School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 261053, China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, Shandong, 266071, China.
State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, Shandong, 266071, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, Shandong, 266071, China.
Exp Eye Res. 2023 Feb;227:109391. doi: 10.1016/j.exer.2023.109391. Epub 2023 Jan 22.
Dry eye is a multifactorial disease that causes dryness, inflammation and damage of ocular surface. Subcutaneous injection of the muscarinic cholinergic antagonist scopolamine under desiccating stress reduces tear production and induces dry eye symptoms in mice. However, the expression profile and pathogenic changes of the lacrimal gland remain incompletely understood. In the present study, we performed comparative transcriptomic analysis of lacrimal glands from the control and scopolamine-treated mice. Primary analysis identified 677 upregulated genes and 269 downregulated genes in the lacrimal gland of mice with scopolamine treatment. Unexpectedly, KEGG pathway and hierarchical clustering analysis showed the enrichment of "DNA replication" and "cell cycle" categories in the upregulated genes. Subsequently, we confirmed that the acinar cells were the major proliferating cells of lacrimal gland, which exhibited significant increasing of the proliferating cell nuclear antigen (PCNA) expression after scopolamine treatment, accompanied with the upregulation of DNA damage marker γ-H2AX. More importantly, both prophylactic and therapeutic administration of the cyclin-dependent kinase (CDK) inhibitor AT7519 rescued the tear reduction and alleviated dry eye severity in the scopolamine-treated mice, including corneal epithelial barrier function, lacrimal and corneal inflammation, and conjunctival goblet cell density. Therefore, we conclude that aberrant acinar cell proliferation is involved in the scopolamine-induced tear reduction and dry eye onset, which can be improved by AT7519 treatment.
干眼症是一种多因素疾病，可导致眼表面干燥、炎症和损伤。在干燥应激下，皮下注射毒蕈碱型乙酰胆碱拮抗剂东莨菪碱可减少泪液产生，并诱导小鼠出现干眼症症状。然而，泪腺的表达谱和发病机制变化仍不完全清楚。在本研究中，我们对对照组和东莨菪碱处理组小鼠的泪腺进行了比较转录组分析。初步分析确定了东莨菪碱处理组小鼠泪腺中有 677 个上调基因和 269 个下调基因。出乎意料的是，KEGG 通路和层次聚类分析显示，上调基因中富含“DNA 复制”和“细胞周期”类别。随后，我们证实，腺泡细胞是泪腺的主要增殖细胞，在东莨菪碱处理后，增殖细胞核抗原（PCNA）表达显著增加，同时 DNA 损伤标志物 γ-H2AX 上调。更重要的是，细胞周期蛋白依赖性激酶（CDK）抑制剂 AT7519 的预防和治疗给药均可挽救东莨菪碱处理小鼠的泪液减少并减轻干眼症的严重程度，包括角膜上皮屏障功能、泪液和角膜炎症以及结膜杯状细胞密度。因此，我们得出结论，异常的腺泡细胞增殖参与了东莨菪碱诱导的泪液减少和干眼症的发生，AT7519 治疗可改善这种情况。
