The human lung normally ventilates by using negative pressure in the thorax. Once positive pressure is applied, some degree of VILI is likely to occur.
One major causative factor is the over stretching of the airways and alveoli. During mechanical ventilation, the flow of gas into the lung will take the path of least resistance. Areas of the lung that are collapsed (atelectasis) or filled with secretions will be under inflated, while those areas that are relatively normal will be over inflated. These areas will become over distended and injured. This may be reduced by using smaller tidal volumes.
During positive pressure ventilation, atelectatic regions will inflate, however the alveoli will be unstable and will collapse during the expiratory phase of the breath. This repeated alveolar collapse and expansion (RACE) is thought to cause VALI. By opening the lung and keeping the lung open RACE (and VALI) is reduced.