gw9662 and Multiple-Organ-Failure

To observe the effects of peroxisome proliferators-activated receptor-gamma (PPARgamma) on the function of the vital organs in rats with pancreatitis.. Acute pancreatitis (AP) was induced in 30 male SD rats by ductal injection of 4% sodium taurocholate at 1.0 ml/kg. The rats received subsequent intravenously injection of 0.3 mg/kg of PPARgamma ligand (rosiglitazone, n=10), PPARgamma antagonist (GW9662, n=10) followed 10 min later by rosiglitazone administration at 0.3 mg/kg, or left untreated (AP model group, n=10). Another 10 male SD rats receiving no particular treatment served as the control group. The rats were sacrificed 6 h after the operation, and blood samples were collected for measurement of the biochemical indices of the vital organs. The histological changes of the pancreas and portal vein blood endotoxin content were examined.. The rats in AP group and GW9662 group showed significantly higher level of the biochemical indices for the vital organs, pathological scores of the pancreas and portal vein blood endotoxin content were significantly higher in the control group and roglitazone-treated groups (P<0.05).. PPARgamma ligand roglitazone can significantly ameliorate multiple organ injuries and effectively protect the functions of the organs in rats with experimental pancreatitis.

Topics: Anilides; Animals; Hypoglycemic Agents; Injections, Intravenous; Male; Multiple Organ Failure; NF-kappa B; Pancreatitis, Acute Necrotizing; PPAR gamma; Random Allocation; Rats; Rats, Sprague-Dawley; Rosiglitazone; Thiazolidinediones

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.. Prospective, randomized study.. University-based research laboratory.. Ninety-nine anesthetized male Wistar rats.. 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).. 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.. 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.

Topics: Anilides; Animals; Benzamides; Endotoxemia; Lipopolysaccharides; Male; Multiple Organ Failure; Pyridines; Rats; Rats, Wistar

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.. Prospective, randomized study.. University-based research laboratory.. Seventy anesthetized male Wistar rats.. 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.. 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.. 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.

Topics: Analysis of Variance; Anilides; Animals; Immunologic Factors; Lipopolysaccharides; Male; Multiple Organ Failure; Prospective Studies; Prostaglandin D2; Random Allocation; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Septic shock is still the major cause of death in surgical intensive care units. Both gram-positive (G+) and gram-negative (G-) bacteria have been isolated in the blood of a large portion of septic patients, and these polymicrobial infections often have a higher mortality than infections due to a single organism. Cell wall fragments from G+ and G- bacteria synergise to cause shock and multiple organ dysfunction in vivo (G+/G- shock). Male Wistar rats were anaesthetised and received a coadministration of wall fragments from G+ and G- bacteria, Staphilococcus aureus (S. aureus) peptidoglycan [0.3 mg/kg, intravenously (i.v.)] and Escherichia coli (E. coli) lipopolysaccharide (1 mg/kg, i.v.) or vehicle (saline, 1 ml/kg, i.v.). G+/G- shock for 6 h resulted in an increase in serum levels of creatinine (indicator of renal dysfunction), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (gamma-GT), bilirubin (markers for hepatic injury and dysfunction) and creatine kinase (CK, an indicator of neuromuscular, skeletal muscle or cardiac injury). Pretreatment of rats with the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist 15d-prostaglandin J2 (0.3 mg/kg, i.v., 30 min prior to G+/G-) reduced the multiple organ injury/dysfunction caused by coadministration of peptidoglycan+lipopolysaccharide. The selective PPAR-gamma antagonist GW9662 (2-Chloro-5-nitrobenzanilide) (1 mg/kg, i.v., given 45 min prior to G+/G-) abolished the protective effects of 15d-prostaglandin J2. 15d- prostaglandin J2 did not affect the biphasic fall in blood pressure or the increase in heart rate caused by administration of peptidoglycan+lipopolysaccharide. The mechanism(s) of the protective effect of this cyclopentenone prostaglandin are-at least in part-PPAR-gamma dependent, as the protection afforded by 15d-prostaglandin J2 was reduced by the PPAR-gamma antagonist GW9662. We propose that 15d-prostaglandin J2 or other ligands for PPAR-gamma may be useful in the therapy of the organ injury associated with septic shock.

Topics: Alanine Transaminase; Anilides; Animals; Aspartate Aminotransferases; Bilirubin; Blood Pressure; Cell Wall; Creatine Kinase; Creatinine; Escherichia coli; gamma-Glutamyltransferase; Heart Rate; Kidney; Lipopolysaccharides; Male; Multiple Organ Failure; Peptidoglycan; PPAR gamma; Prostaglandin D2; Rats; Rats, Wistar; Staphylococcus aureus