title: Pioglitazone, a peroxisome proliferator-activated receptor gamma ligand, suppresses bleomycin-induced acute lung injury and fibrosis.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands have been shown to possess potent anti-inflammatory actions. Idiopathic interstitial pneumonia is defined as a specific form of chronic fibrosing lung disease characterized by progressive fibrosis which leads to deterioration and destruction of the lungs.
  
  
  OBJECTIVE
  To investigate whether the PPARgamma ligand pioglitazone (PGZ) inhibited bleomycin (BLM)-induced acute lung injury and subsequent fibrosis.
  
  
  METHODS
  BLM was administered intratracheally to Wistar rats which were then treated with PGZ. Rat alveolar macrophages were stimulated with BLM for 6 h with or without PGZ pretreatment for 18 h. MRC-5 cells (human lung fibroblasts) were treated with PGZ for 18 h. After the treatment, the cells were stimulated with transforming growth factor- beta (TGF-beta) for 6 h.
  
  
  RESULTS
  PGZ inhibited BLM-induced acute lung injury and subsequent lung fibrosis when it was administered from day -7. PGZ treatment suppressed the accumulation of inflammatory cells in lungs and the concentration of tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-alpha production in alveolar macrophages. Furthermore, PGZ inhibited fibrotic changes and an increase in hydroxyproline content in lungs after instillation of BLM, even when PGZ was administered in the period from day 7 to day 28. Northern blot analyses revealed that PGZ inhibited TGF-beta-induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells.
  
  
  CONCLUSIONS
  These results suggest that activation of PPARgamma ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-alpha, procollagen I and CTGF expression. Beneficial effects of this PPARgamma ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPARgamma as a molecular target in fibroproliferative lung diseases.
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan. mkuraba@med.gunma-u.ac.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Aoki
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Maeno
authors.forename: Kana
authors.initials: K
authors.lastname: Aoyagi
authors.forename: Manabu
authors.initials: M
authors.lastname: Ueno
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Aoki
authors.forename: Nozomi
authors.initials: N
authors.lastname: Aoki
authors.forename: Junichi
authors.initials: J
authors.lastname: Nakagawa
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Sando
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Suga
authors.forename: Masashi
authors.initials: M
authors.lastname: Arai
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kurabayashi
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008168:Lung / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C526316:CCN2 protein, rat; D024042:Collagen Type I; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D055513:Connective Tissue Growth Factor; D000077205:Pioglitazone