15-Deoxy-delta(12,14)-prostaglandin J(2) (15D-PGJ(2)), a peroxisome proliferator activated receptor gamma ligand, reduces tissue leukosequestration and mortality in endotoxic shock.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that requires ligand activation for transcription. Experimental studies have shown that 15-deoxy-Delta-PGJ2 (15d-PGJ2) is a natural PPARgamma ligand which has potent anti-inflammatory properties. This study was designed to examine the effect and the molecular mechanisms of 15d-PGJ2 on tissue neutrophil infiltration and survival in endotoxic shock. Male Swiss albino mice were subjected to intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS, 25 mg/kg). Three hours after LPS mice received vehicle or 15d-PGJ2 (1 mg/kg) and continued treatment every 12 hours. Survival was monitored for 72 hours. In a separate experiment, mice were sacrificed 6 hours after LPS and tissue examined. In vehicle-treated mice, LPS injection resulted in a survival rate of 9%. Marked lung injury was characterized by hemorrhage, infiltration of inflammatory cells and reduction of alveolar space. Elevated levels of myeloperoxidase activity in lung and small intestine were indicative of infiltration of neutrophils. Increased expression of intercellular adhesion molecule-1, vascular cellular adhesion molecule-1 and E-selectin were observed in the lung and small intestine. These inflammatory events were associated with reduced expression of PPARgamma and with activation of nuclear factor-kappaB (NF-kappaB) in the lung. Treatment with 15d-PGJ2 improved survival rate to 55%, downregulated expression of adhesion molecules and reduced neutrophil infiltration in tissues. These beneficial effects were associated with reduced activation of NF-kappaB DNA binding, whereas expression and DNA binding of PPARgamma and expression of the cytoprotective heat shock protein (HSP) 70 were increased in the lung. Our data demonstrate that 15d-PGJ2 ameliorates endotoxic shock most likely through repressing the proinflammatory pathway of NF-kappaB and enhancement of the cytoprotective heat shock response.
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and the College of Medicine, University of Cincinnati, Cincinnati, Ohio 45229, USA.
Jennifer M
JM
Kaplan
James A
JA
Cook
Paul W
PW
Hake
Michael
M
O'Connor
Timothy J
TJ
Burroughs
Basilia
B
Zingarelli
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D009195:Peroxidase; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D015996:Survival Rate
C477819:15-deoxyprostaglandin J2; D018840:HSP70 Heat-Shock Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; C082161:lipopolysaccharide A; D009195:Peroxidase; D015230:Prostaglandin D2