title: Follistatin attenuates radiation-induced fibrosis in a murine model.
abstract: OBJECTIVE
  Fibrosis can be a disabling, severe side effect of radiotherapy that can occur in patients, and for which there is currently no effective treatment. The activins, proteins which are members of the TGFβ superfamily, have a major role in stimulating the inflammatory response and subsequent fibrosis. Follistatin is an endogenous protein that binds the activins virtually irreversibly and inhibits their actions. These studies test if follistatin can attenuate the fibrotic response using a murine model of radiation-induced fibrosis.
  
  
  METHODS
  C57BL/6 mice were subcutaneously injected with follistatin 24 hours prior to irradiation. Mice were irradiated in a 10 x 10 mm square area of the right hind leg with 35 Gy and were given follistatin 24 hours before radiation and three times a week for six months following. Leg extension was measured, and tissue was collected for histological and molecular analysis to evaluate the progression of the radiation-induced fibrosis.
  
  
  RESULTS
  Leg extension was improved in follistatin treated mice compared to vehicle treated mice at six months after irradiation. Also, epidermal thickness and cell nucleus area of keratinocytes were decreased by the follistatin treatment compared to the cells in irradiated skin of control mice. Finally, the gene expression of transforming growth factor β1 (Tgfb1), and smooth muscle actin (Acta2) were decreased in the irradiated skin and Acta2 and inhibin βA subunit (Inhba) were decreased in the irradiated muscle of the follistatin treated mice.
  
  
  CONCLUSIONS
  Follistatin attenuated the radiation-induced fibrotic response in irradiated mice. These studies provide the data to support further investigation of the use of follistatin to reduce radiation-induced fibrosis in patients undergoing radiotherapy for cancer.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: Helen B
authors.initials: HB
authors.lastname: Forrester
authors.affiliation: Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: de Kretser
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Trevor
authors.initials: T
authors.lastname: Leong
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Jim
authors.initials: J
authors.lastname: Hagekyriakou
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: Carl N
authors.initials: CN
authors.lastname: Sprung
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D038681:Follistatin / Q000494:pharmacology*; D028322:Inhibin-beta Subunits / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011832:Radiation Injuries / Q000517:prevention & control*; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D038681:Follistatin; D053773:Transforming Growth Factor beta1; C103008:inhibin beta A subunit; D028322:Inhibin-beta Subunits