Acute lung injury (ALI) still represents a major cause of morbidity and mortality in intensive care units. Beneficial effects have been described after activation of the peroxisome proliferator-activated receptor (PPAR)-alpha by fibrates such as WY 14,643 (WY) in inflammatory models. In the present study, the impact of WY was investigated in a model of endotoxin (lipopolysaccharide; LPS)-induced ALI in mice. Intratracheal LPS challenge dose-dependently resulted in leukocyte invasion, protein leakage and release of tumour necrosis factor-alpha as well as macrophage inflammatory protein-2, prostaglandin E2 and thromboxane B2 into the alveolar space after 8 and 24 h. Lung ventilator compliance was reduced at both time-points. In isolated perfused mouse lungs, platelet-activating factor (PAF) induced an acute increase in pulmonary artery pressure (Ppa) and in capillary filtration coefficient (Kfc). WY significantly improved all features of ALI in vivo and blunted the increase in Kfc in isolated perfused mice lungs. In mice with genetic deletion of PPAR-alpha, all characteristics of ALI, Ppa, and Kfc were not significantly different from wild-type mice but WY failed to improve ALI and PAF-induced increase in Kfc. Activation of peroxisome proliferator-activated receptor-alpha by WY 14,643 reduced acute lung injury and vascular leakage. Fibrates may possess beneficial effects in acute pulmonary diseases beyond their lipid-lowering capability.