The effects of conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation (HFO) on intraalveolar expression of the tumor necrosis factor-alpha (TNF-alpha) gene were studied in surfactant-depleted rabbits. After lung lavage with saline, 13 rabbits were administered either CMV (n = 6) or HFO (n = 7) for 1 h at an FiO2 of 1.0 and a mean airway pressure of 13 cm H2O. Lung lavage was then repeated. The rabbits' RNA was extracted from the lavage cells, and mRNA for TNF-alpha was quantitated by reverse-transcription polymerase chain reaction using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an internal standard. At 1 h of ventilation, PaO2 was slightly lower with CMV than HFO, while lavage cell counts and cytology were similar between the two groups. The ratio of TNF-alpha mRNA to GAPDH mRNA increased with CMV (control, 0.48 +/- 0.04 [SE] versus 1 h, 1.02 +/- 0.14, p < 0.01) but did not change with HFO (0.55 +/- 0.07 versus 0.73 +/- 0.09). In a separate series of experiments, ten surfactant-depleted rabbits continued to be ventilated for 4 h either by CMV (n = 5) or HFO (n = 5). Conventional mechanical ventilation resulted in a progressive hypoxemia, decreased lung compliance, increased number of neutrophils in lung lavage fluid, and substantial morphological changes including hyaline membrane formation and neutrophil accumulation, whereas HFO was associated with minimal changes in such physiological and pathological abnormalities. These results suggest that activation of alveolar macrophages and production of proinflammatory cytokines may play a pivotal role in the early stage of ventilator-induced lung injury, and that ventilator mode (CMV or HFO) substantially modulates macrophage activation and hence the degree of lung injury.