Peroxisome proliferator-activated receptor-γ 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. Design: Prospective, randomized study. Setting. University-based research laboratory. Subjects, Ninety-nine anesthetized male Wistar rats. Interventions. 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). Measurements and Main Results: Lipopolysaccharide preconditoning 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-1 beta 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.