Radiation dermatitis in the hairless mouse model mimics human radiation dermatitis

Abstract

Over half of all people diagnosed with cancer receive radiation therapy. Moderate to severe radiation dermatitis occurs in most human radiation patients, causing pain, aesthetic distress, and a negative impact on tumor control. No effective prevention or treatment for radiation dermatitis exists. The lack of well-characterized, clinically relevant animal models of human radiation dermatitis contributes to the absence of strategies to mitigate radiation dermatitis. Here, we establish and characterize a hairless SKH-1 mouse model of human radiation dermatitis by correlating temporal stages of clinical and pathological skin injury. We demonstrate that a single ionizing radiation treatment of 30 Gy using 6 MeV electrons induces severe clinical grade 3 peak toxicity at 12 days, defined by marked erythema, desquamation and partial ulceration, with resolution occurring by 25 days. Histopathology reveals that radiation-induced skin injury features temporally unique inflammatory changes. Upregulation of epidermal and dermal TGF-β1 and COX-2 protein expression occurs at peak dermatitis, with sustained epidermal TGF-β1 expression beyond resolution. Specific histopathological variables that remain substantially high at peak toxicity and early clinical resolution, including epidermal thickening, hyperkeratosis and dermal fibroplasia/fibrosis, serve as specific measurable parameters for in vivo interventional preclinical studies that seek to mitigate radiation-induced skin injury.

Longitudinal Neuropathological Consequences of Extracranial Radiation Therapy in Mice

“…Cytokines including Il-1, Il-6, TNF-α, and TGF-β are produced by fibroblasts, keratinocytes, endothelial cells, and immune cells at the irradiated site to recruit immune cells to this site [ 34 ]. Studies in rodent skin demonstrate a dose-dependent increase in TGF-β following irradiation that lasts days following treatment [ 19 , 35 ]. TGF-β can recruit inflammatory cells to the skin and is involved in the tissue repair process following radiation treatment [ 35 ].…”

“…The mice were treated with a dose of 20 Gy or 30 Gy radiation to the skin surface of the right hindlimb using 6 MeV electrons (Varian 2100 iX; Varian Medical Systems, Inc., Palo Alto, CA, USA). The dose was selected based on our prior work which demonstrated that 30 Gy induces severe dermatitis and gliosis [ 19 ] in SKH-1 mice, whereas 20 Gy is associated with low grade (hair loss) cutaneous changes [ 105 ]. The radiation treatment protocol was identical to that previously published [ 3 ].…”

“…The severity of this neuroinflammation is comparable to mice exposed to chemotherapy agents of methotrexate or doxorubicin [ 1 , 2 , 3 ]. Our prior work showed that SKH1 mice treated with ECRT caused focal dermatitis and hippocampal dependent memory deficits comparable to SKH1 mice treated with doxorubicin, a potent broad-spectrum anti-cancer drug known to induce cognitive deficits [ 3 , 19 ]. There is a limited understanding as to the clinical cognitive impact of ECRT and the mechanism(s) that link CRCI and radiation prescribed to anatomic sites distant from the brain.…”