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Abstract
Follistatin is a potent regulator of the inflammatory response and binds to and inhibits activin A action. Activin A is a member of the TGFβ protein superfamily which has regulatory roles in the inflammatory response and in the fibrotic process. Fibrosis can occur following cell injury and cell death induced by agents such as ionizing radiation (IR). IR is used to treat cancer and marked fibrotic response is a normal tissue (non-tumour) consequence in a fraction of patients under the current dose regimes. The discovery and development of a therapeutic to abate fibrosis in these radiosensitive patients would be a major advance for cancer radiotherapy. Likewise, prediction of which patients are susceptible to fibrosis would enable individualization of treatment and provide an opportunity for pre-emptive fibrosis control and better tumour treatment outcomes. The levels of activin A and follistatin were measured in fibroblasts derived from patients who developed severe radiation-induced fibrosis following radiotherapy and compared to fibroblasts from patients who did not. Both follistatin and activin A gene expression levels were increased following IR and the follistatin gene expression level was lower in the fibroblasts from fibrosis patients compared to controls at both basal levels and after IR. The major follistatin transcript variants were found to have a similar response to IR and both were reduced in fibrosis patients. Levels of follistatin and activin A secreted in the fibroblast culture medium also increased in response to IR and the relative follistatin protein levels were significantly lower in the samples derived from fibrosis patients. The decrease in the follistatin levels can lead to an increased bioactivity of activin A and hence may provide a useful measurement to identify patients at risk of a severe fibrotic response to IR. Additionally, follistatin, by its ability to neutralise the actions of activin A may be of value as an anti-fibrotic for radiation induced fibrosis.
Highlights
Fibrosis Fibrosis is a major adverse reaction following RT which can significantly compromise quality of life
Follistatin and activin A protein response after ionizing radiation (IR) The response at the transcription level is commonly associated with the translational response; we investigated whether follistatin and activin protein levels were modulated by IR
The present studies have found that follistatin and INHBA gene expression is induced in response to IR which is reflected at the translational level
Summary
Fibrosis Fibrosis is a major adverse reaction following RT which can significantly compromise quality of life. It is characterized by excessive collagens, glycosaminoglycans and other components of the extracellular matrix. One mediator of fibrosis is exposure to ionizing radiation such as that used in radiotherapy This results from the inflammatory reaction to radiation-induced cell death and damage [3]. During this process myofibroblasts are activated which are responsible for tissue remodelling and produce deposits of collagen and other extracellular matrix components [1,4,5,6]. A marked sensitivity to radiation in patients may be due to a profound inflammatory response involving factors that drive the fibrotic process or a reduction in the expression of factors that modulate or block the inflammatory and fibrotic reaction
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