Peroxisome proliferator-activated receptor-gamma antagonists GW9662 and T0070907 reduce the protective effects of lipopolysaccharide preconditioning against organ failure caused by endotoxemia.
OBJECTIVE
There is evidence that a) ligands of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma and b) lipopolysaccharide preconditioning protect the organs against the multiple organ injury and dysfunction caused by endotoxemia. Here we investigate the hypothesis that the protective effects of lipopolysaccharide preconditioning are due to an enhanced formation of endogenous ligands of PPAR-gamma.


METHODS
Prospective, randomized study.


METHODS
University-based research laboratory.


METHODS
Ninety-nine anesthetized male Wistar rats.


METHODS
Rats were pretreated with low-dose lipopolysaccharide (1 mg/kg intraperitoneally, 24 hrs before induction of endotoxemia) in the absence or presence of the selective PPAR-gamma antagonists GW9662 (1 mg/kg intraperitoneally) or T0070907 (1 mg/kg intraperitoneally) or the selective cyclooxygenase-2 inhibitor parecoxib (20 mg/kg intraperitoneally). At 24 hrs after preconditioning with low-dose lipopolysaccharide, the rats were subjected to acute severe endotoxemia (lipopolysaccharide 6 mg/kg intravenously).


RESULTS
Lipopolysaccharide preconditioning significantly attenuated the development of renal dysfunction (serum creatinine), hepatocellular injury (serum alanine aminotransferase and aspartate aminotransferase), and circulatory failure (hypotension) as well as the increase in the plasma levels of interleukin-1beta caused by severe endotoxemia. All of these beneficial effects afforded by preconditioning with lipopolysaccharide were attenuated by the specific PPAR-gamma antagonists used. In contrast, the cyclooxygenase-2 inhibitor parecoxib did not affect the beneficial effects afforded by preconditioning with lipopolysaccharide.


CONCLUSIONS
We propose that endogenous ligands of PPAR-gamma contribute to the protection afforded by lipopolysaccharide preconditioning against the organ injury and dysfunction associated with severe endotoxemia in the rat.
Centre for Experimental Medicine, Nephrology and Critical Care, the William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary-University of London, UK.
Marika
M
Collin
Oliver
O
Murch
Christoph
C
Thiemermann
D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D019446:Endotoxemia / Q000150:complications*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D001549:Benzamides; D008070:Lipopolysaccharides; D011725:Pyridines; C458508:T 0070907