To determine whether low mean airway pressure (MAP) and/or stroke volume (SV) settings cause lung injury during piston-type high-frequency oscillatory ventilation (HFOV), we investigated the influence of various combinations of MAP and SV on the amplitude of the pressure swing at four different sites in the normal lung of rabbits. We also examined the effects of these factors on progression of lung injury in lavaged surfactant-deficient lungs. We measured changes in the mean pressure (MP) and swing pressure (SP) during HFOV at MAPs ranging between 5-30 cm H2O in combination with SVs ranging from 5-30 mL in 13 rabbits at four different sites: 1) the proximal airway, 2) the distal end of the endotracheal tube, 3) the bronchi, and 4) the pleural space. Lung lavage was performed in 8 rabbits and differences in MP and SP between normal and surfactant-deficient rabbits were investigated. In the remaining 5 rabbits, lungs were lavaged and subjected to two trials of sustained inflation to 30 cm H2O for 15 s to reverse atelectasis, and the resulting SP was measured. In normal lungs, SP increased at the bronchial and pleural sites as MAP was increased. Alterations in SV did not affect MP in normal or lavaged lungs. In the lavages, surfactant-deficient lungs at MAPs < or = 15 cm H2O, there were significant increases in SP at the distal end of the endotracheal tube and the bronchial sites. SP decreased to the prelavaged level following sustained inflation to 30 cm H2O for 15 s. We conclude that low MAP settings are insufficient to open alveoli in the low-compliance lung and allow for development of atelectasis rather than air trapping. SP was markedly increased in the presence of atelectasis, possibly leading to excessive expansion of the airway. In the clinical setting, such overexpansion of the distal airways may contribute to lung injury. Our findings suggest that physicians should use caution in reducing MAP during piston-type HFOV until lung compliance has normalized, especially in infants with respiratory distress syndrome.