Journal
FASEB JOURNAL
Volume 16, Issue 14, Pages 1861-1868Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.02-0503com
Keywords
ischemia; reperfusion; early growth response-1; troglitazone
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Funding
- NHLBI NIH HHS [HL60900, HL59488, HL55397] Funding Source: Medline
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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 J(2)) and a PPAR-gamma activator (troglitazone), but not a PPAR-gamma 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-1beta, 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.
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