15 d-prostaglandin J 2 reduces multiple organ failure caused by wall-fragment of Gram-positive and Gram-negative bacteria

Abstract

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), γ-glutamyl transferase (γ-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-γ (PPAR-γ) agonist 15 d-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-γ antagonist GW9662 (2-Chloro-5-nitrobenzanilide) (1 mg/kg, i.v., given 45 min prior to G+/G−) abolished the protective effects of 15 d-prostaglandin J 2. 15 d- 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-γ dependent, as the protection afforded by 15 d-prostaglandin J 2 was reduced by the PPAR-γ antagonist GW9662. We propose that 15 d-prostaglandin J 2 or other ligands for PPAR-γ may be useful in the therapy of the organ injury associated with septic shock.