Rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, reduces acute lung injury in endotoxemic rats

OBJECTIVE:Rosiglitazone, a potent agonist of peroxisome proliferator-activated receptor (PPAR)-γ, exerts anti-inflammatory effects in vitro and in vivo. This study was designated to determine the effects of rosiglitazone on endotoxin-induced acute lung injury in rats. DESIGN:Prospective, experimental study. SETTING:University research laboratory. SUBJECTS:Thirty-six male Wistar rats. INTERVENTIONS:All the animals were randomly assigned to one of six groups (n = 6 per group) and were given either lipopolysaccharide (6 mg/kg intravenously) or saline, pretreated with rosiglitazone (0.3 mg/kg intravenously) or vehicle (10% dimethyl sulphoxide) 30 mins before lipopolysaccharide. The selective PPAR-γ antagonist GW9662 (0.3 mg/kg intravenously) or its vehicle (10% dimethyl sulphoxide) was given 20 mins before rosiglitazone. MEASUREMENTS AND MAIN RESULTS:Endotoxemia for 4 hrs induced evident lung histologic injury and edema, both of which were significantly attenuated by rosiglitazone pretreatment. The protective effects of rosiglitazone were correlated with the reduction by 71% of the increase of myeloperoxidase activity and the reduction by 84% of the increase of malondialdehyde in the lung tissue. The pulmonary hyperproduction of nitric oxide was reduced by 82% of the increase related to lipopolysaccharide challenge. Pretreatment with rosiglitazone also markedly suppressed lipopolysaccharide-induced expression of inducible nitric oxide synthase messenger RNA and protein in the lung, as demonstrated by reverse transcription-polymerase chain reaction or Western blot analysis. Immunohistochemical analysis revealed that rosiglitazone inhibited the formation of nitrotyrosine, a marker for peroxynitrite reactivity, in the lung tissue. In addition, the specific PPAR-γ antagonist GW9662 antagonized the effects of rosiglitazone. CONCLUSIONS:This study provides evidence, for the first time, that the PPAR-γ agonist rosiglitazone significantly reduces endotoxin-induced acute lung injury in rats.