Role of peroxisome proliferator-activated receptor-gamma in the protection afforded by 15-deoxydelta12,14 prostaglandin J2 against the multiple organ failure caused by endotoxin

Abstract

Objective: 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.

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). 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.

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 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.

Conclusions: 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.