We investigated the influence of load impedance on ventilator performance and the resulting effects of reduced tidal volume (Vt) on lung physiology during a 30-min ventilation of normal mice and 10 min of additional ventilation following lavage-induced injury at two positive end-expiratory pressure (PEEP) levels. Respiratory mechanics were regularly monitored, and the lavage fluid was tested for the soluble E-cadherin, an epithelial cell adhesion molecule, and surfactant protein (SP) B. The results showed that, due to the load dependence of the delivered Vt from the small-animal ventilator: 1) uncontrolled ventilation in normal mice resulted in a lower delivered Vt (6 ml/kg at 3-cmH(2)O PEEP and 7 ml/kg at 6-cmH(2)O PEEP) than the prescribed Vt (8 ml/kg); 2) at 3-cmH(2)O PEEP, uncontrolled ventilation in normal mice led to an increase in lung parenchymal functional heterogeneity, a reduction of SP-B, and an increase in E-cadherin; 3) at 6-cmH(2)O PEEP, ventilation mode had less influence on these parameters; and 4) in a lavage model of acute respiratory distress syndrome, delivered Vt decreased to 4 ml/kg from the prescribed 8 ml/kg, which resulted in severely compromised lung function characterized by increases in lung elastance, airway resistance, and alveolar tissue heterogeneity. Furthermore, the low Vt ventilation also resulted in poor survival rate independent of PEEP. These results highlight the importance of delivering appropriate Vt to both the normal and injured lungs. By leaving the Vt uncompensated, it can significantly alter physiological and biological responses in mice.