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Targeting IL6-Edn1-FoxO1 axis enables lung growth in mechanically ventilated newborn mice
Dharmesh Hirani1,2, Jaco Selle2, Virta Wagde2
1Institute for Lung Health (ILH) and Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Insights
Mechanical ventilation harms preterm infant lungs by arresting alveolar growth via IL-6 and Endothelin-1 signaling. Inhibiting these pathways may prevent lung injury in vulnerable newborns.
Area of Science:
- Neonatal Medicine
- Pulmonary Biology
- Developmental Biology
Background:
- Mechanical ventilation is crucial for preterm infants but can cause bronchopulmonary dysplasia (BPD).
- BPD is characterized by reduced alveolar epithelial cells, particularly alveolar epithelial type 2 cells (AT2).
Purpose of the Study:
- To investigate the mechanisms by which mechanical ventilation arrests alveolar development.
- To identify potential therapeutic targets to prevent ventilation-induced lung injury.
Main Methods:
- Utilized a mouse model of neonatal ventilation-induced lung injury (VILI).
- Employed genetic knockout (Il6-null) and pharmacological inhibition of IL-6 and endothelin receptors.
- Analyzed precision-cut lung slices (PCLS), primary lung cells, and infant BPD lungs.
Main Results:
- Mechanical ventilation caused AT2 cell depletion and arrested alveolar growth in mice.
- Identified an IL-6-mediated pathway involving Endothelin-1 (Edn1) and nuclear sequestration of FoxO1 in AT2 cells.
- Inhibition of IL-6 or endothelin receptors prevented FoxO1 sequestration and restored lung growth in ventilated mice.
Conclusions:
- Mechanical ventilation arrests alveolarization through IL-6/Edn1 signaling and FoxO1 sequestration in AT2 cells.
- Pharmacological inhibition of IL-6 and/or endothelin receptors is a potential therapeutic strategy for VILI-associated lung growth arrest in preterm infants.
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.
