Abstract
PurposeFibrosis 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.Experimental designC57BL/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.ResultsLeg 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.ConclusionsFollistatin 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.
Highlights
Normal tissue reactions in response to radiotherapy can be broadly classified into two distinct subtypes; ‘acute’ and ‘chronic’
Epidermal thickness and cell nucleus area of keratinocytes were decreased by the follistatin treatment compared to the cells in irradiated skin of control mice
Since these adverse effects are not predictable in patients before treatment, the radiation doses used in clinical practice are conservative and some patients who could potentially tolerate higher radiation doses do not receive the maximum benefit from radiotherapy
Summary
Normal tissue reactions in response to radiotherapy can be broadly classified into two distinct subtypes; ‘acute’ and ‘chronic (late)’. The late reactions that develop in patients only emerge long after radiotherapy has been completed. Since these adverse effects are not predictable in patients before treatment, the radiation doses used in clinical practice are conservative and some patients who could potentially tolerate higher radiation doses do not receive the maximum benefit from radiotherapy. Some of these late radiation-induced fibrotic reactions are debilitating and can result in death if they occur in critical organs such as the lung or liver
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