15-deoxy-Δ12,14-prostaglandin J2 ameliorates endotoxin-induced acute lung injury in rats

Abstract

Background A proinflammatory milieu emerging in the lung due to neutrophil accumulation and activation is a key in the pathogenesis of acute lung injury (ALI). 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the terminal products of the cyclooxygenase-2 pathway, is known to be the endogenous ligand of peroxisome proliferator-activated receptor γ (PPAR-γ) with multiple physiological properties. Growing evidence indicates that 15d-PGJ2 has anti-inflammatory, anti-proliferative, cytoprotective and pro-resolving effects. We investigated whether 15d-PGJ2 has a protective effect against endotoxin-induced acute lung injury in rats. Methods Twenty-four male Wistar rats were randomly assigned into four groups (n=6 per group): sham+vehicle group, sham+15d-PGJ2 group, LPS+vehicle group, and LPS+15d-PGJ2 group. The rats were given either lipopolysaccharide (LPS, 6 mg/kg intravenously) or saline, and pretreated with 15d-PGJ2 (0.3 mg/kg intravenously) or its vehicle (dimethyl sulphoxide) 30 minutes before LPS. Histological alterations, wet/dry weight (W/D) ratio and myeloperoxidase (MPO) activity as well as tumor necrosis factor (TNF)-α and cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels were determined in lung tissues four hours after LPS injection. Immunohistochemical analysis for intercellular adhesion molecule-1 (ICAM-1) expression and Western blotting analysis for nuclear factor (NF)-κB p65 translocation and IκBα protein levels were also studied. Results 15d-PGJ2 pretreatment significantly attenuated LPS-induced lung injury, and reduced the increased W/D ratio, MPO activity, TNF-α, CINC-1 levels, and ICAM-1 expression in the lung. 15d-PGJ2 also suppressed the nuclear NF-κB p65 translocation and increased cytosolic IκBα levels. Conclusions 15d-PGJ2 protects against endotoxin-induced acute lung injury, most likely through the reduction of pro-inflammatory protein levels during endotoxemia subsequent to the inhibition of NF-κB activation.