氮芥诱导的角膜损伤涉及神经酰胺途径。
Nitrogen mustard-induced corneal injury involves the sphingomyelin-ceramide pathway.
机构信息
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.
Gavin Herbert Eye Institute, University of California, Irvine CA, USA.
出版信息
Ocul Surf. 2018 Jan;16(1):154-162. doi: 10.1016/j.jtos.2017.11.004. Epub 2017 Nov 10.
PURPOSE
Nitrogen mustard (NM), which simulates the effects of sulfur mustard (SM), is a potent vesicant known to cause irreversible corneal damage. This study investigates the mechanisms by which NM induces corneal damage by examining the impact of NM exposure on the morphology and lipidome of the cornea.
METHODS
Intact ex vivo rabbit eyes were placed in serum-free DMEM organ culture. NM (0, 1, 2.5, 5 or 10 mg/ml) was applied to the central cornea for 5, 10 or 15 min using a 5 mm filter disk and subsequently rinsed with DMEM. Corneas were then cultured for 3, 24, or 48 h before being fixed for morphological analysis or for 24 h before being snap frozen for lipidomic analysis.
RESULTS
No morphological changes were detected 3 h after NM exposure. Twenty-four h after exposure, 1 mg/ml NM caused erosion of the corneal epithelium, but no damage to the underlying stroma. Damage caused by 2.5 mg/ml NM extended almost two thirds through the corneal stroma, while 5 mg/ml completely penetrated the corneal stroma. An altered lipid profile occurred 24 h after corneas were exposed to NM. Specific sphingomyelins, ceramides, and diacylglycerols were increased up to 9-, 60- and 10-fold, respectively.
CONCLUSIONS
NM induces concentration- and exposure time-dependent damage to the cornea that increases in severity over time. Alterations in the sphingomyelin-ceramide pathway may contribute to the damaging effects of NM exposure.
目的
氮芥（NM）模拟了芥子气（SM）的作用，是一种已知会造成不可逆转的角膜损伤的强效糜烂剂。本研究通过检查 NM 暴露对角膜形态和脂质组的影响，来研究 NM 引起角膜损伤的机制。
方法
将完整的离体兔眼置于无血清 DMEM 器官培养物中。使用 5mm 滤纸片将 NM（0、1、2.5、5 或 10mg/ml）施加到中央角膜上 5、10 或 15 分钟，然后用 DMEM 冲洗。然后将角膜培养 3、24 或 48 小时，然后固定进行形态分析，或培养 24 小时后立即冷冻用于脂质组学分析。
结果
NM 暴露 3 小时后未检测到形态变化。暴露 24 小时后，1mg/ml NM 导致角膜上皮侵蚀，但对下基质没有损伤。2.5mg/ml NM 引起的损伤几乎延伸到角膜基质的三分之二，而 5mg/ml NM 则完全穿透了角膜基质。暴露于 NM 后 24 小时，脂质谱发生改变。特定的神经鞘磷脂、神经酰胺和二酰基甘油分别增加了 9 倍、60 倍和 10 倍。
结论
NM 引起的角膜损伤呈浓度和暴露时间依赖性，且随时间推移而加重。鞘氨醇-神经酰胺途径的改变可能有助于 NM 暴露的损伤作用。
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