The pathophysiology of ventilator-induced lung injury (VILI) involves multiple mechanisms including inflammation. Histone deacetylase inhibitors have been shown to exert anti-inflammation activity. The purpose of this study was to examine the protecting roles and mechanisms of the histone deacetylase inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) in ventilator-induced lung injury in normal rat lung. Male Sprague-Dawley rats were divided into four groups: lung-protective ventilation (LV), injurious ventilation (HV), HV+TSA and HV+ SAHA groups. Mechanical ventilation (MV) settings were 7 ml/kg VT and 3 cm H2O positive end-expiratorypressure [PEEP], 40 breaths/min for LV group and 42 ml/kg VT, zero end-expiratoryvolume [ZEEP], 40 breaths/min for the HV, HV+TSA and HV+ SAHA groups. After 2 h of MV, acute lung injury (ALI) score, wet-to-dry (W/D) weight ratio and the activity of myeloperoxidase (MPO) were determined. The concentration of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-10(IL-6) in the homogenized lung were measured by ELISA. The expression ICAM-1 was measured by both realtime PCR and Western blot assays. In addition, survival of each group was also assessed. Our results indicated that administration of TSA or SAHA alleviated ventilator-induced lung injury. This was accompanied by reduced neutrophil infiltration, reduced MPO activity, decreased intercellular adhesion molecule-1 (ICAM-1) expression in lung tissue, and lower TNF-α, IL-1β and IL-6 levels. In addition, treatment with HDAC inhibitors significantly prolonged the survival time of ventilator-induced lung injury rats. Our data suggested that TSA and SAHA could significantly alleviate ventilator-induced rat lung injury and prolong the survival time of those rats by attenuate intrapulmonary inflammatory response.