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

Inflamm Res. 2005 Nov;54(11):464-70. doi: 10.1007/s00011-005-1379-0.

Abstract

Objective: The effect of rosiglitazone, a potent peroxisome proliferator-activated receptor gamma (PPAR-gamma) 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-gamma 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-alpha and CINC-1 concentrations were measured in lung tissues 4 h after LPS injection. Expression of ICAM-1, NF-kappaB p65 and PPAR-gamma 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-alpha and CINC-1 as well as expression of ICAM-1 following endotoxemia. Rosiglitazone also inhibited the nuclear localization of NF-kappaB and up-regulated the expression of PPAR-gamma protein. The specific PPAR-gamma antagonist GW9662 abolished the effect of rosiglitazone.

Conclusion: These findings suggest that PPAR-gamma agonists might be used as therapeutic agents in the therapy of inflammatory lung injury related to endotoxemia.

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Anti-Inflammatory Agents*
  • Blotting, Western
  • Chemokine CXCL1
  • Chemokines, CXC / metabolism
  • Endotoxemia / pathology*
  • Immunohistochemistry
  • Intercellular Adhesion Molecule-1 / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lipid Peroxidation / drug effects
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology*
  • Male
  • Malondialdehyde / metabolism
  • NF-kappa B / metabolism
  • Neutrophil Infiltration / drug effects
  • PPAR gamma / agonists*
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / biosynthesis
  • Peroxidase / metabolism
  • Pneumonia / pathology*
  • Pulmonary Edema / drug therapy
  • Pulmonary Edema / pathology
  • Rats
  • Rats, Wistar
  • Rosiglitazone
  • Thiazolidinediones / pharmacology*
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Anti-Inflammatory Agents
  • Chemokine CXCL1
  • Chemokines, CXC
  • Cxcl1 protein, rat
  • Intercellular Signaling Peptides and Proteins
  • NF-kappa B
  • PPAR gamma
  • Thiazolidinediones
  • Tumor Necrosis Factor-alpha
  • Rosiglitazone
  • Intercellular Adhesion Molecule-1
  • Malondialdehyde
  • Peroxidase