Ocular Surface最新文献_第10页

Corneal epithelial cells upregulate macropinocytosis to engulf metabolically active axonal mitochondria released by injured axons 角膜上皮细胞上调巨噬细胞吞噬受损轴突释放的代谢活跃的轴突线粒体

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-07-01 Epub Date: 2025-04-01 DOI: 10.1016/j.jtos.2025.03.007

Sonali Pal-Ghosh , Himani Datta-Majumdar , Soneha Datta , Shelly Dimri , Jordan Hally , Hugo Wehmeyer , Zhong Chen , Mitchell Watsky , Jian-Xing Ma , Wentao Liang , Mary Ann Stepp

Purpose

To determine the mechanisms used to internalize mitochondria by corneal epithelial cells after in vivo corneal trephine injury and in vitro in corneal epithelial cells.

Methods

Male and female mice were subjected to trephine injury and euthanized immediately, 6, and 24 h after injury. Macropinocytosis was quantified in vivo using 70 kD fluorescent dextran. Mitochondrial content was assessed by immunofluorescence and metabolic activity quantified by Seahorse assay immediately and 6 h after injury. In vitro experiments using human corneal and limbal epithelial (HCLE) cells and isolated mitochondria were performed to assess mitochondrial transfer in the presence of the gap junction inhibitor 18α-glycyrrhetinc acid and the macropincytosis inhibitor ethylisopropylamiloride.

Results

Mitochondria accumulate within apical epithelial cell layers within minutes of trephine injury. Macropinocytosis also increases within minutes of trephine injury. Oxygen Consumption Rates increase in the corneal epithelium 6 h after trephine injury in males and females. Inhibiting gap junctions increases mitochondrial engulfment while inhibiting macropinocytosis prevents engulfment of mitochondria by corneal epithelial cells in vitro.

Conclusions

Molecules released by injured cells and severed axons induce macropinocytosis in corneal epithelial cells within minutes of trephine injury. An increase in oxygen consumption rate in the corneal epithelium after trephine injury indicates that axonal mitochondria can evade lysosomal degradation for at least 6 h. In vitro studies using isolated labeled and unlabeled mitochondria and control and mechanically stressed human corneal epithelial cells confirm the involvement of macropinocytosis in the engulfment of free and vesicle bound mitochondria by corneal epithelial cells.

目的探讨活体角膜环钻损伤和体外角膜上皮细胞内化线粒体的机制。方法将雄性和雌性小鼠分别于伤后即刻、6和24 h实施安乐死。用70kd荧光葡聚糖定量体内巨量红细胞增多。损伤后立即及6 h，用免疫荧光法测定线粒体含量，用海马法测定代谢活性。利用人角膜和角膜缘上皮（HCLE）细胞和分离的线粒体进行体外实验，以评估间隙连接抑制剂18α-甘草次酸和巨噬细胞症抑制剂乙基异丙基酰胺存在下的线粒体转移。结果环钻损伤后几分钟内，线粒体在顶端上皮细胞层内积累。环钻损伤后几分钟内巨噬细胞增多。环钻损伤后6小时，男性和女性角膜上皮耗氧量增加。抑制间隙连接增加线粒体吞噬，而抑制巨噬细胞作用可防止角膜上皮细胞对线粒体的吞噬。结论角膜环钻损伤后数分钟内，损伤细胞和断轴突释放的分子可诱导角膜上皮细胞巨噬细胞增多。角膜外伤后角膜上皮耗氧量的增加表明轴突线粒体可以逃避溶酶体降解至少6小时。使用分离的标记和未标记线粒体以及对照和机械应激的人角膜上皮细胞进行的体外研究证实，大胞饮作用参与角膜上皮细胞吞噬游离和囊泡结合的线粒体。

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引用次数: 0

Decoding the corneal immune microenvironment in healthy and diabetic mice during corneal wound healing 解码健康小鼠和糖尿病小鼠角膜伤口愈合过程中的角膜免疫微环境。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-07-01 Epub Date: 2025-02-27 DOI: 10.1016/j.jtos.2025.02.010

Yujing Lin , Xiaowen Zhang , Di Sun , Qun Wang , Shengqian Dou , Qingjun Zhou

Diabetic keratopathy (DK) is an underdiagnosed ocular complication of diabetes mellitus. The changes of ocular immune microenvironment contribute to the pathogenesis of DK, while precise mechanisms remain inadequately understood. Here, we employed single-cell RNA sequencing (scRNA-seq) to elucidate the transcriptional alterations of immune cells from diabetic and healthy control mouse corneas during homeostasis and wound healing. Unbiased clustering analysis unveiled 3 major cell subsets and 11 subdivided cell clusters, including T cells, monocyte lineages, and neutrophil subpopulations. The further sub-clustering analysis demonstrated that T cells exhibited cytotoxicity characteristics in both homeostasis and wound healing of diabetic cornea. Moreover, dendritic cells preferred the migratory and maturation phenotype and may recruit and maintain cytotoxic T cells. Macrophages in diabetic cornea preferred the pro-inflammatory M1 phenotype. Under injury conditions, diabetic corneal neutrophils exhibited a more mature and functional possession of neutrophil extracellular traps (NETs). Furthermore, cell-cell communication revealed that the immune cells exhibited hyperactivation and pro-inflammatory responses, while the monocyte lineages exhibited the activating effect on T cells in diabetic cornea. This study represents the inaugural effort to establish a comprehensive scRNA-Seq transcriptomic profile of corneal immune cells during wound healing in healthy and diabetic mice, which offers a valuable reference for subsequent investigations into the pathological roles of immune cells in DK.

糖尿病性角膜病变（DK）是糖尿病的一种未被诊断的眼部并发症。眼部免疫微环境的改变参与了DK的发病机制，但其具体机制尚不清楚。在这里，我们使用单细胞RNA测序（scRNA-seq）来阐明来自糖尿病小鼠和健康对照小鼠角膜的免疫细胞在体内平衡和伤口愈合过程中的转录改变。无偏聚类分析揭示了3个主要的细胞亚群和11个细分的细胞群，包括T细胞、单核细胞谱系和中性粒细胞亚群。进一步的亚聚类分析表明，T细胞在糖尿病角膜的稳态和伤口愈合中都表现出细胞毒性特征。此外，树突状细胞倾向于迁移和成熟表型，并可能招募和维持细胞毒性T细胞。糖尿病角膜中的巨噬细胞倾向于促炎性M1表型。在损伤条件下，糖尿病角膜中性粒细胞表现出更成熟和功能性的中性粒细胞细胞外陷阱（NETs）。此外，细胞间通讯显示，免疫细胞表现出过度活化和促炎反应，而单核细胞谱系则表现出对糖尿病角膜T细胞的激活作用。本研究首次建立了健康和糖尿病小鼠创面愈合过程中角膜免疫细胞的scRNA-Seq转录组图谱，为后续研究免疫细胞在DK中的病理作用提供了有价值的参考。

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引用次数: 0

Impact of botulinum toxin type A on ocular pain with neuropathic features A型肉毒毒素对具有神经性特征的眼痛的影响。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-07-01 Epub Date: 2025-02-12 DOI: 10.1016/j.jtos.2025.02.007

Elyana V.T. Locatelli , Jaxon J. Huang , Jason D. Betz , Jordan J. Huang , Nicole B. Kantor , Nicholas Reyes , Elizabeth R. Felix , Wendy W. Lee , Anat Galor

Purpose

To investigate the impact of botulinum toxin type A (BoNT-A) on neuropathic/nociplastic ocular pain (NOP) and identify predictors of patient outcomes.

Methods

A retrospective study of individuals with NOP symptoms (light sensitivity, wind/air sensitivity, persistent pain despite dry eye treatment) who received ≥1 BoNT-A injection. Primary outcome measures included if (responders vs. non-responders) and to what degree (none vs. mild vs. moderate vs. marked) individuals experienced pain improvement 4–6 weeks post-injection. Demographics and clinical exam information was compared between the groups.

Results

27 individuals received BoNT-A for NOP symptoms. 74 % (n = 20) reported an improvement in pain and were classified as responders. Among responders, the degree of benefit varied, with 25 % reporting mild, 45 % moderate, and 30 % marked pain improvement. Improvements in light sensitivity (37 %), wind/air sensitivity (33 %), and quality of life (QoL) (59 %) were reported by fewer individuals. 80 % of responders and 0 % of non-responders reported QoL improvements afer BoNT-A. In a multivariable model that examined predictors of response (none to marked, 0–3), the presence of fibromyalgia (FM) (β = 0.50; p = 0.004) portended a better response, while shooting pain (β = −0.47; p = 0.007) portended a worse response to BoNT-A, (full model r² = 0.53; p < 0.001). Degree of pain improvement significantly correlated with improvements in light sensitivity, wind/air sensitivity, and QoL (ρ range: 0.42–0.63; p < 0.05).

Conclusion

After BoNT-A, most individuals reported improved ocular pain and QoL, while fewer noted improved light and wind/air sensitivity. Some systemic and ocular factors predicted treatment response and may thus guide treatment.

目的：探讨A型肉毒毒素（BoNT-A）对神经性/伤害性眼痛（NOP）的影响，并确定患者预后的预测因素。方法：回顾性研究接受≥1次BoNT-A注射的有NOP症状（光敏感、风/空气敏感、干眼治疗后持续疼痛）的个体。主要结果测量包括注射后4-6周个体是否（有反应者vs无反应者）以及疼痛改善程度（无反应者vs轻度反应者vs中度反应者vs明显反应者）。比较两组间的人口统计学和临床检查信息。结果：27例患者接受BoNT-A治疗NOP症状。74% （n=20）的患者报告疼痛有所改善，并被归类为应答者。在应答者中，获益程度各不相同，25%报告轻度，45%报告中度，30%报告显着疼痛改善。光敏感性（37%）、风/空气敏感性（33%）和生活质量（QoL）（59%）的改善报告个体较少。80%的应答者和0%的无应答者报告BoNT-A后生活质量有所改善。在检验反应预测因子的多变量模型中（无标记，0-3），纤维肌痛（FM）的存在(β=0.50；P =0.004)预示着更好的反应，而射击痛(β=-0.47；p=0.007)预示着BoNT-A的反应更差，(全模型r2=0.53；结论：在BoNT-A后，大多数人报告眼痛和生活质量得到改善，而较少的人报告光和风/空气敏感性得到改善。一些系统和眼部因素可以预测治疗反应，从而指导治疗。

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引用次数: 0

Essential roles of sensory nerve in maintenance of cornea-phenotype in mice 感觉神经在小鼠角膜表型维持中的重要作用。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-07-01 Epub Date: 2025-03-01 DOI: 10.1016/j.jtos.2025.02.012

Yuka Okada , Takayoshi Sumioka , Hiroki Iwanishi , Shingo Yasuda , Jianhua Zhang , Yong Yuan , Chia-Yang Liu , Winston Whei-Yang Kao , Shizuya Saika

Purpose

To the best of our knowledge, no reports have been published on the long-term changes in corneal tissue during the course of neuroparalytic keratopathy caused by destruction of the ophthalmic nerve in experimental animals. To bridge this research gap, we investigated the histopathology of the cornea in mice 3, 12, and 24 months after coagulation of the ophthalmic nerve.

Methods

Nerves were severely coagulated by inserting an 18-gauge bipolar needle into the skull of C57Bl/6 mice, as previously reported. Mice were sacrificed 3, 12, and 24 months later. Eyes were processed for histological and immunohistochemical analyses to identify the phenotypes of corneal epithelium and stroma.

Results

At 3 months after denervation, the affected eyes showed severe inflammation and epithelial damage. In 3-, 14- and 24-month-old corneas, the stroma was found to be hypercellular with stromal neovascularization and keratinized epithelial hyperplasia. Such epithelium no longer expressed keratin 12, but markedly featured keratinization markers. The affected stroma had no keratocan expression, indicating loss of keratocyte cell-type differentiation. Neutrophils, macrophages, and Sox10-positive putative Schwann cells were found distributed in the affected stroma in association with the accumulation of Sonic hedgehog and galectin-3.

Conclusions

Ophthalmic denervation causes prolonged inflammation lasting up to 2 years, the appearance of repair-type Schwann cells in the stroma, loss of cornea-type differentiation of the epithelium with keratinization, and loss of stroma-specific gene expression. Sonic hedgehog and galectin-3 are upregulated in tissues and thought to be involved in pathology.

目的：据我们所知，尚无关于实验动物眼神经破坏引起的神经麻痹性角膜病变过程中角膜组织长期变化的报道。为了弥补这一研究空白，我们研究了眼神经凝固后3、12和24个月小鼠角膜的组织病理学。方法：根据文献报道，将18号双极针插入C57Bl/6小鼠颅骨，使神经严重凝固。3、12、24个月后处死小鼠。对眼睛进行组织学和免疫组织化学分析，以确定角膜上皮和基质的表型。结果：去神经支配术后3个月，患眼出现严重炎症和上皮损伤。在3、14和24个月大的角膜中，发现间质细胞增多，伴有间质新生血管和角化上皮增生。这种上皮不再表达角蛋白12，但明显具有角化标志物。受影响的基质没有角质蛋白表达，表明角质细胞类型分化的丧失。中性粒细胞、巨噬细胞和推测的sox10阳性雪旺细胞分布在受影响的基质中，与Sonic hedgehog和半乳糖凝集素-3的积累有关。结论：眼球去神经支配可引起长达2年的长期炎症，在基质中出现修复型雪旺细胞，角膜上皮的角膜型分化丧失，并伴有角化，基质特异性基因表达丧失。Sonic hedgehog和半乳糖凝集素-3在组织中表达上调，被认为与病理有关。

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引用次数: 0

Tear fluid derived extracellular vesicles for new biomarker discovery 泪液衍生的细胞外囊泡：发现新的生物标志物。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-07-01 Epub Date: 2025-05-12 DOI: 10.1016/j.jtos.2025.05.001

Natalie Phan , Yi Li , Menglu Yang , Fei Liu

Various cell types release extracellular vesicles (EVs) containing proteins, DNA, and RNA essential for intercellular communication. The bioactive molecules from EVs can reflect disease status and monitor progression, while their communication abilities suggest therapeutic potential. We will review various EV isolation methods, EV-enriched fluids, and studies analyzing differential mi-RNA and protein levels extracted from EVs. Specifically, tear-derived EVs, which protect their molecular content and allow for real-time monitoring of ocular conditions such as Dry Eye Disease (DED), Sjögren's disease (SJD), Ocular graft-versus-host disease (oGVHD), and Diabetic Retinopathy (DR), which all currently remain undiagnosed in patients. EVs also provide potential as carriers for gene transfer, and mesenchymal stem cell (MSCs)-derived EVs are shown to be immunomodulatory, demonstrating promise for autoimmune ocular diseases. Through the multi-omic analysis of tear-fluid content, EVs are promising biomarkers and therapeutic agents in ocular diseases.

不同类型的细胞释放细胞外囊泡（EVs），其中含有细胞间通讯所必需的蛋白质、DNA和RNA。来自ev的生物活性分子可以反映疾病状态和监测进展，而它们的交流能力表明了治疗潜力。我们将回顾各种EV分离方法，EV富集液，以及分析从EV中提取的差异mi-RNA和蛋白质水平的研究。具体来说，泪源性EVs可以保护其分子含量，并允许实时监测眼部疾病，如干眼病（DED）、Sjögren病（SJD）、眼部移植物抗宿主病（oGVHD）和糖尿病视网膜病变（DR），这些疾病目前在患者中仍未得到诊断。EVs还提供了作为基因转移载体的潜力，并且间充质干细胞（MSCs）衍生的EVs被证明具有免疫调节作用，显示出对自身免疫性眼病的希望。通过对泪液含量的多组学分析，EVs是一种有前景的眼部疾病生物标志物和治疗药物。

引用次数: 0

Bringing ophthalmology into the scientific world: Novel nanoparticle-based strategies for ocular drug delivery 将眼科带入科学世界：新型纳米颗粒为基础的眼部药物输送策略。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-07-01 Epub Date: 2025-03-25 DOI: 10.1016/j.jtos.2025.03.004

Milad Abbasi , Hossein Aghamollaei , Ahmad Vaez , Ali Mohammad Amani , Hesam Kamyab , Shreeshivadasan Chelliapan , Sajad Jamalpour , Renato Zambrano-Dávila

The distinctive benefits and drawbacks of various drug delivery strategies to supply corneal tissue improvement for sense organs have been the attention of studies worldwide in recent decades. Static and dynamic barriers of ocular tissue prevent foreign chemicals from entering and inhibit the active absorption of therapeutic medicines. The distribution of different medications to ocular tissue is one of the most appealing and demanding tasks for investigators in pharmacology, biomaterials, and ophthalmology, and it is critical for cornea wound healing due to the controlled release rate and increased drug bioavailability. It should be mentioned that the transport of various types of medications into the different sections of the eye, particularly the cornea, is exceedingly challenging because of its distinctive structure and various barriers throughout the eye. Nanoparticles are being studied to improve medicine delivery strategies for ocular disease. Repetitive corneal drug delivery using biodegradable nanocarriers allows a medicine to remain in different parts of the cornea for extended periods of time and thus improve administration route effectiveness. In this review, we discussed eye anatomy, ocular delivery barriers, as well as the emphasis on the biodegradable nanomaterials ranging from organic nanostructures, such as nanomicelles, polymers, liposomes, niosomes, nanowafers, nanoemulsions, nanosuspensions, nanocrystals, cubosomes, olaminosomes, hybridized NPs, dendrimers, bilosomes, solid lipid NPs, nanostructured lipid carriers, and nanofiber to organic nanomaterials like silver, gold, and mesoporous silica nanoparticles. In addition, we describe the nanotechnology-based ophthalmic medications that are presently on the market or in clinical studies. Finally, drawing on current trends and therapeutic approaches, we discuss the challenges that innovative optical drug delivery systems confront and propose future research routes. We hope that this review will serve as a source of motivation and inspiration for developing innovative ophthalmic formulations.

近几十年来，为改善感官器官角膜组织而采用的各种给药策略的独特益处和弊端一直是全球研究的焦点。眼组织的静态和动态屏障会阻止外来化学物质进入，并抑制治疗药物的有效吸收。对于药理学、生物材料学和眼科学研究人员来说，将不同药物分配到眼部组织是最吸引人也是最艰巨的任务之一，而且由于可控释放率和药物生物利用度的提高，这对角膜伤口愈合至关重要。值得一提的是，由于角膜的独特结构和整个眼球的各种屏障，将各种药物输送到眼球的不同部分，尤其是角膜，是一项极具挑战性的工作。目前正在对纳米颗粒进行研究，以改进眼部疾病的给药策略。使用可生物降解的纳米载体在角膜上重复给药，可使药物在角膜的不同部位停留较长时间，从而提高给药途径的有效性。在这篇综述中，我们讨论了眼部解剖、眼部给药屏障，并重点介绍了可生物降解的纳米材料，包括有机纳米结构，如纳米细胞、聚合物、脂质体、niosomes、纳米晶片、纳米乳液、纳米悬浮液、纳米晶体、立方体、橄榄体、杂化 NPs、树枝状分子、双体、固态脂质 NPs、纳米结构脂质载体和纳米纤维，以及银、金和介孔二氧化硅纳米粒子等有机纳米材料。此外，我们还介绍了目前已上市或正在进行临床研究的基于纳米技术的眼科药物。最后，我们借鉴当前的趋势和治疗方法，讨论了创新型光学给药系统所面临的挑战，并提出了未来的研究路线。我们希望这篇综述能成为开发创新眼科制剂的动力和灵感来源。

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引用次数: 0

Ranking the efficacy of topical treatments for ocular allergy: A network meta-analysis of current evidence 眼过敏局部治疗的疗效排名：当前证据的网络荟萃分析

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-07-01 Epub Date: 2025-05-08 DOI: 10.1016/j.jtos.2025.05.003

Luksanaporn Krungkraipetch , Taweelarp Tansavadi , Dechathorn Krungkraipetch

Purpose

To evaluate and rank the comparative effectiveness of topical treatments for different types of ocular allergies through a systematic review and network meta-analysis.

Methods

A systematic search of electronic databases identified between January 2000 and December 2024 from PubMed, Cochrane CENTRAL, Google Scholar, and Scopus databases. Study Selection; randomized controlled trials assessing topical treatments for ocular allergy, including antihistamines, corticosteroids, immunomodulators, and combination therapies. Data Extraction and Synthesis; data were independently extracted and analyzed following PRISMA guidelines. Direct and indirect comparisons were evaluated using network meta-analysis, and SUCRA rankings assessed relative efficacy. Main Outcomes and Measures; reduction in ocular itching, redness, and inflammation. PROSPERO Registration number: CRD42025634572.

Results

Olopatadine 0.1 % demonstrated highest efficacy in seasonal and perennial allergic conjunctivitis (SUCRA 0.88 and 0.85, respectively), while Tacrolimus 0.1 % showed superior effectiveness in vernal and atopic keratoconjunctivitis (SUCRA 0.92 and 0.89, respectively). Overall treatment effect was significant (OR = 6.95, 95 % CI: 6.24–7.75) with moderate heterogeneity (I² = 50.8 %). Subgroup analysis revealed consistent efficacy across different types of allergic conjunctivitis, with seasonal allergic conjunctivitis showing the highest cumulative ranking probability (89.0 %).

Conclusions

This network meta-analysis provides strong evidence supporting condition-specific treatment approaches in ocular allergies. Newer antihistamines, particularly Olopatadine, are most effective for mild-moderate conditions, while immunomodulators, especially Tacrolimus, show superior efficacy in severe cases. These findings provide clear evidence-based hierarchies for clinical decision-making in the management of different types of allergic conjunctivitis.

目的通过系统综述和网络荟萃分析，对不同类型眼部过敏的局部治疗效果进行评价和排序。方法系统检索2000年1月至2024年12月PubMed、Cochrane CENTRAL、谷歌Scholar和Scopus数据库中的电子数据库。研究选择;随机对照试验评估眼部过敏的局部治疗，包括抗组胺药、皮质类固醇、免疫调节剂和联合治疗。数据提取与综合；数据按照PRISMA指南独立提取和分析。使用网络荟萃分析评估直接和间接比较，SUCRA排名评估相对疗效。主要成果和措施；减轻眼部瘙痒、红肿和炎症。普洛斯彼罗注册号：CRD42025634572。结果0.1%索洛他定对季节性和常年性变应性结膜炎的疗效最高（SUCRA分别为0.88和0.85），0.1%他克莫司对春季性和特应性角膜结膜炎的疗效最高（SUCRA分别为0.92和0.89）。总体治疗效果显著（OR = 6.95, 95% CI: 6.24-7.75），异质性中等（I2 = 50.8%）。亚组分析显示，不同类型变应性结膜炎的疗效一致，季节性变应性结膜炎的累积排名概率最高（89.0%）。结论：该网络荟萃分析为眼部过敏的特异性治疗方法提供了强有力的证据。较新的抗组胺药，特别是奥洛帕他定，对轻中度疾病最有效，而免疫调节剂，特别是他克莫司，在严重病例中表现出更好的疗效。这些发现为不同类型过敏性结膜炎的临床决策提供了明确的循证分级。

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引用次数: 0

Endoplasmic reticulum stress contributes to the development of ocular graft-vs-host disease in the eyelids and the ocular surface 内质网应激有助于眼睑和眼表眼部移植物抗宿主病的发展。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-07-01 Epub Date: 2025-03-22 DOI: 10.1016/j.jtos.2025.03.003

Shinri Sato , Yoko Ogawa , Eisuke Shimizu , Kazuki Asai , Kazuno Negishi , Kazuo Tsubota , Masatoshi Hirayama

Background

While endoplasmic reticulum (ER) stress has been implicated in various aspects of graft-versus-host disease (GVHD), its effects on the eyelids and ocular surface in patients with chronic GVHD (cGVHD) remains poorly understood. We aimed to investigate the relationship between ER stress and ocular GVHD using the ER stress suppressor, 4-phenylbutyric acid (PBA).

Methods

The study used allogeneic bone marrow transplantation (BMT) and syngeneic BMT to establish a cGVHD mouse model. cGVHD mice were treated with either intraperitoneal administration of PBA or 2 % PBA eye drops following BMT.

Results

The Intraperitoneal PBA-treated (PBAip) group retained a larger meibomian gland (MG) area and corneal epithelial damage and inflammatory and fibrotic cell infiltration in the ocular surface was attenuated compared to vehicle-treated cGVHD mice. The expression of unfolded protein response markers was significantly elevated in the vehicle group compared to the syngeneic control and the PBAip group. Electron microscopy and immunohistochemistry revealed that fibroblasts and macrophages infiltrated the eyelids and ocular surface of cGVHD mice under ER stress. The corneal fluorescein staining score was significantly lower in the PBA eye drop-treated group than in the vehicle-treated group. The numbers of leukocyte marker CD45-, T cell marker CD4-, and macrophage marker F4/80-positive cells were significantly reduced in the PBA eye drop-treated group compared to the vehicle group.

Conclusions

The study suggests that the ER stress response, which is triggered by cGVHD in ocular surface tissues, can be suppressed by PBA, an ER stress suppressor, potentially offering therapeutic benefits in ocular GVHD.

背景：虽然内质网（ER）应激与移植物抗宿主病（GVHD）的各个方面有关，但其对慢性移植物抗宿主病（cGVHD）患者眼睑和眼表的影响仍知之甚少。我们的目的是通过内质网应激抑制剂4-苯基丁酸（PBA）来研究内质网应激与眼GVHD之间的关系。方法：采用同种异体骨髓移植（BMT）和同基因骨髓移植（BMT）建立cGVHD小鼠模型。cGVHD小鼠在BMT后分别腹腔注射PBA或2% PBA滴眼液。结果：腹腔注射pbap组小鼠的睑板腺（MG）面积较大，角膜上皮损伤和眼表炎症、纤维化细胞浸润均明显减轻。与同基因对照组和PBAip组相比，载药组未折叠蛋白反应标志物的表达显著升高。电镜和免疫组织化学显示，内质网应激下，成纤维细胞和巨噬细胞浸润到cGVHD小鼠的眼睑和眼表。PBA滴眼液治疗组角膜荧光素染色评分明显低于载药治疗组。PBA滴眼液治疗组白细胞标记物CD45-、T细胞标记物CD4-、巨噬细胞标记物f4 /80阳性细胞数量较对照药组明显减少。结论：本研究提示，由cGVHD在眼睑引发的内质网应激反应可以被内质网应激抑制因子PBA抑制，这可能为眼部GVHD的治疗提供益处。

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引用次数: 0

Use of a transgenic mouse model for in vivo monitoring of corneal pathologies following Sulfur Mustard Exposure 利用转基因小鼠模型在体内监测硫芥暴露后角膜病变

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-07-01 Epub Date: 2025-04-24 DOI: 10.1016/j.jtos.2025.04.007

Ariel Gore, Rahav Efrati, Shelly Atanelov, Pnina Glick, Maayan Cohen, Hila Gutman, Relli Gez, Vered Horwitz

Purpose

The dynamic course of sulfur mustard (SM)-induced ocular insult involves an acute phase, which may progress to a chronic phase or a quiescent period, followed by late pathology. Visualizing pathological corneal changes in vivo could enhance understanding of this process and aid treatment development.

Methods

SM burn was induced in the right eyes of three transgenic mouse strains—expressing RFP under the VE-Cadherin promoter (blood vessels and hematopoietic cells), GFP under the keratin 15 promoter (limbal stem cells), and YFP under the Thy-1 promoter (mid-stromal nerve fibers, MSNFs)—by vapor exposure. Cell infiltration, neovascularization (NV), innervation loss, and stem cell (SC) depletion were monitored in vivo by stereomicroscopy for up to 8 weeks. Corneal whole-mounts were used to assess 360° structures, infiltrating cells, and subbasal nerve plexus (SNP) loss. Histology included H&E, Masson-Trichrome, and periodic acid-Schiff staining.

Results

A 35-s exposure caused minor ocular insult with moderate SNP changes, corneal cell infiltration, and reversible SC loss, mostly resolving by 4 weeks. A 120-s exposure caused severe insult with NV, extensive MSNF and SNP loss, marked CD45⁺ and Iba1⁺ infiltration, and irreversible SC depletion. NV, stromal inflammation, edema, epithelial changes, and goblet cells were seen in histology and correlated with fluorescence imaging.

Conclusions

This study demonstrates the utility of transgenic mice as powerful models for studying SM-induced ocular injury and for developing novel therapeutic strategies.

目的硫芥（SM）致眼损伤的动态过程包括急性期，可发展为慢性期或静息期，随后是晚期病理。在体内观察角膜病理变化可以加深对这一过程的理解，并有助于治疗的发展。方法采用蒸汽暴露法，在VE-Cadherin启动子（血管和造血细胞）下表达RFP，在角蛋白15启动子（角膜干细胞）下表达GFP，在hy-1启动子（中基质神经纤维，MSNFs）下表达YFP的三种转基因小鼠右眼诱导ssm烧伤。通过体视显微镜观察细胞浸润、新生血管形成（NV）、神经支配丧失和干细胞（SC）耗竭长达8周。角膜全支架用于评估360°结构、浸润细胞和基底下神经丛（SNP）损失。组织学包括H&；E，马松-三色，周期性酸-希夫染色。结果sa - 35-s暴露引起轻度眼损伤，伴有中度SNP改变、角膜细胞浸润和可逆性SC丢失，大部分在4周内消退。暴露120 s可引起NV的严重损伤，广泛的MSNF和SNP丢失，明显的CD45+和Iba1+浸润，以及不可逆的SC消耗。组织学上可见NV、间质炎症、水肿、上皮改变和杯状细胞，并与荧光成像相关。结论转基因小鼠可作为研究sm致眼损伤的有效模型，并可用于开发新的治疗策略。

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引用次数: 0

A prospective, longitudinal study to assess progression of ocular surface signs, tear cytokines and protein profiles in young adults 一项前瞻性的纵向研究，以评估年轻人眼表体征，泪液细胞因子和蛋白质谱的进展。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-07-01 Epub Date: 2025-02-25 DOI: 10.1016/j.jtos.2025.02.011

Rachel K. Casemore , James S. Wolffsohn , Tor Paaske Utheim , Sjur Reppe , Hans Christian D. Aass , Debarun Dutta

Purpose

To compare ocular surface characteristics, tear protein profiles, and cytokines in young adults with and without evaporative dry eye disease (DED), exploring any associations with lifestyle factors, and determine any progression after one year.

Methods

Fifty participants, aged 18–25 years, were recruited. Detailed ocular surface parameters were assessed following administration of lifestyle and symptom questionnaires. Tear samples collected by microcapillary tubes were analysed using the Agilent Bioanalyzer (7 proteins between 14 and 230 kDa); tears collected with Schirmer strips were analysed for ten cytokines using Luminex Assay.

Results

56 % of participants fulfilled the TFOS DEWS II criteria for DED. 48 % had at least 25 % meibomian gland loss in either lid regardless of dry eye status, while over 90 % had at least one diagnostic sign. Progression was observed, characterised by significant increases (p < 0.05) in ocular redness, lid wiper epitheliopathy and blink rate. Albumin was upregulated (p = 0.003) in DED, while zinc-α2-glycoprotein, which showed significant correlations with several meibomian gland parameters, was downregulated. Upregulation of both pro- and anti-inflammatory cytokines was observed, with several significant clinical correlations, including IL-1β with meibomian gland parameters.

Conclusions

Evidence of inflammation and overlap of ocular signs in these young adults reinforces the need for early detection and differentiation of those likely to progress to DED. While upregulation of both pro- and anti-inflammatory cytokines has provided evidence of a mechanism to maintain homeostasis, the subtle progression of ocular surface disease observed suggests that counselling is required around the modifiable risk factors of DED identified, regardless of whether symptoms are present or not.

目的：比较患有和未患有蒸发性干眼症（DED）的年轻人的眼表特征、泪液蛋白图谱和细胞因子，探讨与生活方式因素的关联，并确定一年后的病情发展情况：方法：招募了 50 名 18-25 岁的参与者。方法：招募了 50 名 18-25 岁的参与者，在发放生活方式和症状调查问卷后，对他们的眼表参数进行了详细评估。使用微毛细管采集的泪液样本用安捷伦生物分析仪进行分析（7 种蛋白质的含量在 14-230 kDa 之间）；使用施尔默试纸采集的泪液样本用 Luminex 分析仪分析 10 种细胞因子：56% 的参与者符合 TFOS DEWS II 的 DED 标准。48%的受试者无论是否患有干眼症，两侧眼睑均有至少25%的睑板腺脱落，而90%以上的受试者至少有一种诊断征兆。研究发现，干眼症患者的眼睑睑板腺脱落程度在不断加深，其特征是眼睑睑板腺脱落程度显著增加（pConclusions）：在这些年轻人中，炎症和眼部体征重叠的证据加强了早期发现和区分可能发展为 DED 的人群的必要性。虽然促炎和抗炎细胞因子的上调提供了维持平衡机制的证据，但观察到的眼表疾病的微妙进展表明，无论是否出现症状，都需要围绕已确定的 DED 可改变风险因素进行咨询。

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引用次数: 0