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The aim of this study was to evaluate the effects of respiratory rate (RR) at a constant Paco2 and conventional tidal volume (VT) on the development of ventilator-induced lung injury in normal lungs.Prospective, randomized, experimental study.University research laboratory.Adult male C57BL/6 mice.Four groups of anesthetized mice were exposed to mechanical ventilation with different RRs and VTs. Three groups were assigned to one of three RRs (80, 120, and 160 breaths/min), and VT was set to 12, 10, and 8 mL/kg, respectively (RR80VT12, RR120VT10, and RR160VT8), to achieve normal Paco2. A fourth group was ventilated at 160 breaths/min and VT of 10 mL/kg (RR160VT10) with adjustment of dead space. All animals were ventilated for 120 mins with a positive end-expiratory pressure of 1.5 cm H2O and Fio2 of 1. Nonventilated animals were also studied.Arterial blood gases and static pressure–volume curves were not different among groups at the end of the experiment. Independent of ventilator settings, mechanical ventilation was associated with increased bronchoalveolar lavage protein and increased bronchoalveolar lavage and serum interleukin-6. Total bronchoalveolar lavage protein and interleukin-6 were significantly lower in RR80VT12 and RR160VT8 compared with RR120VT10 and RR160VT10. In all experimental conditions, mechanical ventilation was associated with activation of AKT and ERK1/2 kinases, known to be activated on stretch. Phosphorylation both of AKT and ERK1/2 was lower in RR80VT12 compared with other groups of ventilated animals. Histologic injury did not differ among nonventilated, RR80VT12, and RR160VT8 animals; however, it increased significantly and progressively in RR120VT10 and RR160VT10 animals.Mechanical ventilation with conventional VT induces lung injury in normal lungs, even without alteration in lung mechanics. Reduction of RR and VT ameliorates lung inflammation and injury.