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Am J Physiol Gastrointest Liver Physiol 286: G606-G612, 2004. First published November 13, 2003; doi:10.1152/ajpgi.00191.2003
0193-1857/04 $5.00
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INFLAMMATION/IMMUNITY/MEDIATORS

Peroxisome proliferator-activated receptor-{alpha} regulates postischemic liver injury

Tomohisa Okaya and Alex B. Lentsch

The Laboratory of Trauma, Sepsis and Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, Ohio 45267

Submitted 25 April 2003 ; accepted in final form 11 November 2003

Peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) is a transcription factor that in some in vitro systems has been linked with downregulation of proinflammatory mediators, thus implicating a potential role for PPAR{alpha} in the regulation of inflammatory processes. Hepatic ischemia-reperfusion injury is characterized by an intense acute inflammatory response that is dependent on a number of proinflammatory mediators. PPAR{alpha} is abundantly expressed in hepatic parenchymal cells but not in Kupffer cells. This study examined whether PPAR{alpha} is involved in regulation of the hepatic inflammatory response to ischemia-reperfusion. Mice nullizygous for PPAR{alpha} had significantly greater liver injury than did their wild-type counterparts. Consistent with these findings, C57BL/6 mice treated with the PPAR{alpha} agonist, WY-14643, had significantly less liver injury than mice receiving vehicle. PPAR{alpha}-knockout mice also had greatly augmented liver neutrophil accumulation and modest increases in activation of the transcription factors NF-{kappa}B and activator protein-1. However, these effects were not associated with increased expression of proinflammatory cytokines or chemokines. In addition, PPAR{alpha}-knockout mice expressed far less inducible nitric oxide synthase in liver than did wild-type mice after ischemia-reperfusion. Finally, treatment of cultured murine hepatocytes with WY-14643, a specific agonist of PPAR{alpha}, protected cells against oxidant-induced injury. The data suggest that PPAR{alpha} is an important regulator of the hepatic inflammatory response to ischemia-reperfusion in a manner that is independent of proinflammatory cytokines.

reperfusion injury; neutrophils; inflammation


Address for reprint requests and other correspondence: A. B. Lentsch, Univ. of Cincinnati, Dept. of Surgery, Division of Trauma and Critical Care, 231 Albert Sabin Way, Cincinnati, OH 45267-0558 (E-mail: alex.lentsch{at}uc.edu).






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