title: Receptor-activated Smad localisation in bleomycin-induced pulmonary fibrosis.
abstract: BACKGROUND
  Recent advances in fibrosis biology have identified transforming growth factor (TGF)-beta type I receptor-mediated activation of Smads as playing a central part in the development of fibrosis. However, to date, there have been few studies that examined the localisation and distribution of receptor-activated Smads protein (R-Smads: Smad2 and 3) during the fibrosis progression.
  
  
  OBJECTIVE
  To histopathologically assess the time-course change of the localisation and distribution of the Smads protein in pulmonary fibrosis.
  
  
  METHODS
  Pulmonary fibrosis was induced by intranasal injection of bleomycin (0.3 U/mouse). Lungs were isolated 2, 5, 7, 9 and 14 days after bleomycin treatment. Histological changes in the lungs were evaluated by haematoxylin-eosin stain or Masson's trichrome stain, and scored. TGF-beta1, Smad3 and phosphorylated Smad2 localisations in lung tissues were determined by immunohistochemistry.
  
  
  RESULTS
  The bleomycin treatment led to considerable pulmonary fibrotic changes accompanied by marked increase in TGF-beta1 expression in infiltrating macrophages. With the progression in fibrosis (day 7-14), marked increases in Smad3-positive and pSmad2-positive cells were observed. There were intense Smad3-positive and pSmad2-positive signals localised to the nuclei of the infiltrating macrophages and to type II epithelial cells, and less intense signals in fibroblasts and hyperplastic alveolar/bronchiolar epithelial cells.
  
  
  CONCLUSIONS
  The time-course data of TGF-beta1 and R-Smads indicate that progressive enhancement of TGF-beta1 signalling via R-Smad is activated in the process of fibrosis progression.
authors.affiliation: Department of Pharmacology, Tsukuba Research Laboratories, GlaxoSmithKline, Tsukuba, Ibaraki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Higashiyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yoshimoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Hideo
authors.initials: H
authors.lastname: Kikkawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Asano
authors.forename: Mine
authors.initials: M
authors.lastname: Kinoshita
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D004195:Disease Models, Animal; D018450:Disease Progression; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D051896:Smad Proteins, Receptor-Regulated; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D001761:Bleomycin