Role of peroxisome proliferator-activated receptor-γ in the protection afforded by 15-deoxyΔ12,14 prostaglandin J2 against the multiple organ failure caused by endotoxin

Objective. The cyclopentenone prostaglandin 15-deoXyDelta(12,14)- prostaglandin J(2) (15d-PGJ(2)) 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 15d PGJ(2) on the multiple organ injury/dysfunction associated with severe endotoxemia. Design. Prospective, randomized study. Setting: University-based research laboratory. Subjects. Seventy anesthetized male Wistar rats. Interventions. Rats received either Escherichia coli lipopolysaccharide (endotoxin, 6 mg/kg intravenously) or vehicle (saline, 1 mL/kg intravenously). 15d-PGJ(2) (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 suffoxide) was given 45 mins before endotoxin. Measurements and Main Results. 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 15d-PGJ(2) attenuated the increases in the serum concentrations of these variables, indicating a protective effect of 15d-PGJ(2) against the multiple organ injury/ dysfunction caused by endotoxin. The specific PPAR-gamma antagonist GW9662 reduced the protective effects afforded by 15d-PGJ(2). 15dPGJ(2) did not affect the biphasic decrease in blood pressure or the increase in heart rate caused by endotoxemia. Conclusions. The patent PPAR-gamma agonist 15dwPGJ(2) 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 15d-PGJ(2) was reduced by the PPAR-gamma antagonist GW9662. We propose that 15d-PGJ(2) or other ligands for PPAR-gamma may be useful in treating organ injury associated with endotoxic shock.