prostaglandin-d2 and Shock--Septic

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.

Topics: Animals; Chemotaxis, Leukocyte; HSP70 Heat-Shock Proteins; Injections, Intraperitoneal; Leukocytes; Ligands; Lipopolysaccharides; Lung Injury; Male; Mice; NF-kappa B; Peroxidase; PPAR gamma; Prostaglandin D2; Shock, Septic; Survival Rate

We demonstrate here for the first time that the endogenous cyclopentenone prostaglandin 15-deoxy-Delta12,14-prostaglandin J2 (15d-prostaglandin J2) reduces the liver injury (rise in serum transaminases) caused by severe endotoxaemia (6 mg/kg Escherichia coli endotoxin i.v. for 6 h) in the anaesthetised rat. The protection of the liver afforded by this potent agonist of PPAR-gamma was not secondary to a haemodynamic effect. Thus, 15d-prostaglandin J2 and other PPAR-gamma agonists may be useful in the therapy of septic shock.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Endotoxins; Escherichia coli; Ligands; Liver Diseases; Male; Prostaglandin D2; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Shock, Septic; Transcription Factors

This canine study was designed to evaluate the effects of the intravenous infusion of coliform endotoxin with a simultaneous infusion of prostaglandin D2 (PGD2) on hemodynamics, blood gas, blood chemistry, and some hematologic parameters. The information derived from the present study supports the view that the intravenous administration of PGD2 moderates the effects of endotoxin, with its main beneficial effect being on the renal vascular bed. Treatment with PGD2 did not change the endotoxin-induced hemoconcentration, or the reduction in the platelet and white blood cell counts. However, four of nine animals survived more than 7 days when treated with PGD2, whereas without it only one of nine animals survived the administration of the same dose of endotoxin. Although the mechanism of action is not clear, the correlation between PGD2 infusion and improved renal blood flow warrants further study in endotoxic shock.

Topics: Animals; Blood Pressure; Carbon Dioxide; Dogs; Enterobacteriaceae; Female; Heart Rate; Hematocrit; Hemodynamics; Hemoglobins; Infusions, Parenteral; Oxygen; Prostaglandin D2; Prostaglandins D; Renal Circulation; Shock, Septic; Vascular Resistance