15-deoxy-delta(12-14)-prostaglandin-j2 and Multiple-Organ-Failure

Topics: Animals; Disease Models, Animal; Immunologic Factors; Mice; Multiple Organ Failure; Pentoxifylline; PPAR gamma; Prostaglandin D2; Vasodilator Agents; Zymosan

Multiple-organ failure (MOF) is defined as the progressive deterioration in function which occurs in several organs or systems in patients with septic shock, multiple trauma, severe burns, or pancreatitis. This study investigated the effect of 15-deoxy-delta(12,14)-PGJ2 (15d-PGJ2), a PPAR-gamma ligand, in a model of zymosan-induced nonseptic shock in mice.. Mice were randomly assigned to one of four groups (n=10 each) and treated i.p. as follows: group 1, zymosan (500 mg/kg suspended in saline solution) and vehicle (10% DMSO); group 2, zymosan (500 mg/kg suspended in saline solution) plus 15d-PGJ2 (30 microg/kg, suspended in 10% DMSO) 1 h before and 6 h after zymosan administration; group 3, 15d-PGJ2 (30 microg/kg, suspended in 10% DMSO; group 4, vehicle for PGJ2 (10% DMSO) always 1 h before and 6 h after saline administration. After 18 h mice were killed and tissues and biological fluids used for biochemical, immunohistochemical, and histological analysis.. 15d-PGJ2 inhibited the inflammatory response and significantly reduced peritoneal mononuclear cell infiltration and histological injury in mice. A significant protection was demonstrated in kidney, liver, and pancreas injury by the reduction in amylase, lipase, creatinine, AST, ALT, bilirubin, and alkaline phosphatase levels. 15d-PGJ2 also reduced the appearance of nitrotyrosine in the inflamed intestinal tissues. Histological examination revealed a significant reduction in zymosan-induced intestinal damage in 15d-PGJ2 treated mice.. Our findings demonstrate that 15d-PGJ2 exerts potent anti-inflammatory effects on zymosan-induced shock.

Topics: Analysis of Variance; Animals; Animals, Outbred Strains; Immunohistochemistry; Immunologic Factors; Male; Mice; Multiple Organ Failure; Nitric Oxide; Peroxynitrous Acid; PPAR gamma; Prostaglandin D2; Random Allocation; Zymosan

The cyclopentenone prostaglandin 15-deoxydelta-prostaglandin J2 (15 d-PGJ2) exerts potent anti-inflammatory effects in vivo, which are in part due to the activation of peroxisome proliferator-activated receptor (PPAR)-gamma. Here we investigate the effects of 15 d-PGJ2 on the multiple organ injury/dysfunction associated with severe endotoxemia.. Prospective, randomized study.. University-based research laboratory.. Seventy anesthetized male Wistar rats.. Rats received either Escherichia coli lipopolysaccharide (endotoxin, 6 mg/kg intravenously) or vehicle (saline, 1 mL/kg intravenously). 15 d-PGJ2 (0.3 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered 30 mins before endotoxin. The selective PPAR-gamma antagonist GW9662 (0.3 mg/kg intravenously) or its vehicle (10% dimethyl sulfoxide) was given 45 mins before endotoxin.. Endotoxemia for 6 hrs increased serum concentrations of creatinine (indicator of renal dysfunction), aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, bilirubin (markers for hepatic injury and dysfunction), lipase (indicator of pancreatic injury), and creatine kinase (an indicator of neuromuscular skeletal muscle or cardiac injury). The potent PPAR-gamma agonist 15 d-PGJ2 attenuated the increases in the serum concentrations of these variables, indicating a protective effect of 15 d-PGJ2 against the multiple organ injury/dysfunction caused by endotoxin. The specific PPAR-gamma antagonist GW9662 reduced the protective effects afforded by 15 d-PGJ2. 15 d-PGJ2 did not affect the biphasic decrease in blood pressure or the increase in heart rate caused by endotoxemia.. The potent PPAR-gamma agonist 15 d-PGJ2 reduces the multiple organ injury and dysfunction, but not the hypotension, caused by endotoxin in the rat. The mechanisms of the protective effect of this cyclopentenone prostaglandin are--at least in part--PPAR-gamma dependent, as the protection afforded by 15 d-PGJ2 was reduced by the PPAR-gamma antagonist GW9662. We propose that 15 d-PGJ2 or other ligands for PPAR-gamma may be useful in treating organ injury associated with endotoxic shock.

Topics: Analysis of Variance; Anilides; Animals; Immunologic Factors; Lipopolysaccharides; Male; Multiple Organ Failure; Prospective Studies; Prostaglandin D2; Random Allocation; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Transcription Factors