Nitrogen Mustard-Induced Corneal Injury Involves DNA Damage and Pathways Related to Inflammation, Epithelial-Stromal Separation, and Neovascularization
Nitrogen Mustard-Induced Corneal Injury Involves DNA Damage and Pathways Related to Inflammation, Epithelial-Stromal Separation, and Neovascularization
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DOI：
10.1097/ico.0000000000000685
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发表时间：
2016-02-01
期刊：
影响因子：
2.8
通讯作者：
Agarwal, Rajesh
中科院分区：
文献类型：
--
作者：
Goswami, Dinesh G.;Tewari-Singh, Neera;Agarwal, Rajesh
目的：为了评估角膜组织暴露于发泡剂，氮芥（NM），化学战剂硫芥的双功能烷基化类似物的毒性作用和相关机制。方法：毒性作用和相关机制进行了研究，在最大限度地影响角膜组织使用角膜培养和人角膜上皮（HCE）细胞暴露于NM。结果：分析离体兔角膜显示，NM暴露增加凋亡细胞死亡，上皮厚度，上皮-基质分离，血管内皮生长因子，环氧合酶2和基质金属蛋白酶-9的水平。在HCE细胞中，NM暴露导致细胞活力和增殖的剂量依赖性降低，这与DNA损伤有关，包括p53 ser 15、总p53和H2A.X ser 139水平的增加。NM暴露也诱导caspase-3和聚ADP核糖聚合酶裂解，表明它们参与NM诱导的兔角膜和HCE细胞凋亡。与兔角膜相似，NM暴露导致HCE细胞中环氧合酶2、基质金属蛋白酶9和血管内皮生长因子水平增加，表明这些分子和相关途径在NM诱导的角膜炎症、上皮-基质分离和新生血管形成中的作用。NM暴露也诱导激活蛋白1转录因子蛋白和上游信号通路，包括丝裂原活化蛋白激酶和Akt蛋白激酶的激活，这表明这些可能是参与NM诱导的角膜injury.Conclusions的关键因素：从这项研究的结果提供了深入了解的分子靶点和途径，可能参与NM诱导的角膜损伤奠定了背景，为进一步调查这些途径在水疱剂诱导的眼损伤，这可能有助于靶向治疗的发展。
Purpose:To evaluate the toxic effects and associated mechanisms in corneal tissue exposed to the vesicating agent, nitrogen mustard (NM), a bifunctional alkylating analog of the chemical warfare agent sulfur mustard.Methods:Toxic effects and associated mechanisms were examined in maximally affected corneal tissue using corneal cultures and human corneal epithelial (HCE) cells exposed to NM.Results:Analysis of ex vivo rabbit corneas showed that NM exposure increased apoptotic cell death, epithelial thickness, epithelial-stromal separation, and levels of vascular endothelial growth factor, cyclooxygenase 2, and matrix metalloproteinase-9. In HCE cells, NM exposure resulted in a dose-dependent decrease in cell viability and proliferation, which was associated with DNA damage in terms of an increase in p53 ser15, total p53, and H2A.X ser139 levels. NM exposure also induced caspase-3 and poly ADP ribose polymerase cleavage, suggesting their involvement in NM-induced apoptotic death in the rabbit cornea and HCE cells. Similar to rabbit cornea, NM exposure caused an increase in cyclooxygenase 2, matrix metalloproteinase-9, and vascular endothelial growth factor levels in HCE cells, indicating a role of these molecules and related pathways in NM-induced corneal inflammation, epithelial-stromal separation, and neovascularization. NM exposure also induced activation of activator protein 1 transcription factor proteins and upstream signaling pathways including mitogen-activated protein kinases and Akt protein kinase, suggesting that these could be key factors involved in NM-induced corneal injury.Conclusions:Results from this study provide insight into the molecular targets and pathways that could be involved in NM-induced corneal injuries laying the background for further investigation of these pathways in vesicant-induced ocular injuries, which could be helpful in the development of targeted therapies.