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 J(2) (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 J(2). 15d- prostaglandin J(2) 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 J(2) was reduced by the PPAR-gamma antagonist GW9662. We propose that 15d-prostaglandin J(2) or other ligands for PPAR-gamma may be useful in the therapy of the organ injury associated with septic shock. (C) 2004 Elsevier B.V. All rights reserved.