15d-prostaglandin J2 reduces multiple organ failure caused by wall-fragment of Gram-positive and Gram-negative bacteria.
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.
Dugo
Laura
L
Department of Experimental Medicine, Nephrology and Critical Care Medicine, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.
Collin
Marika
M
Cuzzocrea
Salvatore
S
Thiemermann
Christoph
C
D000410:Alanine Transaminase / Q000097:blood; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002473:Cell Wall / Q000737:chemistry; D003402:Creatine Kinase / Q000097:blood; D003404:Creatinine / Q000097:blood; D004926:Escherichia coli / Q000737:chemistry; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000633:toxicity; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D047495:PPAR gamma / Q000819:agonists; D010457:Peptidoglycan / Q000008:administration & dosage* / Q000633:toxicity; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013211:Staphylococcus aureus / Q000737:chemistry; D005723:gamma-Glutamyltransferase / Q000097:blood
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D008070:Lipopolysaccharides; D047495:PPAR gamma; D010457:Peptidoglycan; C037112:9-deoxy-delta-9-prostaglandin D2; D003404:Creatinine; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase; D001663:Bilirubin; D015230:Prostaglandin D2