Radiation Fibrosis

One long-term side effect of radiation therapy for cancer patients is radiation-induced fibrosis, more commonly referred to as radiation fibrosis syndrome (RFS).  RFS can manifest in various tissues including lung, skin, gastrointestinal tract, muscle, and numerous other tissues depending on treatment.  Symptoms of this disease can begin appearing weeks to months after treatment and severity of disease generally correlates with increased and prolonged doses of targeted radiation.  The general features of this disease include the presence of infiltrating inflammatory cells into tissue, the differentiation of fibroblasts into myofibroblasts, and excessive production of extracellular matrix components including collagen.  As with other forms of fibrosis, TGFβ plays a key role in this process and leads to increased levels of growth factors and pro-inflammatory mediators.  While this may present an interesting target for drug development, many other factors must also be considered, as radiation fibrosis is a complex disease.  Radiation can induce both direct and indirect injury to the target tissue.  Radiation causes excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which in turn leads to both vascular and parenchymal cell death and tissue damage.  Radiation also leads to upregulation of a number of pro-inflammatory cytokines and chemokines.  The increased inflammation that occurs after radiation also drives the recruitment of bone marrow-derived cells to the site of injury, including mesenchymal stem cells, endothelial progenitor cells, and myelomonocytic cells, all of which may play a role in the progression of fibrosis. 

Numerous tissues are affected by radiation therapy.  Skin is often affected, with both acute and chronic phases of skin injury.  Early effects of radiation on skin include increased erythema, desquamation, and possibly ulceration.  Later effects include dermal fibrosis, sebaceous and sweat gland atrophy, hair loss, and telangiectasia.  The gastrointestinal (GI) tract is also often affected by radiation.  Symptoms in patients with GI damage include pain, blood loss, diarrhea, fecal incontinence and changes to bowel movements.  In addition, lung tissue in often damaged following radiation therapy.  Acutely, patients may develop pneumonitis, though chronic fibrosis, which often leads to respiratory dysfunction and decreased quality of life, accompanies radiation therapy months to years after initial treatments. 

Although many treatments exist to deal with symptoms of this disease, there exists a real need to develop drugs that can prevent formation of fibrosis or to treat the disease in patients with RFS. 

Radiation-Induced Pulmonary Fibrosis

A critical need exists to develop therapies that prevent fibrosis in patients exposed to high levels of radiation during cancer therapy.  To test the efficacy of compounds that target radiation-induced pulmonary fibrosis and fibrosis resulting in other tissues, this model represents a likely scenario of radiation exposure in the human population undergoing radiation therapy.  In this study the radiation is targeted to the thorax, while the remainder of the body is protected with a lead shield.  The development of fibrosis can be monitored in this study through lung mechanic measurements, body weight analysis and wheel activity.  Additionally, endpoint analysis of lung collagen content, bronchoalveolar lavage contents, and histological analysis can determine how well targeted therapies affected the progression of lung fibrosis and give insight into mechanism of action of particular drug candidates.   

Study Design Table

Model Description Duration Endpoints
Radiation-Induced Pulmonary Fibrosis The thorax of a mouse is exposed to 20 Gy irradiation and progression of fibrosis is monitored over 16 weeks 112 Days (16 weeks) Wheel running activity, Lung mechanics measurement, BAL analysis, Histology, Body weights, and Collagen content measurement

 

Pressure Volume Curves measured in Naïve and irradiated (20 Gy) mice over 16 weeks
Total and inflammatory cells in addition to lung and tissue elastance are increased in mice exposed to 20 Gy irradiation
Decreased wheel running activity can be observed in mice exposed to radiation when compared to non-irradiated control mice
Radiation-Induced Dermal Fibrosis Model

Hamsters provide an excellent model for radiation-induced fibrosis because of several biological similarities to humans. Furthermore, the cheek pouch is pliable and can be extracted, allowing for radiation to be targeted to the cheek pouch while the rest of the animal is shielded. The result is formation of fibrotic skin tissue on the cheek pouch approximately 16 days following radiation. Primary end points in this model include collagen content measurement and histology.

Study Design Table

Model Description Duration Endpoints
Acute Radiation-Induced Fibrosis in Hamsters The cheek pouch is treated with an acute dose of 40 Gy radiation resulting in the formation of fibrotic dermal tissue 28 Days Collagen content measurement, Histology

 

Appearance of fibrosis in cheek pouches of hamsters exposed to 40 Gy radiation.  Representative Masson’s trichrome-stained samples from Day 0 (A, B), Day 16 (C, D), and Day 28 (E, F) after radiation.
Fractionated-Radiation Induced Dermal Fibrosis Model

In the fractionated-radiation induced dermal fibrosis model the back of the mouse is shaved and/or depilated and the skin is temporarily tented such that it can be selectively targeted with radiation while the rest of the mouse is protected by a lead shield.  Animals receive 6 fractions of radiation on a schedule of 3 days on, 2 days off. The progression of disease, which can also be observed in an acute radiation model, displays with mild erythema typically observed 8-10 days following radiation exposure, with disease severity peaking between Days 12-16 (depending on the dose of radiation),  and with desquamation of approximately 50% of the irradiated area. Endpoints include dermatitis severity scores, collagen content measurement, and histological analyses.

Study Design Table

Acute Radiation Dose (Day 0) Dermatitis Evaluation (every 2 days) Disease Peak Duration Endpoints
6 Gy Day 8 to 36 Day 16 36 Days Dermatitis Severity Scores, Collagen content measurement, Histology
8 Gy
10 Gy

 

Masson’s Trichrome staining of fibrosis at peak of disease showing appearance of fibrosis, inflammation, damaged epithelium and necrosis of the skin as a result of radiation exposure. NR = non-irradiated.
Subscribe to RSS - Radiation Fibrosis