Department of Ophthalmology, Keio university school of medicine, Tokyo, Japan.
Centre for Rare Disease Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
Sci Rep. 2017 Nov 14;7(1):15584. doi: 10.1038/s41598-017-15682-1.
Dry eye disease (DED) is a common disorder causing discomfort and ocular fatigue. Corneal nerves are compromised in DED, which may further cause loss of corneal sensation and decreased tear secretion. Semaphorin 3A (Sema3A) is expressed by the corneal epithelium under stress, and is known as an inhibitor of axonal regeneration. Using a murine dry eye model, we found that topical SM-345431, a selective Sema3A inhibitor, preserved corneal sensitivity (2.3 ± 0.3 mm versus 1.4 ± 0.1 mm in vehicle control, p = 0.004) and tear volume (1.1 ± 0.1 mm versus 0.3 ± 0.1 mm in vehicle control, p < 0.001). Fluorescein staining area of the cornea due to damage to barrier function was also reduced (4.1 ± 0.9% in SM-345431 group versus 12.9 ± 2.2% in vehicle control, p < 0.001). The incidence of corneal epithelial erosions was significantly suppressed by SM-345431 (none in SM-345431 group versus six (21%) in vehicle control, p = 0.01). Furthermore, sub-epithelial corneal nerve density and intraepithelial expression of transient receptor potential vanilloid receptor 1 (TRPV1) were significantly preserved with SM-345431. Our results suggest that inhibition of Sema3A may be an effective therapy for DED.
干眼症（DED）是一种常见的疾病，会引起不适和眼部疲劳。角膜神经在 DED 中受损，这可能进一步导致角膜感觉丧失和泪液分泌减少。Semaphorin 3A（Sema3A）在应激下由角膜上皮表达，是轴突再生的抑制剂。使用小鼠干眼症模型，我们发现局部应用 Sema3A 抑制剂 SM-345431 可维持角膜敏感性（2.3±0.3mm 对载体对照组 1.4±0.1mm，p=0.004）和泪液体积（1.1±0.1mm 对载体对照组 0.3±0.1mm，p<0.001）。由于屏障功能受损导致的角膜荧光素染色面积也减少（SM-345431 组 4.1±0.9%对载体对照组 12.9±2.2%，p<0.001）。SM-345431 显著抑制了角膜上皮糜烂的发生率（SM-345431 组无，载体对照组 6 例（21%），p=0.01）。此外，SM-345431 可显著保存亚上皮角膜神经密度和上皮内瞬时受体电位香草酸受体 1（TRPV1）的表达。我们的结果表明，抑制 Sema3A 可能是 DED 的有效治疗方法。
