We hypothesized that lung inflammation and parenchymal apoptosis in ventilator-induced lung injury (VILI) are related to angiotensin (ANG) II and assessed the ability of angiotensin-converting enzyme inhibitor captopril to attenuate VILI in rats. Adult male Sprague-Dawley rats were randomized to receive two ventilation strategies for 2 h: 1) HVZP (high-volume zero PEEP) group at a tidal volume of 40 mL/kg, a respiratory rate of 25 breaths/min, and an FiO2 of 0.21. 2) HVZP+CAP (captopril) group received i.p. injection of CAP (100 mg/kg) 30 min before the HVZP ventilation. Another group which did not receive ventilation served as the control. HVZP+CAP group had significantly lower mean arterial pressure than HVZP group at 2 h of ventilation. Total protein recovered from bronchoalveolar lavage fluid (BALF) was significantly higher in rats ventilated with HVZP protocols than in control rats. Rats treated with HVZP ventilation had significantly higher BALF macrophage inflammatory protein (MIP)-2 and lung ANG II than did the control and HVZP+CAP groups. Lung ANG II levels correlated positively with BALF protein and MIP-2. Rats subjected to HVZP and HVZP+CAP ventilation exhibited significantly higher apoptotic airway and alveolar wall cells than did the non-ventilated control group and HVZP+CAP group had significantly lower apoptotic airway and alveolar wall cells than did the HVZP group. These results suggest that the efficiency of captopril to attenuate VILI is related to reduction of inflammatory cytokines and inhibition of apoptosis and indicate that VILI is partly mediated by the local angiotensin system.