title: Peroxisome proliferator activator receptor-gamma ligands, 15-deoxy-Delta(12,14)-prostaglandin J2 and ciglitazone, reduce systemic inflammation in polymicrobial sepsis by modulation of signal transduction pathways.
abstract: Peroxisome proliferator activator receptor-gamma (PPARgamma) is a nuclear receptor that controls the expression of several genes involved in metabolic homeostasis. We investigated the role of PPARgamma during the inflammatory response in sepsis by the use of the PPARgamma ligands, 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(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. PPARgamma 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 kappaBalpha (IkappaBalpha), activation of IkappaB kinase complex, and c-Jun NH(2)-terminal kinase and, subsequently, activation of NF-kappaB and AP-1 in the lung. In vivo treatment with ciglitazone or 15d-PGJ(2) ameliorated hypotension and survival, blunted cytokine production, and reduced neutrophil infiltration in lung, colon, and liver. These beneficial effects of the PPARgamma ligands were associated with the reduction of IkappaB kinase complex and c-Jun NH(2)-terminal kinase activation and the reduction of NF-kappaB and AP-1 DNA binding in the lung. Furthermore, treatment with ciglitazone or 15d-PGJ(2) up-regulated the expression of PPARgamma in lung and thoracic aorta and abolished nitrotyrosine formation and poly(ADP-ribose) expression in aorta. Our data suggest that PPARgamma ligands attenuate the inflammatory response in sepsis through regulation of the NF-kappaB and AP-1 pathways.
authors.affiliation: Division of Critical Care, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. basilia.zingarelli@cchmc.org
authors.forename: Basilia
authors.initials: B
authors.lastname: Zingarelli
authors.forename: Maeve
authors.initials: M
authors.lastname: Sheehan
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hake
authors.forename: Michael
authors.initials: M
authors.lastname: O'Connor
authors.forename: Alvin
authors.initials: A
authors.lastname: Denenberg
authors.forename: James A
authors.initials: JA
authors.lastname: Cook
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000201:enzymology / Q000378:metabolism; D016470:Bacteremia / Q000378:metabolism / Q000517:prevention & control; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007958:Leukocyte Count; D008024:Ligands; D008168:Lung / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism* / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D015996:Survival Rate; D045162:Thiazolidinediones / Q000378:metabolism* / Q000627:therapeutic use; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D016753:Interleukin-10; D015850:Interleukin-6; D008024:Ligands; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D011065:Poly(ADP-ribose) Polymerases; D015230:Prostaglandin D2; D017346:Protein Serine-Threonine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D000093242:Interleukin-6 Inhibitors; C097240:15-deoxy-delta(12,14)-prostaglandin J2; C000606206:Nfkbia protein, rat; C002744:3-nitrotyrosine; C039671:ciglitazone