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Objectives: To test the hypothesis that protective ventilation strategy (PVS) as defined by the use of low stretch ventilation (tidal volume of 5 ml·kg−1 and employing 5 cm of positive end expiratory pressure (PEEP) during one lung ventilation (OLV) in piglets would result in reduced injury compared to a control group of piglets who received the conventional ventilation (tidal volume of 10 ml·kg−1 and no PEEP). Background: PVS has been found to be beneficial in adults to minimize injury from OLV. We designed the current study to test the beneficial effects of PVS in a piglet model of OLV. Methods: Ten piglets each were assigned to either ‘Control’ group (tidal volume of 10 ml·kg−1 and no PEEP) or ‘PVS’ group (tidal volume of 5 ml·kg−1 during the OLV phase and PEEP of 5 cm of H2O throughout the study). Experiment consisted of 30 min of baseline ventilation, 3 h of OLV, and again 30 min of bilateral ventilation. Respiratory parameters and proinflammatory markers were measured as outcome. Results: There was no difference in PaO2 between groups. PaCO2 ( P < 0.01) and ventilatory rate ( P < 0.01) were higher at 1.5 h OLV and at the end point in the PVS group. Peak inflating pressure (PIP) and pulmonary resistance were higher ( P < 0.05) in the control group at 1.5 h OLV. tumor necrosis factor-alpha ( P < 0.04) and IL-8 were less ( P < 0.001) in the plasma from the PVS group, while IL-6 and IL-8 were less ( P < 0.04) in the lung tissue from ventilated lungs in the PVS group. Conclusions: Based on this model, PVS decreases inflammatory injury both systemically and in the lung tissue with no adverse effect on oxygenation, ventilation, or lung function. [ABSTRACT FROM AUTHOR]