Follistatin attenuates radiation-induced fibrosis in a murine model

• Published in: PloS one Vol. 12; no. 3; p. e0173788
• Main Authors: Forrester, Helen B, de Kretser, David M, Leong, Trevor, Hagekyriakou, Jim, Sprung, Carl N
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.03.2017; Public Library of Science (PLoS)
• Subjects: Actin; Actins - metabolism; Animal models; Animals; Attenuation; Binding proteins; Binding sites; Biology and Life Sciences; Cancer; Care and treatment; Clinical medicine; Cytokines; Disease Models, Animal; Experimental design; Extracellular matrix; Fibroblasts; Fibrosis; Follistatin; Follistatin - pharmacology; Gene expression; Growth factors; Infectious diseases; Inflammation; Inflammatory response; Inhibin; Inhibin-beta Subunits - metabolism; Irradiated; Irradiation; Keratinocytes; Kinases; Leg; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Muscles; Nuclei; Nuclei (cytology); Oncology; Patients; Proteins; Pulmonary fibrosis; Radiation; Radiation effects; Radiation Injuries - prevention & control; Radiation therapy; Radiotherapy; Real-Time Polymerase Chain Reaction; Research and Analysis Methods; Risk factors; Rodents; Skin; Skin - drug effects; Skin - metabolism; Skin - radiation effects; Smooth muscle; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Wound healing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0173788

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. 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. 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. 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.