15-deoxyΔ12,14-prostaglandin J2 (15D-PGJ2), a peroxisome proliferator activated receptor γ ligand, reduces tissue leukosequestrationand mortality in endotoxic shock

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a nuclear receptor that requires ligand activation for transcription. Experimental studies have shown that 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) is a natural PPARy ligand which has potent anti-inflammatory properties. This study was designed to examine the effect and the molecular mechanisms of 15d-PGJ(2) on tissue neutrophil infiltration and survival in endotoxic shock. Male Swiss albino mice were subjected to intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS, 25 mg/kg). Three hours after LPS mice received vehicle or 15d-PGJ(2) (1 mg/kg) and continued treatment every 12 hours. Survival was monitored for 72 hours. In a separate experiment, mice were sacrificed 6 hours after LPS and tissue examined. In vehicle-treated mice, LPS injection resulted in a survival rate of 9%. Marked lung injury was characterized by hemorrhage, infiltration of inflammatory cells and reduction of alveolar space. Elevated levels of myeloperoxidase activity in lung and small intestine were indicative of infiltration of neutrophils. Increased expression of intercellular adhesion molecule-1, vascular cellular adhesion molecule-1 and E-selectin were observed in the lung and small intestine. These inflammatory events were associated with reduced expression of PPAR gamma and with activation of nuclear factor-kappa B (NF-kappa B) in the lung. Treatment with 15d-PGJ(2) improved survival rate to 55%, downregulated expression of adhesion molecules and reduced neutrophil infiltration in tissues. These beneficial effects were associated with reduced activation of NF-kappa B DNA binding, whereas expression and DNA binding of PPARy and expression of the cytoprotective heat shock protein (HSP) 70 were increased in the lung. Our data demonstrate that 15d-PGJ(2) ameliorates endotoxic shock most likely through repressing the proinflammatory pathway of NF-kappa B and enhancement of the cytoprotective heat shock response.