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Deshea L Harris, Takefumi Yamaguchi, Ulrich von Andrian, Pedram Hamrah; A Novel Mouse Model for Radiation Keratopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3223.
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© ARVO (1962-2015); The Authors (2016-present)
Radiation therapy can result in severe chronic radiation keratopathy and dry eye disease, but the specific mechanisms remain elusive. The purpose of this study was to develop a novel mouse model for radiation keratopathy.
6- to 8-week-old BALB/c mice were anesthetized and placed upright in a 50 ml conical tube wrapped in 6.6 mm lead shielding with the heads exposed. The mice underwent sub-lethal irradiation from a Cesium-137 irradiator, 2 x 550 rads, 3 hrs apart. Irradiated mice were clinically evaluated by corneal fluorescein staining (CFS) at 2 and 3 months, after which normal and irradiated corneas were excised, and immunofluorescence histochemistry was performed with anti-CD45 and anti-MHC class II to determine immune cell alterations, and with anti-βΙΙΙ-tubulin antibody to evaluate corneal nerve changes.
The survival rate was 100% with the body lead shielding, not requiring generation of bone marrow chimeras. Mice demonstrated both significant CFS, as well as hair loss around the eyes at both 2 and 3 months post-irradiation. Corneal nerve density decreased in the central cornea from 135.29±11.67 mm/mm2 (control) to 92.84±6.42 (p=0.009) and 78.83±8.17 (p=0.005) at 2 and 3 mos, respectively. Peripheral corneal nerve density decreased from122.01±3.49 mm/mm2 (control) to 72.55±4.93 (p<0.001) and 82.10±2.80 (p<0.001) at 2 and 3 months, respectively. CD45+ cell densities continuously increased in the central cornea from 66.42±13.27 cells/mm2 (control) to 141.15±29.39 (p=0.004) and 297.81±32.42 (p<0.001) and in the peripheral cornea from 103.79±17.34 cells/mm2 (control) to 159.42±23.94 (p=0.002) and 208.13±10.15 (p<0.001) at 2 and 3 mos, respectively. Further, MHC class II, a sign of antigen presenting cell activation, significantly increased after irradiation in both the central cornea (p=0.02), as well as in the peripheral cornea (p=0.002) at 2 and 3 mos compared to controls. A strong inverse correlation was noted between decreased corneal nerves and increase in CD45+ cells in the central cornea at 2 (P=0.04, r=-0.89) and 3 mos (P=0.03, r=-0.91) post irradiation.
Our studies present the first model of radiation keratopathy and demonstrate significant nerve loss and increase in immune cell influx and activation within months. This model will enable future investigations to understand the effects of radiation therapy on the eye, and to study the effects of chronic nerve loss on the corneal immune system.
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