The Involvement of Unfolded Protein Response in the Mechanism of Nitrogen Mustard-Induced Ocular Toxicity.
The Involvement of Unfolded Protein Response in the Mechanism of Nitrogen Mustard-Induced Ocular Toxicity.
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DOI：
10.1124/jpet.123.001814
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发表时间：
2024-01-17
期刊：
影响因子：
--
通讯作者：
Gorbatyuk M
中科院分区：
文献类型：
--
作者：
Zhylkibayev A;Ung TT;Mobley J;Athar M;Gorbatyuk M
氮芥（NM）是硫芥的已知替代品，硫芥是一种化学战剂，可引起广泛的眼部症状，从视力永久性下降到接触后失明。虽然已经提出这两种起泡剂具有相似的毒性机制，但纳米颗粒诱导眼组织细胞死亡的模式尚未得到充分探讨。因此，我们假设，小鼠眼部直接暴露于NM，通过慢性激活角膜细胞中的未折叠蛋白反应（UPR） PERK臂和VEGF分泌，导致视网膜组织损伤，最终导致细胞死亡。我们将纳米直接局部应用于小鼠，在暴露后2周分析眼部和视网膜组织。通过暗位和光位视网膜电图反应，在小鼠中检测到视网膜功能的急剧下降。这种下降与角膜和视网膜组织TUNEL染色增强有关。此外，将角膜细胞暴露于NM下，发现228种差异表达和专一表达的蛋白主要与UPR、铁下垂和坏死性下垂相关。此外，这些细胞表现出UPR PERK臂的激活和VEGF分泌的增加。随后观察到暴露小鼠角膜中VEGF染色增强。因此，我们的数据表明，纳米颗粒诱导眼毒性的机制应该仔细研究，未来的研究应该确定通过角膜到视网膜的前死亡途径传递的信号分子。本研究表明，纳米粒子局部暴露在小鼠体内导致视网膜功能急剧下降，角膜和视网膜组织TUNEL染色增强。我们还发现NM处理角膜细胞导致228个主要与铁下垂相关的差异和专一表达蛋白。此外，这些细胞表现出UPR PERK激活和VEGF分泌增加。后者也在暴露的小鼠的角膜中发现。
Nitrogen mustard (NM) is a known surrogate of sulfur mustard, a chemical-warfare agent that causes a wide range of ocular symptoms, from a permanent reduction in visual acuity to blindness upon exposure. Although it has been proposed that the two blistering agents have a similar mechanism of toxicity, the mode of NM-induced cell death in ocular tissue has not been fully explored. Therefore, we hypothesized that direct ocular exposure to NM in mice leads to retinal tissue injury through chronic activation of the unfolded protein response (UPR) PERK arm in corneal cells and VEGF secretion, eventually causing cell death. We topically applied NM directly to mice to analyze ocular and retinal tissues at 2 weeks postexposure. A dramatic decline in retinal function, measured by scotopic and photopic electroretinogram responses, was detected in the mice. This decline was associated with enhanced TUNEL staining in both corneal and retinal tissues. In addition, exposure of corneal cells to NM revealed 228 differentially and exclusively expressed proteins primarily associated with the UPR, ferroptosis, and necroptosis. Moreover, these cells exhibited activation of the UPR PERK arm and an increase in VEGF secretion. Enhancement of VEGF staining was later observed in the corneas of the exposed mice. Therefore, our data indicated that the mechanism of NM-induced ocular toxicity should be carefully examined and that future research should identify a signaling molecule transmitted via a prodeath pathway from the cornea to the retina. This study demonstrated that NM topical exposure in mice results in dramatic decline in retinal function associated with enhanced TUNEL staining in both corneal and retinal tissues. We also found that the NM treatment of corneal cells resulted in 228 differentially and exclusively expressed proteins primarily associated with ferroptosis. Moreover, these cells manifest the UPR PERK activation and an increase in VEGF secretion. The latter was also found in the corneas of the cexposed mice.
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