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(The FASEB Journal. 2002;16:1861-1868.)
© 2002 FASEB

Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets

MORIHITO OKADA, SHI FANG YAN and DAVID J. PINSKY1

College of Physicians & Surgeons of Columbia University, New York, New York, USA

1Correspondence: Columbia University, College of Physicians and Surgeons, PH 10 Stem, 630 West 168th St., New York, NY 10032, USA. E-mail: djp5{at}columbia.edu

The peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor whose activation regulates metabolism and inflammation. Recent data indicate that the zinc finger transcription factor early growth response gene-1 (Egr-1) acts as a master switch for the inflammatory response in ischemic vessels. Experiments tested the hypothesis that activation of endogenous PPAR-{gamma} inhibits induction of Egr-1. Egr-1 is rapidly induced in murine lungs after ischemia-reperfusion, as well as in alveolar mononuclear phagocytes deprived of oxygen as an ischemic model. In vitro, the natural PPAR-{gamma} ligand (15-deoxy-{Delta}12,14-prostaglandin J2) and a PPAR-{gamma} activator (troglitazone), but not a PPAR-{alpha} activator (bezafibrate), strikingly diminished Egr-1 mRNA and protein expression and nuclear DNA binding activity corresponding to Egr-1. In vivo, treatment with troglitazone before ischemia prevented induction of Egr-1 and its target genes such as interleukin-1ß, monocyte chemotactic protein-1, and macrophage inflammatory protein-2. As a consequence of PPAR-{gamma} activation, pulmonary leukostasis was decreased and oxygenation and overall survival were improved. Activation of PPAR-{gamma} suppresses activation of Egr-1 and its inflammatory gene targets and provides potent protection against ischemic pulmonary injury. These data reveal a new mechanism whereby PPAR-{gamma} activation may decrease tissue inflammation in response to an ischemic insult.—Okada, M., Yan, S. F., Pinsky, D. J. Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) activation suppresses induction of Egr-1 and its inflammatory gene targets in ischemic lungs.


Key Words: ischemia • reperfusion • early growth response-1 • troglitazone




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