BACKGROUND: Ventilator-induced lung injury has been attributed to the interaction of several factors: tidal volume (VT), positive end-expiratory pressure (PEEP), transpulmonary driving pressure (difference between transpulmonary pressure at end-inspiration and end-expiration, DeltaP,L), and respiratory system plateau pressure (Pplat,rs). METHODS: Forty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, animals were randomized into combinations of VT and PEEP, yielding three different DeltaP,L levels: DeltaP,LLOW (VT = 6 ml/kg, PEEP = 3 cm H2O); DeltaP,LMEAN (VT = 13 ml/kg, PEEP = 3 cm H2O or VT = 6 ml/kg, PEEP = 9.5 cm H2O); and DeltaP,LHIGH (VT = 22 ml/kg, PEEP = 3 cm H2O or VT = 6 ml/kg, PEEP = 11 cm H2O). In other groups, at low VT, PEEP was adjusted to obtain a Pplat,rs similar to that achieved with DeltaP,LMEAN and DeltaP,LHIGH at high VT. RESULTS: At DeltaP,LLOW, expressions of interleukin (IL)-6, receptor for advanced glycation end products (RAGE), and amphiregulin were reduced, despite morphometric evidence of alveolar collapse. At DeltaP,LHIGH (VT = 6 ml/kg and PEEP = 11 cm H2O), lungs were fully open and IL-6 and RAGE were reduced compared with DeltaP,LMEAN (27.4 +/- 12.9 vs. 41.6 +/- 14.1 and 0.6 +/- 0.2 vs. 1.4 +/- 0.3, respectively), despite increased hyperinflation and amphiregulin expression. At DeltaP,LMEAN (VT = 6 ml/kg and PEEP = 9.5 cm H2O), when PEEP was not high enough to keep lungs open, IL-6, RAGE, and amphiregulin expression increased compared with DeltaP,LLOW (41.6 +/- 14.1 vs. 9.0 +/- 9.8, 1.4 +/- 0.3 vs. 0.6 +/- 0.2, and 6.7 +/- 0.8 vs. 2.2 +/- 1.0, respectively). At Pplat,rs similar to that achieved with DeltaP,LMEAN and DeltaP,LHIGH, higher VT and lower PEEP reduced IL-6 and RAGE expression. CONCLUSION: In the acute respiratory distress syndrome model used in this experiment, two strategies minimized ventilator-induced lung injury: (1) low VT and PEEP, yielding low DeltaP,L and Pplat,rs; and (2) low VT associated with a PEEP level sufficient to keep the lungs open.