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.
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.


METHODS
Prospective, randomized study.


METHODS
University-based research laboratory.


METHODS
Seventy anesthetized male Wistar rats.


METHODS
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.


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.
Collin
Marika
M
William Harvey Research Institute, Department of Experimental Medicine, Nephrology and Critical Care, St. Bartholomew's, and The Royal London School of Medicine and Dentistry, London, UK.
Patel
Nimesh S A
NS
Dugo
Laura
L
Thiemermann
Christoph
C
D000704:Analysis of Variance; D000813:Anilides; D000818:Animals; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008297:Male; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000378:metabolism; D011446:Prospective Studies; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015230:Prostaglandin D2