Wu Rong, Liu Shuwan, Shen Zhan, Zhao Yinghan, Hong Jing, Ma Jiao
Department of Ophthalmology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China.
Department of Ophthalmology, Peking University Shenzhen Hospital, Shenzhen, 518000, China.
BMC Ophthalmol. 2025 Jul 1;25(1):379. doi: 10.1186/s12886-025-04210-9.
Chronic graft-versus-host disease (cGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation, frequently associated with severe dry eye syndrome. Using a murine cGVHD model, this study investigates the roles of oxidative stress, inflammation, and cellular senescence in corneal damage.
A cGVHD mouse model was established by transplanting bone marrow cells and splenocytes from male C57BL/6J (H-2b) donors into lethally irradiated female BALB/c (H-2d) recipients. Clinical parameters (including survival rates and tear volume), corneal damage(assessed by fluorescein staining score), and ocular tissue inflammation/fibrosis (via histological analysis) were evaluated. Oxidative stress markers (8-OHdG), 4-Hydroxynonenal (4HNE), antioxidant enzymes (catalase), Nuclear factor erythroid 2-related factor 2 (Nrf2), senescence-related genes (P16INK4A, P38 MARK), and inflammation-related proteins (IL6, IL8, NF-κB) were detected using immunohistochemistry (IHC), qPCR, and SA-β-gal staining. Gene Ontology (GO) enrichment analysis was performed to illustrate alterations in gene expression.
Chronic ocular GVHD (coGVHD) mice presented with higher clinical scores, characterized by weight loss, skin lesions, and systemic symptoms. They also exhibited reduced tear volume and exacerbated corneal epithelial damage. Histological analysis showed significant inflammation and fibrosis in Meibomian glands (MGs) and lacrimal glands (LGs). Upregulation of 8-OHdG and 4HNE, along with downregulation of catalase and Nrf2, was observed, indicating enhanced oxidative stress and compromised antioxidant defense. Elevated levels of pro-inflammatory markers (IL-6, IL-8, NF-κB), the pro-fibrotic marker α-SMA, and senescence markers (P16INK4A, P38 MARK) were detected. These findings suggest a complex interplay among inflammation, fibrosis, and cellular senescence in the pathogenesis of coGVHD corneas. Bioinformatics analysis revealed significant changes in gene expression related to oxidative stress, inflammation, and senescence in coGVHD corneas.
The study elucidates the central roles of oxidative stress, inflammation, and cellular senescence in corneal pathology in cGVHD, identifying potential targets for innovative therapeutic strategies.
Not applicable.
慢性移植物抗宿主病（cGVHD）是异基因造血干细胞移植的一种严重并发症，常与严重的干眼综合征相关。本研究利用小鼠cGVHD模型，探讨氧化应激、炎症和细胞衰老在角膜损伤中的作用。
通过将雄性C57BL/6J（H-2b）供体的骨髓细胞和脾细胞移植到经致死剂量照射的雌性BALB/c（H-2d）受体中，建立cGVHD小鼠模型。评估临床参数（包括生存率和泪液量）、角膜损伤（通过荧光素染色评分评估）以及眼组织炎症/纤维化（通过组织学分析）。使用免疫组织化学（IHC）、qPCR和SA-β-半乳糖苷酶染色检测氧化应激标志物（8-羟基脱氧鸟苷）、4-羟基壬烯醛（4HNE）、抗氧化酶（过氧化氢酶）、核因子红细胞2相关因子2（Nrf2）、衰老相关基因（P16INK4A、P38 MARK）和炎症相关蛋白（IL6、IL8、NF-κB）。进行基因本体（GO）富集分析以阐明基因表达的变化。
慢性眼部移植物抗宿主病（coGVHD）小鼠表现出较高的临床评分，特征为体重减轻、皮肤病变和全身症状。它们还表现出泪液量减少和角膜上皮损伤加剧。组织学分析显示睑板腺（MGs）和泪腺（LGs）有明显的炎症和纤维化。观察到8-羟基脱氧鸟苷和4HNE上调，同时过氧化氢酶和Nrf2下调，表明氧化应激增强和抗氧化防御受损。检测到促炎标志物（IL-6、IL-8、NF-κB）、促纤维化标志物α-平滑肌肌动蛋白（α-SMA）和衰老标志物（P16INK4A、P38 MARK）水平升高。这些发现表明在coGVHD角膜的发病机制中，炎症、纤维化和细胞衰老之间存在复杂的相互作用。生物信息学分析揭示了coGVHD角膜中与氧化应激、炎症和衰老相关的基因表达有显著变化。
本研究阐明了氧化应激、炎症和细胞衰老在cGVHD角膜病变中的核心作用，确定了创新治疗策略的潜在靶点。
不适用。
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