title: Upregulation of activin-B and follistatin in pulmonary fibrosis - a translational study using human biopsies and a specific inhibitor in mouse fibrosis models.
abstract: BACKGROUND
  Activins are members of the TGF-ß superfamily of growth factors. First, we identified by expression array screening that activin-B and follistatin are upregulated in human idiopathic pulmonary fibrosis (IPF). Next, we wanted to clarify their specific role in lung fibrosis formation.
  
  
  METHODS
  We used specific antibodies for activin-A and -B subunits and follistatin to measure and localize their levels in idiopathic pulmonary fibrosis and control lung biopsies. To inhibit activin signaling, we used soluble activin type IIB receptor fused to the Fc portion of human IgG1 (sActRIIB-Fc) in two different mouse models of pulmonary fibrosis.
  
  
  RESULTS
  Activin-B and follistatin mRNA levels were elevated in the human IPF lung. Immunoreactivity to activin-A, -B and follistatin localized predominantly to the hyperplastic, activated alveolar epithelium, but was also seen in inflammatory cells. Mice treated with sActRIIB-Fc showed increased skeletal muscle mass and a clear reduction in alveolar cell counts in bronchoalveolar lavage fluid, but no significant antifibrotic effect in the lung was observed.
  
  
  CONCLUSIONS
  The upregulation of activin-B and follistatin in IPF is a novel finding. Our results indicate that activin inhibition is not an efficient tool for antifibrotic therapy, but could be useful in reducing alveolar cellular response to injury. Activin-B and follistatin levels may be useful as biomarkers of IPF.
authors.affiliation: Department of Medicine, Division of Pulmonary Medicine, University of Helsinki and Helsinki University Central Hospital, PO Box 63, FI-00014 Helsinki, Finland. marjukka.myllarniemi@helsinki.fi.
authors.forename: Marjukka
authors.initials: M
authors.lastname: Myllärniemi
authors.forename: Jussi
authors.initials: J
authors.lastname: Tikkanen
authors.forename: Juha J
authors.initials: JJ
authors.lastname: Hulmi
authors.forename: Arja
authors.initials: A
authors.lastname: Pasternack
authors.forename: Eva
authors.initials: E
authors.lastname: Sutinen
authors.forename: Mikko
authors.initials: M
authors.lastname: Rönty
authors.forename: Outi
authors.initials: O
authors.lastname: Leppäranta
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Ma
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
authors.forename: Katri
authors.initials: K
authors.lastname: Koli
mesh_terms: D028341:Activins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D004195:Disease Models, Animal; D038681:Follistatin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D028322:Inhibin-beta Subunits / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014176:Protein Biosynthesis; D011650:Pulmonary Alveoli / Q000737:chemistry / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D052097:Quadriceps Muscle / Q000033:anatomy & histology / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000737:chemistry / Q000276:immunology; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D038681:Follistatin; C498905:Inhbb protein, mouse; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C044147:activin B; C103008:inhibin beta A subunit; C000601041:sActRIIB-Fc fusion protein; D028341:Activins; D028322:Inhibin-beta Subunits