Peroxisome Proliferator Activator Receptor- gamma Ligands, 15-Deoxy-[Delta] super(12,14)-Prostaglandin J sub(2) and Ciglitazone, Reduce Systemic Inflammation in Polymicrobial Sepsis by Modulation of Signal Transduction Pathways

• Published in: The Journal of immunology (1950) Vol. 171; no. 12; pp. 6827 - 6837
• Main Authors: Zingarelli, B, Sheehan, M, Hake, P W, O'Connor, M, Denenberg, A, Cook, JA
• Format: Journal Article
• Language: English
• Published: 01.01.2003
• Subjects: ciglitazone; polymicrobial sepsis; PPAR^g ligands
• ISSN: 0022-1767

Peroxisome proliferator activator receptor- gamma (PPAR gamma ) is a nuclear receptor that controls the expression of several genes involved in metabolic homeostasis. We investigated the role of PPAR gamma during the inflammatory response in sepsis by the use of the PPAR gamma ligands, 15-deoxy- [Delta] super(12,14)-PGJ sub(2) (15d-PGJ sub(2)) 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 gamma 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- alpha , 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 Kappa B alpha (I Kappa B alpha ), activation of I Kappa B kinase complex, and c-Jun NH sub(2)-terminal kinase and, subsequently, activation of NF- Kappa B and AP-1 in the lung. In vivo treatment with ciglitazone or 15d-PGJ sub(2) ameliorated hypotension and survival, blunted cytokine production, and reduced neutrophil infiltration in lung, colon, and liver. These beneficial effects of the PPAR gamma ligands were associated with the reduction of I Kappa B kinase complex and c-Jun NH sub(2)-terminal kinase activation and the reduction of NF- Kappa B and AP-1 DNA binding in the lung. Furthermore, treatment with ciglitazone or 15d-PGJ sub(2) up-regulated the expression of PPAR gamma in lung and thoracic aorta and abolished nitrotyrosine formation and poly(ADP-ribose) expression in aorta. Our data suggest that PPAR gamma ligands attenuate the inflammatory response in sepsis through regulation of the NF- Kappa B and AP-1 pathways.