Liu Ren, Xue Jianwen, Han Jiaxu, Tu Mengqian, Wang Wenhui, Chen Ziyan, Qian Xiaobing, Xiao Bing, Liang Lingyi
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China.
Ocul Surf. 2024 Oct;34:444-458. doi: 10.1016/j.jtos.2024.10.002. Epub 2024 Oct 10.
Cytarabine (Ara-C) chemotherapy causes symptoms resembling meibomian gland dysfunction (MGD), suggesting potential associations between Ara-C and MGD. In this study, the pathological effects of Ara-C on MGD were investigated in a rodent model.
Mice received Ara-C with or without rosiglitazone (PPARγ agonist) for 7 consecutive days. Slit-lamp biomicroscope was used for ocular examinations. Immunofluorescence detected acinar cell proliferation, differentiation, and ductal keratinization in the meibomian gland (MG). Lipid accumulation was evaluated by Oil Red O and LipidTox staining. Lipogenic status, FoxO1/FoxO3a cellular localization, and oxidative stress were visualized via immunohistochemistry. Western blotting assessed relative protein expression and AKT/FoxO1/FoxO3a pathway phosphorylation.
Ara-C (50 mg/kg) did not affect mouse survival but induced damage to ocular surface microenvironment, including corneal epithelial defects, MG orifice plugging and acinar dropout, and lacrimal gland (LG) dysfunction. Ara-C intervention inhibited proliferation and caused progenitor loss in the MG, as evidenced by reduced PCNA + labeling and P63+/Lrig1+ basal cell numbers. The MG ducts of Ara-C-treated mice exhibited marked dilatation, lipid deposition, and hyperkeratinization (K1/K10 overexpression). Ara-C disrupted MG lipid metabolism by downregulating PPARγ and its downstream lipogenic targets AWAT2/SOAT1/ELOVL4 and upregulating HMGCR. Dephosphorylation of AKT and the subsequent nuclear translocation of FoxO1/FoxO3a contributed to Ara-C-induced PPARγ downregulation. Ara-C triggered oxidative stress with increases in 4-HNE and 8-OHdG and Keap1/Nrf2/HO-1/SOD1 axis dysregulation. Rosiglitazone treatment ameliorated MGD-associated pathological manifestations, LG function, MG lipid metabolism, and oxidative stress in Ara-C-exposed mice.
Systemic Ara-C chemotherapy exerted topical cytotoxic effects on the ocular surface, and PPARγ restoration by rosiglitazone mitigated Ara-C-induced MGD alterations.
阿糖胞苷（Ara-C）化疗会引发类似睑板腺功能障碍（MGD）的症状，提示Ara-C与MGD之间可能存在关联。在本研究中，我们在啮齿动物模型中研究了Ara-C对MGD的病理影响。
小鼠连续7天接受Ara-C治疗，部分小鼠同时接受罗格列酮（PPARγ激动剂）治疗。使用裂隙灯生物显微镜进行眼部检查。免疫荧光检测睑板腺（MG）腺泡细胞增殖、分化及导管角化情况。通过油红O和LipidTox染色评估脂质蓄积。通过免疫组化观察脂质生成状态、FoxO1/FoxO3a细胞定位及氧化应激情况。蛋白质免疫印迹法评估相关蛋白表达及AKT/FoxO1/FoxO3a信号通路磷酸化情况。
Ara-C（50mg/kg）不影响小鼠存活，但会导致眼表微环境受损，包括角膜上皮缺损、MG开口堵塞、腺泡缺失及泪腺（LG）功能障碍。Ara-C干预抑制了MG中的增殖并导致祖细胞丢失，PCNA+标记减少及P63+/Lrig1+基底细胞数量减少证明了这一点。接受Ara-C治疗的小鼠的MG导管表现出明显扩张、脂质沉积和过度角化（K1/K10过表达）。Ara-C通过下调PPARγ及其下游脂质生成靶点AWAT2/SOAT1/ELOVL4并上调HMGCR来破坏MG脂质代谢。AKT的去磷酸化以及随后FoxO1/FoxO3a的核转位导致了Ara-C诱导的PPARγ下调。Ara-C通过增加4-HNE和8-OHdG以及Keap1/Nrf2/HO-1/SOD1轴失调引发氧化应激。罗格列酮治疗改善了Ara-C暴露小鼠中与MGD相关的病理表现、LG功能、MG脂质代谢和氧化应激。
全身应用Ara-C化疗对眼表产生局部细胞毒性作用，罗格列酮恢复PPARγ可减轻Ara-C诱导的MGD改变。
