Simvastatin mitigates ventilator-induced lung injury in mice with acute respiratory distress syndrome via a mechanism partly dependent on neutrophil extracellular traps.

Summary

In an LPS+MV mouse ARDS model, simvastatin reduced lung injury score and wet/dry ratio and improved oxygenation compared with LPS+MV alone. Mechanistically, benefit was partly NETs-dependent, supported by effects paralleling PAD4 inhibition (GSK484) and reduced apoptosis.

Key Findings

• Simvastatin decreased lung injury score and lung wet/dry ratio in LPS+MV mice versus LPS+MV alone.
• Oxygenation (PaO2-related indices) improved with simvastatin treatment.
• Mechanistic benefit was partly NETs-dependent, paralleling effects of PAD4 inhibition (GSK484) and reducing apoptosis.

Clinical Implications

Although preclinical and prophylactic dosing was used, findings motivate clinical evaluation of timing/dose of statins or NET-targeted strategies to reduce VILI risk in ventilated ARDS.

Limitations

• Mouse preclinical model with prophylactic dosing starting 3 days before ventilation; limited clinical translatability
• Sample size and blinding not reported in abstract; survival and long-term outcomes not assessed

Future Directions

Define optimal timing/dose and assess therapeutic (post-injury) statin use; integrate NET biomarkers and combine with NET-targeted agents in preclinical and early-phase clinical trials.