BACKGROUND: 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors have several pleiotropic effects, including anti-inflammatory properties, and are reported to improve endothelial functions. Pathophysiologically, acute lung injury (ALI) is caused by a severe inflammatory response and endothelial dysfunction. OBJECTIVE: To investigate the effects of simvastatin (an HMG-CoA reductase inhibitor) on oxidative stress and lung histopathology in 2 murine models of ALI, induced by oleic acid and endotoxin. METHODS: The mice were randomly divided into 2 groups: one received 2 mg/kg/d intraperitoneal simvastatin for 15 days. Then the groups were further divided into 3, which received saline, oleic acid, or endotoxin. Four hours after inducing ALI we obtained lung samples for histopathology analysis, myeloperoxidase, glutathione, and malondialdehyde measurement, and blood samples for malondialdehyde measurement. RESULTS: Endotoxin and oleic acid lung injury increased tissue myeloperoxidase (P =.009 for both), decreased tissue glutathione (P =.02 and P =.009, respectively), and increased tissue malondialdehyde (P =.009 for both), compared to the control group. Simvastatin decreased myeloperoxidase only in the oleic acid group (P =.01). Simvastatin increased glutathione (P =.005 and P =.003, respectively) and lowered malondialdehyde in both the endotoxin and oleic acid groups (P =.003 for both). Histopathology revealed that simvastatin protected the lung tissue in both ALI models, but the protection was greater in the endotoxin group. CONCLUSIONS: Pretreatment with simvastatin decreased the severity of ALI in oleic acid and endotoxin ALI models, by decreasing inflammation and oxidative stress. © 2011 Daedalus Enterprises.