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Peroxisome proliferator-activated receptor- reduces inflammation and vascular leakage in a murine model of acute lung injury

University of Giessen Lung Center, Medical Clinic II, Justus-Liebig-University Giessen, Giessen, Germany.

CORRESPONDENCE: K. Mayer, University of Giessen Lung Center, Medical Clinic II, Justus-Liebig-University Giessen, Klinikstr. 36, D - 35392 Giessen, Germany. Fax: 49 6419942359. E-mail: Konstantin.Mayer{at}uglc.de

Keywords: Acute lung injury, inflammation, peroxisome proliferator-activated receptor-, vascular leakage

Received: March 9, 2008
Accepted July 11, 2008

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)- 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- 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 (P_pa) and in capillary filtration coefficient (K_fc). WY significantly improved all features of ALI in vivo and blunted the increase in K_fc in isolated perfused mice lungs. In mice with genetic deletion of PPAR-, all characteristics of ALI, P_pa, and K_fc were not significantly different from wild-type mice but WY failed to improve ALI and PAF-induced increase in K_fc.

Activation of peroxisome proliferator-activated receptor- 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.

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