PCLS, lung epithelial cells and transgenic mice with inducible constitutive active FoxO1. In vivo, Il6-null mice and pharmacological inhibition of IL-6 or endothelin A and B receptors prevented nuclear sequestration of FoxO1, thereby enabling lung growth of newborn mice exposed to mechanical ventilation.

CONCLUSION: Mechanical ventilation causes an arrest of alveolarisation in newborn mice through an IL-6-mediated activation of Edn1 signalling and nuclear sequestration of FoxO1 in AT2. Thus, this study provides rationale for considering pharmacological inhibition of IL-6 and/or endothelin receptors as a therapeutic strategy for preterm newborns at risk of VILI-associated lung growth arrest.