Ibuki Mari, Shoda Chiho, Miwa Yukihiro, Ishida Ayako, Tsubota Kazuo, Kurihara Toshihide
Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan.
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
Front Pharmacol. 2020 Feb 28;11:174. doi: 10.3389/fphar.2020.00174. eCollection 2020.
Lactoferrin, a type of glycoprotein, is contained in exocrine fluids such as tears, breast milk, sweat, and saliva, and is known to have anti-microbial, antioxidant, and anti-cancer effects. In the ophthalmological field, topical administration of lactoferrin has been reported to have a therapeutic effect in a murine dry eye model. Hypoxia-inducible factor (HIF) regulates various gene expressions under hypoxia, including vascular endothelial growth factor (VEGF), and is considered as an alternative target for neovascular ocular diseases such as age-related macular degeneration (AMD). We previously screened natural products and identified lactoferrin as a novel HIF inhibitor. In this study, we confirmed that lactoferrin has an HIF inhibitory effect and a therapeutic effect in a murine model of neovascular AMD.
HIF inhibitory effects of lactoferrin were evaluated using a luciferase assay and western blotting . The quantified volume of choroidal neovascularization (CNV) induced by laser irradiation was compared with oral lactoferrin administration or conditional tissue specific knockout mice.
Lactoferrin administration showed a significant HIF inhibitory effect in the retinal neuronal cells. Oral administration of lactoferrin or conditional gene deletion significantly reduced CNV volume compared to controls.
Lactoferrin has a therapeutic effect in a laser CNV model by suppressing the retinal HIF activity.
乳铁蛋白是一种糖蛋白，存在于泪液、母乳、汗液和唾液等外分泌液中，已知具有抗菌、抗氧化和抗癌作用。在眼科领域，据报道局部应用乳铁蛋白对小鼠干眼模型具有治疗作用。缺氧诱导因子（HIF）在缺氧条件下调节包括血管内皮生长因子（VEGF）在内的多种基因表达，被认为是年龄相关性黄斑变性（AMD）等新生血管性眼病的替代靶点。我们之前筛选天然产物并确定乳铁蛋白为一种新型HIF抑制剂。在本研究中，我们证实乳铁蛋白在新生血管性AMD小鼠模型中具有HIF抑制作用和治疗作用。
使用荧光素酶测定法和蛋白质印迹法评估乳铁蛋白的HIF抑制作用。将激光照射诱导的脉络膜新生血管（CNV）定量体积与口服乳铁蛋白给药或条件性组织特异性敲除小鼠进行比较。
给予乳铁蛋白在视网膜神经细胞中显示出显著的HIF抑制作用。与对照组相比，口服乳铁蛋白或条件性基因缺失显著降低了CNV体积。
乳铁蛋白通过抑制视网膜HIF活性在激光诱导的CNV模型中具有治疗作用。
