Department of Ophthalmology, Otorhinolaringology and Head & Neck Surgery, Faculty of Medicine of Ribeirão Preto, São Paulo University, Ribeirao Preto 14049900, Brazil.
Hum Gene Ther. 2013 Apr;24(4):417-23. doi: 10.1089/hum.2012.111.
Therapeutic doses of radiation (RTx) causes dry eye syndrome (DES), dry mouth, and as in other sicca syndromes, they are incurable. The aims of this work are as follows: (a) to evaluate a mouse model of DES induced by clinically relevant doses of radiation, and (b) to evaluate the protective effect of erythropoietin (Epo) in preventing DES. C3H female mice were subjected to five sessions of RTx, with or without pre-RTx retroductal administration of the AdLTR2EF1a-hEPO (AdEpo) vector in the salivary glands (SG), and compared with naïve controls at Day 10 (10d) (8 Gy fractions) and 56 days (56d) (6 Gy fractions) after RTx treatment. Mice were tested for changes in lacrimal glands (LG), tear secretion (phenol red thread), weight, hematocrit (Hct), and markers of inflammation, as well as microvessels and oxidative damage. Tear secretion was reduced in both RTx groups, compared to controls, by 10d. This was also seen at 56d in RTx but not AdEpo+RTx group. Hct was significantly higher in all AdEpo+RTx mice at 10d and 56d. Corneal epithelium was significantly thinner at 10d in the RTx group compared with AdEpo+RTx or the control mice. There was a significant reduction at 10d in vascular endothelial growth factor (VEGF)-R2 in LG in the RTx group that was prevented in the AdEpo+RTx group. In conclusion, RTx is able to induce DES in mice. AdEpo administration protected corneal epithelia and resulted in some recovery of LG function, supporting the value of further studies using gene therapy for extraglandular diseases.
治疗剂量的辐射（RTx）会导致干眼症（DES）、口干等症状，并且与其他干燥综合征一样，这些症状是无法治愈的。本研究的目的如下：（a）评估由临床相关剂量辐射诱导的 DES 小鼠模型，（b）评估促红细胞生成素（Epo）在预防 DES 中的保护作用。C3H 雌性小鼠接受了五次 RTx 治疗，其中一些接受了 AdLTR2EF1a-hEPO（AdEpo）载体的 retroductal 给药，然后与未接受 RTx 治疗的对照组进行比较，分别在 10d（8Gy 剂量）和 56d（6Gy 剂量）后。检测小鼠的泪腺（LG）、泪液分泌（酚红线）、体重、红细胞压积（Hct）、炎症标志物、微血管和氧化损伤的变化。与对照组相比，两组 RTx 组的泪液分泌在 10d 时均减少，在 56d 时也仅在 RTx 组中观察到这种情况。在 10d 和 56d 时，所有 AdEpo+RTx 小鼠的 Hct 均显著升高。与 AdEpo+RTx 组或对照组相比，RTx 组在 10d 时的角膜上皮明显更薄。在 RTx 组中，LG 中的血管内皮生长因子（VEGF）-R2 在 10d 时显著减少，而在 AdEpo+RTx 组中则得到了预防。总之，RTx 能够在小鼠中诱导 DES。AdEpo 给药可保护角膜上皮，并导致 LG 功能部分恢复，支持对用于治疗外分泌疾病的基因治疗进行进一步研究。
