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Objective To compare effect of high-frequency oscillation ventilation (HFOV) and conventional mandatory ventilation (CMV) on lung injury development in rabbit with acute respiratory distress syndrome (ARDS). Methods Animals that underwent saline lung lavage to produce lung injury were randomized to one of the two treatment groups (HFOV or CMV, n=6). PaCO2 was maintained between 35-45mmHg and arterial oxygen saturation (SaO2) was maintain >88% by adjusting corresponding ventilator parameters. Ventilation period was 6h. Lung fluids were aspirated before and at the end of ventilation for cell analysis. Then the animals were euthanized, lung tissue was removed for wet/dry weight measurement, light and electron microscopic examination.Results The difference of artery blood gas analyses(pH, PaO2, PaCO2) between HFOV and CMV was insignificant. The difference between HFOV and CMV in cytological examination of lung fluids, wet/dry weight measurement was also insignificant. But compared with CMV,HFOV not only reduced the area of lung injury, but also reduced lung injury score in light and electron microscopic examination. Conclusion When same artery blood gas analysis was obtained, HFOV significantly reduced lung injury development in ARDS animal than CMV. As a lung protection strategy, HFOV can be used in the treatment of ARDS.