title: Loss of peroxisome proliferator-activated receptor gamma in mouse fibroblasts results in increased susceptibility to bleomycin-induced skin fibrosis.
abstract: OBJECTIVE
  There is increasing evidence that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in controlling cell differentiation, and that PPARgamma ligands can modify inflammatory and fibrotic responses. The aim of the present study was to examine the role of PPARgamma in a mouse model of skin scleroderma, in which mice bearing a fibroblast-specific deletion of PPARgamma were used.
  
  
  METHODS
  Cutaneous sclerosis was induced by subcutaneous injection of bleomycin, while untreated control groups were injected with phosphate buffered saline. Mice bearing a fibroblast-specific deletion of PPARgamma were investigated for changes in dermal thickness, inflammation, collagen content, and the number of alpha-smooth muscle actin-positive cells. The quantity of the collagen-specific amino acid hydroxyproline was also measured. In addition, the effect of PPARgamma deletion on transforming growth factor beta1 (TGFbeta1) signaling in the fibroblasts was investigated.
  
  
  RESULTS
  Bleomycin treatment induced marked cutaneous thickening and fibrosis in all treated mice. Deletion of PPARgamma resulted in enhanced susceptibility to bleomycin-induced skin fibrosis, as indicated by increases in all measures of skin fibrosis and enhanced sensitivity of fibroblasts to TGFbeta1 in PPAR-deficient mice.
  
  
  CONCLUSIONS
  These results indicate that PPARgamma suppresses fibrogenesis. Specific agonists of PPARgamma may therefore alleviate the extent of the development of cutaneous sclerosis.
authors.affiliation: University of Western Ontario, London, Ontario, Canada.
authors.forename: Mohit
authors.initials: M
authors.lastname: Kapoor
authors.forename: Matthew
authors.initials: M
authors.lastname: McCann
authors.forename: Shangxi
authors.initials: S
authors.lastname: Liu
authors.forename: Kun
authors.initials: K
authors.lastname: Huh
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.forename: David J
authors.initials: DJ
authors.lastname: Abraham
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics* / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000473:pathology; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000199:Actins; D047495:PPAR gamma; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D001761:Bleomycin