PDF(Pubmed)
Abstract：
Sulfur mustard (SM), a bi-functional alkylating agent, was used during World War I and the Iran-Iraq war. SM toxicity is ten times higher in eyes than in other tissues. Cornea is exceptionally susceptible to SM-injuries due to its anterior positioning and mucous-aqueous interphase. Ocular SM exposure induces blepharitis, photosensitivity, dry eye, epithelial defects, limbal ischemia and stem cell deficiency, and mustard gas keratopathy leading to temporary or permanent vision impairments. We demonstrated that dexamethasone (Dex) is a potent therapeutic intervention against SM-induced corneal injuries; however, its mechanism of action is not well known. Investigations employing proteomic profiling (LC-MS/MS) to understand molecular mechanisms behind SM-induced corneal injury and Dex efficacy were performed in the rabbit cornea exposed to SM and then received Dex treatment. PEAKS studio was used to extract, search, and summarize peptide identity. Ingenuity Pathway Analysis was used for pathway identification. Validation was performed using immunofluorescence. One-Way ANOVA (FDR < 0.05; p < 0.005) and Student\'s t-test (p < 0.05) were utilized for analyzing proteomics and IF data, respectively. Proteomic analysis revealed that SM-exposure upregulated tissue repair pathways, particularly actin cytoskeleton signaling and inflammation. Prominently dysregulated proteins included lipocalin2, coronin1A, actin-related protein2, actin-related protein2/3 complex subunit2, actin-related protein2/3 complex subunit4, cell division cycle42, ezrin, bradykinin/kininogen1, moesin, and profilin. Upregulated actin cytoskeleton signaling increases F-actin formation, dysregulating cell shape and motility. Dex reversed SM-induced increases in the aforementioned proteins levels to near control expression profiles. Dex aids corneal wound healing and improves corneal integrity via actin cytoskeletal signaling and anti-inflammatory effects following SM-induced injuries.
摘要：
目标：硫芥子气（SM），一种双官能的烷化剂，在第一次世界大战和伊伊拉克战争期间使用。SM在眼睛中的毒性比在其他组织中高十倍。角膜由于其前部定位和粘液-水性相间而特别容易受到SM损伤。眼部SM暴露会引起眼睑炎，光敏性,干眼症,上皮缺损,角膜缘缺血和干细胞缺乏，和芥子气角膜病导致暂时性或永久性视力障碍。我们证明了地塞米松（Dex）是针对SM引起的角膜损伤的有效治疗干预措施；然而，其作用机制尚不清楚。在暴露于SM然后接受Dex治疗的兔角膜中进行了使用蛋白质组学分析（LC-MS/MS）来了解SM诱导的角膜损伤和Dex功效的分子机制的研究。PEAKS工作室被用来提取，搜索,并总结了肽的身份。将独创性路径分析用于途径鉴定。使用免疫荧光进行验证。单因素方差分析(FDR<0.05;p<0.005)和学生t检验(p<0.05)用于分析蛋白质组学和IF数据,分别。蛋白质组学分析显示SM暴露上调组织修复途径，特别是肌动蛋白细胞骨架信号和炎症。明显失调的蛋白质包括脂质运载蛋白2，coronin1A，肌动蛋白相关蛋白2，肌动蛋白相关蛋白2/3复合物亚基2，肌动蛋白相关蛋白2/3复合物亚基4，细胞分裂周期42，ezrin，缓激肽/激肽原1，膜蛋白，和profilin。上调的肌动蛋白细胞骨架信号增加F-肌动蛋白形成，细胞形状和运动失调。Dex将SM诱导的上述蛋白质水平的增加逆转至接近对照表达谱。Dex有助于角膜伤口愈合，并通过肌动蛋白细胞骨架信号传导和SM诱导损伤后的抗炎作用改善角膜完整性。
