Cho Yang Kyung, Shin Eun Young, Uehara Hironori, Ambati Balamurali K
Department of Ophthalmology, St.Vincent's Hospital, College of Medicine, the Catholic University of Korea, Suwon, Gyeonggi-Do 16247, Korea.
Research Institute of Medical Science, St.Vincent's Hospital, College of Medicine, the Catholic University of Korea, Suwon, Gyeonggi-Do 16247, Korea.
Int J Ophthalmol. 2017 Jun 18;10(6):834-839. doi: 10.18240/ijo.2017.06.02. eCollection 2017.
To evaluate the effect of sorafenib in murine high risk keratoplasty model.
Graft survival, corneal neovascularization, and corneal lymphangiogenesis were compared among the sorafenib, dexamethasone, dimethyl sulfoxide (DMSO), and phosphate buffered saline (PBS) groups following subconjunctival injection in mice that underwent high risk penetrating keratoplasty (HRPK). Real-time polymerase chain reaction was performed to quantify the expression of inflammatory cytokines and vascular endothelial growth factor (VEGF)-A, VEGF-C, vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3.
The two-month graft survival rate for HRPK was 42.86% in sorafenib group, 37.50% in dexamethasone group, 0 in DMSO group, and 0 in PBS group. Sorafenib significantly increased graft survival compared to the DMSO and PBS group (<0.05). The sorafenib didn't show significant effect in decreasing neovascularization compared with dexamethsone, DMSO, and PBS group. The sorafenib showed less total lymphangiogenesis than the dexamethasone, DMSO, and PBS group (=0.011, <0.001, <0.001, respectively). The sorafenib group showed reduced expression of VEGF-C, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, VEGFR-2 and VEGFR-3 compared with DMSO group and PBS group (all <0.05). The sorafenib group didn't show difference in the expression of VEGF-A compared with DMSO, neither with PBS. The sorafenib group showed reduced expression of VEGFR-3 compared with dexamethasone (=0.051).
The subconjunctivally administered sorafenib shows significant anti-lymphangiogenic effect, resulting in increased transplant survival in a murine high risk keratoplasty model. We suggest that a close linkage between decreased VEGF-C/VEGFR-2 and -3 signaling and increased corneal graft survival by sorafenib seems to exist.
评估索拉非尼在小鼠高危角膜移植模型中的作用。
在接受高危穿透性角膜移植术（HRPK）的小鼠结膜下注射后，比较索拉非尼、地塞米松、二甲基亚砜（DMSO）和磷酸盐缓冲盐水（PBS）组的移植物存活情况、角膜新生血管形成和角膜淋巴管生成情况。进行实时聚合酶链反应以定量炎症细胞因子和血管内皮生长因子（VEGF）-A、VEGF-C、血管内皮生长因子受体（VEGFR）-2、VEGFR-3的表达。
索拉非尼组HRPK的两个月移植物存活率为42.86%，地塞米松组为37.50%，DMSO组为0，PBS组为0。与DMSO和PBS组相比，索拉非尼显著提高了移植物存活率（<0.05）。与地塞米松、DMSO和PBS组相比，索拉非尼在减少新生血管形成方面未显示出显著效果。索拉非尼组的总淋巴管生成少于地塞米松、DMSO和PBS组（分别为=0.011、<0.001、<0.001）。与DMSO组和PBS组相比，索拉非尼组的VEGF-C、肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6、VEGFR-2和VEGFR-3表达降低（均<0.05）。与DMSO组相比，索拉非尼组在VEGF-A表达上无差异，与PBS组相比也无差异。与地塞米松组相比，索拉非尼组的VEGFR-3表达降低（=0.051）。
结膜下注射索拉非尼显示出显著的抗淋巴管生成作用，导致小鼠高危角膜移植模型中的移植存活率增加。我们认为，索拉非尼降低VEGF-C/VEGFR-2和-3信号传导与提高角膜移植存活率之间似乎存在密切联系。
