Rosiglitazone, an agonist of peroxisome proliferator-activated receptor γ, reduces pulmonary inflammatory response in a rat model of endotoxemia

Objective: The effect of rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, on pulmonary inflammation in endotoxemia was investigated. Materials and methods: Male Wistar rats were given either lipopolysaccharide (LPS, 6 mg/kg i.v.) or saline, pretreated with rosiglitazone (0.3 mg/kg i.v.) or its vehicle (dimethyl sulphoxide) 30 min before LPS. The selective PPAR-γ antagonist GW9662 (0.3 mg/kg i.v.) was given 20 min before rosiglitazone. Wet/dry weight (W/D) ratio, myeloperoxidase (MPO) activity, malondialdehyde (MDA) as well as TNF-α and CINC-1 concentrations were measured in lung tissues 4 h after LPS injection. Expression of ICAM-1, NF-κB p65 and PPAR-γ were also determined by immunohistochemistry or Western blot analysis. Results: Rosiglitazone pretreatment significantly attenuated the increases in W/D ratio, MPO activity and MDA levels, and reduced pulmonary overproduction of TNF-α and CINC-1 as well as expression of ICAM-1 following endotoxemia. Rosiglitazone also inhibited the nuclear localization of NF-κB and up-regulated the expression of PPAR-γ protein. The specific PPAR-γ antagonist GW9662 abolished the effect of rosiglitazone. Conclusion: These findings suggest that PPAR-γ agonists might be used as therapeutic agents in the therapy of inflammatory lung injury related to endotoxemia. Received 8 January 2005; returned for revision 6 July 2005; returned for final revision 20 July 2005; accepted by M. Katori 31 July 2005