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Published online before print July 24, 2008
Eur Respir J 2008, doi:10.1183/09031936.00035808
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ORIGINAL ARTICLE

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

M.B. Schaefer 1, A. Pose 1, J. Ott 1, M. Hecker 1, A. Behnk 1, R. Schulz 1, N. Weissmann 1, A. Günther 1, W. Seeger 1, K. Mayer 1*

1 University of Giessen Lung Center (UGLC), Medical Clinic II, Justus-Liebig-University Giessen, Klinikstr. 36, D – 35392 Giessen, Germany

* To whom correspondence should be addressed. E-mail: Konstantin.Mayer{at}uglc.de.


  Abstract

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 in inflammatory models. We investigated the impact of WY 14,643 in a model of endotoxin (LPS)-induced ALI in mice.

Intratracheal LPS-challenge dose-dependently resulted in leukocyte invasion, protein leakage, release of tumour-necrosis factor (TNF)-{alpha} as well as macrophage inflammatory protein (MIP)-2, prostaglandin (PG)E2 and thromboxane (Tx)B2 into the alveolar space after 8 and 24 hours. Lung ventilator compliance was reduced at both time points. In isolated perfused mice lungs (ILU), platelet-activating factor (PAF) induced an acute increase in pulmonary artery pressure (PAP) and in capillary filtration coefficient (Kfc). WY 14,643 significantly improved all features of ALI in vivo and Kfc in ILU. In mice with genetic deletion of PPAR-{alpha}, all characteristics of ALI, PAP, and Kfc were not significantly different from wild-type mice but WY 14,643 failed to improve ALI and PAF-induced increase in Kfc.

Activation of PPAR-{alpha} by WY 14,643 reduced ALI and vascular leakage. Fibrates may possess beneficial effects in acute pulmonary diseases beyond their lipid-lowering capability.

Keywords:  Acute lung injury, inflammation, PPAR-{alpha}, vascular leakage




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