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

RATIONALE Mechanical ventilation (MV) 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 Investigate and target the mechanisms by which MV causes an arrest of alveolarisation. METHODS Experimental mouse model of neonatal ventilation-induced lung injury (nVILI) in wildtype mice, Il6 null mice, and pharmacological inhibition of IL-6 and Endothelin receptors. Complimentary, precision-cut lung slices (PCLS) and primary cells were analysed. Moreover, lungs of infants with BPD were studied. RESULTS MV 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 anti-proliferative 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 receptor [ET(A)] and ET(B) prevented nuclear sequestration of FoxO1, enabling thereby lung growth of newborn mice exposed to MV. CONCLUSION MV causes an arrest of alveolarisation in newborn mice through an IL-6-mediated activation of Edn1 signaling 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 for VILI-associated lung growth arrest.