BACKGROUND: Gradually changing respiratory rate (RR) during time to reduce ventilation-induced lung injury has not been investigated. The authors hypothesized that gradual, compared with abrupt, increments in RR would mitigate ventilation-induced lung injury and that recruitment maneuver before abruptly increasing RR may prevent injurious biologic impact. METHODS: Twenty-four hours after intratracheal administration of Escherichia coli lipopolysaccharide, 49 male Wistar rats were anesthetized and mechanically ventilated (tidal volume, 6 ml/kg; positive end-expiratory pressure, 3 cm H2O) with RR increase patterns as follows (n = 7 per group): (1) control 1, RR = 70 breaths/min for 2 h; (2) and (3) abrupt increases of RR for 1 and 2 h, respectively, both for 2 h; (4) shorter RR adaptation, gradually increasing RR (from 70 to 130 breaths/min during 30 min); (5) longer RR adaptation, more gradual increase in RR (from 70 to 130 breaths/min during 60 min), both for 2 h; (6) control 2, abrupt increase of RR maintained for 1 h; and (7) control 3, recruitment maneuver (continuous positive airway pressure, 30 cm H2O for 30 s) followed by control-2 protocol. RESULTS: At the end of 1 h of mechanical ventilation, cumulative diffuse alveolar damage scores were lower in shorter (11.0 [8.0 to 12.0]) and longer (13.0 [11.0 to 14.0]) RR adaptation groups than in animals with abrupt increase of RR for 1 h (25.0 [22.0 to 26.0], P = 0.035 and P = 0.048, respectively) and 2 h (35.0 [32.0 to 39.0], P = 0.003 and P = 0.040, respectively); mechanical power and lung heterogeneity were lower, and alveolar integrity was higher, in the longer RR adaptation group compared with abruptly adjusted groups; markers of lung inflammation (interleukin-6), epithelial (club cell secretory protein [CC-16]) and endothelial cell damage (vascular cell adhesion molecule 1 [VCAM-1]) were higher in both abrupt groups, but not in either RR adaptation group, compared with controls. Recruitment maneuver prevented the increase in VCAM-1 and CC-16 gene expressions in the abruptly increased RR groups. CONCLUSIONS: In mild experimental acute respiratory distress syndrome in rats, gradually increasing RR, compared with abruptly doing so, can mitigate the development of ventilation-induced lung injury. In addition, recruitment maneuver prevented the injurious biologic impact of abrupt increases in RR.