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Ligands, 15-Deoxy-
12,14-Prostaglandin J2 and Ciglitazone, Reduce Systemic Inflammation in Polymicrobial Sepsis by Modulation of Signal Transduction Pathways 1
* Division of Critical Care, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; and
Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC 29425
Peroxisome proliferator activator receptor-
(PPAR) is a nuclear receptor that controls the expression of several genes involved in metabolic homeostasis. We investigated the role of PPAR during the inflammatory response in sepsis by the use of the PPAR ligands, 15-deoxy-
12,14-PGJ2 (15d-PGJ2) and ciglitazone. Polymicrobial sepsis was induced by cecal ligation and puncture in rats and was associated with hypotension, multiple organ failure, and 50% mortality. PPAR expression was markedly reduced in lung and thoracic aorta after sepsis. Immunohistochemistry showed positive staining for nitrotyrosine and poly(ADP-ribose) synthetase in thoracic aortas. Plasma levels of TNF-
, IL-6, and IL-10 were increased. Elevated activity of myeloperoxidase was found in lung, colon, and liver, indicating a massive infiltration of neutrophils. These events were preceded by degradation of inhibitor 
B (IB), activation of IB kinase complex, and c-Jun NH2-terminal kinase and, subsequently, activation of NF-B and AP-1 in the lung. In vivo treatment with ciglitazone or 15d-PGJ2 ameliorated hypotension and survival, blunted cytokine production, and reduced neutrophil infiltration in lung, colon, and liver. These beneficial effects of the PPAR ligands were associated with the reduction of IB kinase complex and c-Jun NH2-terminal kinase activation and the reduction of NF-B and AP-1 DNA binding in the lung. Furthermore, treatment with ciglitazone or 15d-PGJ2 up-regulated the expression of PPAR in lung and thoracic aorta and abolished nitrotyrosine formation and poly(ADP-ribose) expression in aorta. Our data suggest that PPAR ligands attenuate the inflammatory response in sepsis through regulation of the NF-B and AP-1 pathways.
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