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Harmful effects of spontaneous breathing have been shown in experimental severe acute respiratory distress syndrome (ARDS). However, in the clinical setting, spontaneous respiration has been indicated only in mild ARDS. To date, no study has compared the effects of spontaneous assisted breathing with those of fully controlled mechanical ventilation at different levels of positive end-expiratory pressure (PEEP) on lung injury in ARDS.To compare the effects of assisted pressure support ventilation (PSV) with pressure-controlled ventilation (PCV) on lung function, histology and biological markers at two different PEEP levels in mild ARDS in rats.Randomised controlled experimental study.Basic science laboratory.Thirty-five Wistar rats (weight ± SD, 310 ± 19) g received Escherichia coli lipopolysaccharide (LPS) intratracheally. After 24 h, the animals were anaesthetised and randomly allocated to either PCV (n=14) or PSV (n=14) groups. Each group was further assigned to PEEP = 2 cmH2O or PEEP = 5 cmH2O. Tidal volume was kept constant (≈6 ml kg−1). Additional nonventilated animals (n=7) were used as a control for postmortem analysis.Ventilatory and mechanical parameters, arterial blood gases, diffuse alveolar damage score, epithelial integrity measured by E-cadherin tissue expression, and biological markers associated with inflammation (IL-6 and cytokine-induced neutrophil chemoattractant, CINC-1) and type II epithelial cell damage (surfactant protein-B) were evaluated.In both PCV and PSV, peak transpulmonary pressure was lower, whereas E-cadherin tissue expression, which is related to epithelial integrity, was higher at PEEP = 5 cmH2O than at PEEP = 2 cmH2O. In PSV, PEEP = 5 cmH2O compared with PEEP = 2 cmH2O was associated with significantly reduced diffuse alveolar damage score [median (interquartile range), 11 (8.5 to 13.5) vs. 23 (19 to 26), P = 0.005] and expressions of IL-6 and CINC-1 (P = 0.02 for both), whereas surfactant protein-B mRNA expression increased (P = 0.03). These changes suggested less type II epithelial cell damage at a PEEP of 5 cmH2O. Peak transpulmonary pressure correlated positively with IL-6 [Spearman's rho (ρ) = 0.62, P = 0.0007] and CINC-1 expressions (ρ = 0.50, P = 0.01) and negatively with E-cadherin expression (ρ = −0.67, P = 0.0002).During PSV, PEEP of 5 cmH2O, but not a PEEP of 2 cmH2O, reduced lung damage and inflammatory markers while maintaining epithelial cell integrity.