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Comparative analysis of long-term results of three epithelial cell transplantation procedures for treating limbal stem cell deficiency 比较分析三种上皮细胞移植手术治疗角膜干细胞缺乏症的长期效果
IF 6.4 1区 医学 Q1 OPHTHALMOLOGY Pub Date : 2024-01-13 DOI: 10.1016/j.jtos.2024.01.003
Sathiya Kengpunpanich , Chareenun Chirapapaisan , Panotsom Ngowyutagon , Suksri Chotikavanich , Rosanun Sikarinkul , Nuttacha Taetrongchit , Simaporn Setthawong , Pinnita Prabhasawat

This study compared the long-term outcome of different epithelial transplantation techniques to treat limbal stem cell deficiency (LSCD). We conducted a retrospective 15-year comparative systematic cohort study of patients with LSCD who underwent either cultivated limbal epithelial transplantation (CLET), simple limbal epithelial transplantation (SLET), or cultivated oral mucosal epithelial transplantation (COMET). We reviewed the demographic data, etiology, LSCD severity, best-corrected visual acuity, surgical outcomes, and complications. A total of 103 eyes of 94 patients (mean age, 45.0 ± 16.4 years) with LSCD were enrolled. The most common cause of LSCD was chemical injury (42.7 %). The median follow-up time was 75 months. The success rates of CLET, SLET, and COMET were 45.5 %, 77.8 %, and 57.8 %, respectively. The 7-year survival rates after CLET, SLET, and COMET were 50.0 %, 72.2 %, and 53.2 %, respectively. Steven-Johnson syndrome (SJS) had a significantly lower survival rate than other causes (p < 0.001), but SLET had a significantly higher survival rate than CLET (p = 0.018) and COMET (p = 0.047). Visual improvement of more than four Snellen lines was achieved in 53.1 % of successful cases and 28.2 % of failed cases. SJS, Schirmer I test <5 mm, and the presence of postoperative recurrent epithelial defects were significant risk factors for a failed surgery. All epithelial transplantation techniques had favorable long-term surgical outcomes. More than half of the patients achieved a stable ocular surface and visual acuity improvement up to 7 years postoperatively. SLET tends to have a better surgical outcome than CLET and COMET, especially in patients with SJS.

本研究比较了不同上皮移植技术治疗瓣膜干细胞缺乏症(LSCD)的长期疗效。我们对接受培养瓣上皮移植术(CLET)、单纯瓣上皮移植术(SLET)或培养口腔粘膜上皮移植术(COMET)的LSCD患者进行了一项为期15年的回顾性系统队列比较研究。我们回顾了人口统计学数据、病因、LSCD 严重程度、最佳矫正视力、手术效果和并发症。我们共纳入了 94 名 LSCD 患者(平均年龄为 45.0 ± 16.4 岁)的 103 只眼睛。导致 LSCD 的最常见原因是化学损伤(42.7%)。中位随访时间为 75 个月。CLET、SLET和COMET的成功率分别为45.5%、77.8%和57.8%。CLET、SLET和COMET术后的7年生存率分别为50.0%、72.2%和53.2%。史蒂文-约翰逊综合征(SJS)的存活率明显低于其他病因(p <0.001),但SLET的存活率明显高于CLET(p = 0.018)和COMET(p = 0.047)。53.1%的成功病例和 28.2%的失败病例的视力改善超过四条斯奈伦线。SJS、Schirmer I测试<5 mm和术后复发上皮缺损是手术失败的重要风险因素。所有上皮移植技术都有良好的长期手术效果。半数以上的患者眼表稳定,术后 7 年视力有所提高。SLET的手术效果往往优于CLET和COMET,尤其是在SJS患者中。
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引用次数: 0
Self-complementary AAV vector therapy for treating corneal cloudiness of mucopolysaccharidosis type VII (MPS VII) 治疗七型粘多糖病(MPS VII)角膜混浊的自补体AAV载体疗法
IF 6.4 1区 医学 Q1 OPHTHALMOLOGY Pub Date : 2024-01-12 DOI: 10.1016/j.jtos.2024.01.002
Jhuwala Venkatakrishnan , Yong Yuan , Jianhua Zhang , Yang Yu , Yueh-Chiang Hu , Winston W-Y Kao

Purpose

To design a novel efficacious scAAV-Gusb viral vector for treating Mucopolysaccharidosis Type VII (MPS VII) caused by a mutation in the β-Glu gene (Gusb allele).

Methods

β-Glu expression of single-stranded AAV-Gusb (ssAAV-Gusb) and self-complementary AAV (scAAV-Gusb) vectors are tested with cultured murine Gusb fibroblasts. The scAAV-Gusb vector was chosen in further studies to prolong the life span and treat corneal pathology of Gusb mice via intrahepatic injection of neonates and intrastromal injection in adults, respectively. Corneal pathology was studied using HRT2 in vivo confocal microscope and histochemistry in mice corneas.

Results

Both ssAAV-Gusb and scAAV-Gusb vectors expressed murine β-Glu in cultured Gusb fibroblasts. The scAAV-Gusb vector had higher transduction efficiency than the ssAAV-Gusb vector. To prolong the life span of Gusb mice, neonates (3 days old) were administered with scAAV-Gusb virus via intrahepatic injection. The treatment improves the survival rate of Gusb mice, prolonging the median survival rate from 22.5 weeks (untreated) to 50 weeks (treated). Thereafter, we determined the efficacy of the scAAV-Gusb virus in ameliorating corneal cloudiness observed in aged Gusb mice. Both corneal cloudiness and stroma thickness decreased, and there was the presence of β-Glu enzyme activity in the Gusb corneas receiving scAAV-Gusb virus associated with morphology change of amoeboid stromal cells in untreated to characteristic dendritic keratocytes morphology after 4–12 weeks of scAAV-Gusb virus injection.

Conclusion

Intrahepatic injection of scAAV-Gusb is efficacious in prolonging the life span of Gusb mice, and intrastromal injection can ameliorate corneal phenotypes. Both strategies can be adapted for treating other MPS.

目的设计一种新型高效的scAAV-Gusb病毒载体,用于治疗由β-Glu基因突变(Gusb等位基因)引起的七型粘多糖病(MPS VII)。方法用培养的小鼠Gusb成纤维细胞测试单链AAV-Gusb(ssAAV-Gusb)和自补体AAV(scAAV-Gusb)载体的β-Glu表达。进一步的研究选择了 scAAV-Gusb 载体,分别通过新生小鼠的肝内注射和成年小鼠的基质内注射来延长 Gusb 小鼠的寿命和治疗角膜病变。结果ssAAV-Gusb和scAAV-Gusb载体都在培养的Gusb成纤维细胞中表达了小鼠β-Glu。scAAV-Gusb载体的转导效率高于ssAAV-Gusb载体。为了延长 Gusb 小鼠的寿命,新生小鼠(3 天大)通过肝内注射 scAAV-Gusb 病毒。治疗提高了 Gusb 小鼠的存活率,将中位存活率从 22.5 周(未治疗)延长至 50 周(已治疗)。随后,我们测定了 scAAV-Gusb 病毒对改善老年 Gusb 小鼠角膜混浊的疗效。在注射 scAAV-Gusb 病毒 4-12 周后,角膜混浊度和基质厚度均有所下降,接受 scAAV-Gusb 病毒治疗的 Gusb 角膜中出现了 β-Glu 酶活性,同时基质细胞形态也发生了变化,由未治疗时的非变形基质细胞形态转变为特征性的树枝状角膜细胞形态。结论肝内注射 scAAV-Gusb 可有效延长 Gusb 小鼠的寿命,而基质内注射可改善角膜表型。这两种策略都可用于治疗其他 MPS。
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引用次数: 0
Tissue-targeted and localized AAV5-DCN and AAV5-PEDF combination gene therapy abrogates corneal fibrosis and concurrent neovascularization in rabbit eyes in vivo 组织靶向和定位 AAV5-DCN 和 AAV5-PEDF 组合基因疗法可在体内减轻兔眼的角膜纤维化和并发新生血管形成
IF 6.4 1区 医学 Q1 OPHTHALMOLOGY Pub Date : 2024-01-06 DOI: 10.1016/j.jtos.2024.01.001
Rajiv R. Mohan , Suneel Gupta , Rajnish Kumar , Nishant R. Sinha , James Landreneau , Prashant R. Sinha , Ashish Tandon , Shyam S. Chaurasia , Nathan P. Hesemann

Purpose

Corneal fibrosis and neovascularization (CNV) after ocular trauma impairs vision. This study tested therapeutic potential of tissue-targeted adeno-associated virus5 (AAV5) mediated decorin (DCN) and pigment epithelium-derived factor (PEDF) combination genes in vivo.

Methods

Corneal fibrosis and CNV were induced in New Zealand White rabbits via chemical trauma. Gene therapy in stroma was delivered 30-min after chemical-trauma via topical AAV5-DCN and AAV5-PEDF application using a cloning cylinder. Clinical eye examinations and multimodal imaging in live rabbits were performed periodically and corneal tissues were collected 9-day and 15-day post euthanasia. Histological, cellular, and molecular and apoptosis assays were used for efficacy, tolerability, and mechanistic studies.

Results

The AAV5-DCN and AAV5-PEDF combination gene therapy significantly reduced corneal fibrosis (p < 0.01 or p < 0.001) and CNV (p < 0.001) in therapy-given (chemical-trauma and AAV5-DCN + AAV5-PEDF) rabbit eyes compared to the no-therapy given eyes (chemical-trauma and AAV5-naked vector). Histopathological analyses demonstrated significantly reduced fibrotic α-smooth muscle actin and endothelial lectin expression in therapy-given corneas compared to no-therapy corneas on day-9 (p < 0.001) and day-15 (p < 0.001). Further, therapy-given corneas showed significantly increased Fas-ligand mRNA levels (p < 0.001) and apoptotic cell death in neovessels (p < 0.001) compared to no-therapy corneas. AAV5 delivered 2.69 × 107 copies of DCN and 2.31 × 107 copies of PEDF genes per μg of DNA. AAV5 vector and delivered DCN and PEDF genes found tolerable to the rabbit eyes and caused no significant toxicity to the cornea.

Conclusion

The combination AAV5-DCN and AAV5-PEDF topical gene therapy effectively reduces corneal fibrosis and CNV with high tolerability in vivo in rabbits. Additional studies are warranted.

目的眼外伤后角膜纤维化和新生血管形成(CNV)会损害视力。本研究测试了组织靶向腺相关病毒 5(AAV5)介导的装饰素(DCN)和色素上皮衍生因子(PEDF)组合基因在体内的治疗潜力。化学创伤后 30 分钟,使用克隆圆筒通过局部应用 AAV5-DCN 和 AAV5-PEDF 在基质中进行基因治疗。定期对活兔进行临床眼部检查和多模态成像,并在安乐死后 9 天和 15 天收集角膜组织。结果 AAV5-DCN 和 AAV5-PEDF 联合基因疗法显著减少了角膜纤维化(p < 0.01 或 p < 0.001)和 CNV(p < 0.001)。组织病理学分析表明,在第 9 天(p < 0.001)和第 15 天(p < 0.001),接受治疗的角膜与未接受治疗的角膜相比,纤维化的 α-平滑肌肌动蛋白和内皮凝集素表达明显减少。此外,与未接受治疗的角膜相比,接受治疗的角膜的 Fas-配体 mRNA 水平(p <0.001)和新生血管细胞凋亡(p <0.001)明显增加。AAV5 每微克 DNA 可提供 2.69×107 个 DCN 和 2.31×107 个 PEDF 基因拷贝。结论 AAV5-DCN 和 AAV5-PEDF 联合局部基因疗法能有效减少兔子体内的角膜纤维化和 CNV,且具有很高的耐受性。有必要进行更多研究。
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引用次数: 0
A closer look into the cellular and molecular biology of myoepithelial cells across various exocrine glands 近距离观察各种外分泌腺肌上皮细胞的细胞和分子生物学特性
IF 6.4 1区 医学 Q1 OPHTHALMOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.jtos.2023.12.003
Olivier Mauduit , Vanessa Delcroix , Andrew Wong , Anastasiia Ivanova , Lindsey Miles , Hyun Soo Lee , Helen Makarenkova

Myoepithelial cells (MECs) are a unique subset of epithelial cells that possess several smooth muscle cell characteristics, such as a high number of actin-myosin filaments and the ability to contract. These cells are primarily located around the secretory cells of exocrine glands, including the salivary, mammary, lacrimal, and sweat glands. Their primary functions involve the construction of the basement membrane and help with secretion of gland products through contraction. So far, no comparative analysis of MECs in different exocrine glands had ever evaluated their differences. In this review, we took advantage of the various publicly available scRNAseq data from mouse exocrine glands to identify their shared and unique characteristics.

The aim of this review is to compare the role of MECs in maintaining healthy glandular function, their involvement in disease states, and their regenerative capacity, with a particular emphasis on the latest research findings in these areas.

肌上皮细胞(Moepithelial cells,MECs)是上皮细胞的一个独特亚群,具有平滑肌细胞的一些特征,如大量肌动蛋白-肌球蛋白丝和收缩能力。这些细胞主要位于唾液腺、乳腺、泪腺和汗腺等外分泌腺分泌细胞周围。它们的主要功能是构建基底膜,并通过收缩帮助分泌腺体产物。迄今为止,还没有对不同外分泌腺中的 MECs 进行过比较分析,以评估它们之间的差异。本综述旨在比较 MECs 在维持健康腺体功能、参与疾病状态以及再生能力方面的作用,尤其侧重于这些领域的最新研究成果。
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引用次数: 0
Modeling meibum secretion: Alternatives for obstructive Meibomian Gland Dysfunction (MGD) 模拟睑脂分泌:阻塞性睑脂腺功能障碍(MGD)的替代方法。
IF 6.4 1区 医学 Q1 OPHTHALMOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.jtos.2023.11.005
Shangbang Luo , Gagik P. Djotyan , Rohan Joshi , Tibor Juhasz , Donald J. Brown , James V. Jester

Purpose

While changes in meibum quality are correlated with severity of meibomian gland dysfunction (MGD) and dry eye disease, little is known regarding the mechanics of meibum secretion. The purpose of this study was to develop a finite element model of meibum secretion and evaluate the effect of various factors that might impact meibum delivery to the ocular surface.

Methods

A finite element analysis in COMSOL 6.0 was used to simulate the flow of meibum within the gland's terminal excretory duct. Historical normal human meibum rheology data taken over the meibum melting range from fluid (35–40 °C) to solid (25–30 °C) were then used to calculate the minimum yield stress and plastic viscosity of meibum. The effects of meibum melting state, eyelid pressure and terminal duct diameter on meibum flow rates were then systematically investigated.

Results

The melting state of meibum from liquid to solid was associated with an increase in the minimum yield stress and plastic viscosity that caused an exponential decrease in meibum flow. Modeling also established that there was a linear correlation between meibum flow rate and eyelid pressure needed to express meibum and the 4th power of the terminal duct radius.

Conclusions

Our results suggest that changes in the melting state of meibum from fluid to solid, as well as changes in the radius of the terminal excretory duct and the force exerted by the eyelid can lead to dramatic decreases in the flow of meibum. Together these findings suggest alternative mechanisms for meibomian gland obstruction.

目的:虽然睑板质量的变化与睑板腺功能障碍(MGD)和干眼病的严重程度相关,但对睑板分泌的机制知之甚少。本研究的目的是建立睑壁分泌的有限元模型,并评估可能影响睑壁输送到眼睑的各种因素的影响。方法:采用COMSOL 6.0软件进行有限元分析,模拟腺体末端排泄管内代谢液的流动。然后,使用从流体(35-40 °C)到固体(25-30 °C)熔融范围内的历史正常人体meibum流变学数据来计算meibum的最小屈服应力和塑性粘度。然后系统地研究了meibum熔化状态、眼睑压和末端导管直径对meibum流速的影响。结果:微生物从液体到固体的熔化状态与最小屈服应力和塑性粘度的增加有关,导致微生物流动呈指数下降。通过建模还发现,mebum流速与表达mebum所需的眼睑压及终管半径的4次幂之间存在线性相关关系。结论:我们的研究结果表明,memebum从液体到固体的融化状态的变化,以及终端排泄管半径的变化和眼睑施加的力的变化都可以导致memebum流量的急剧减少。总之,这些发现提示了睑板腺梗阻的其他机制。
{"title":"Modeling meibum secretion: Alternatives for obstructive Meibomian Gland Dysfunction (MGD)","authors":"Shangbang Luo ,&nbsp;Gagik P. Djotyan ,&nbsp;Rohan Joshi ,&nbsp;Tibor Juhasz ,&nbsp;Donald J. Brown ,&nbsp;James V. Jester","doi":"10.1016/j.jtos.2023.11.005","DOIUrl":"10.1016/j.jtos.2023.11.005","url":null,"abstract":"<div><h3>Purpose</h3><p><span>While changes in meibum quality are correlated with severity of meibomian gland dysfunction (MGD) and dry eye disease, little is known regarding the mechanics of meibum secretion. The purpose of this study was to develop a finite element model of meibum secretion and evaluate the effect of various factors that might impact meibum delivery to the </span>ocular surface.</p></div><div><h3>Methods</h3><p><span>A finite element analysis in COMSOL 6.0 was used to simulate the flow of meibum within the gland's terminal excretory duct. Historical normal human meibum </span>rheology data taken over the meibum melting range from fluid (35–40 °C) to solid (25–30 °C) were then used to calculate the minimum yield stress and plastic viscosity of meibum. The effects of meibum melting state, eyelid pressure and terminal duct diameter on meibum flow rates were then systematically investigated.</p></div><div><h3>Results</h3><p>The melting state of meibum from liquid to solid was associated with an increase in the minimum yield stress and plastic viscosity that caused an exponential decrease in meibum flow. Modeling also established that there was a linear correlation between meibum flow rate and eyelid pressure needed to express meibum and the 4th power of the terminal duct radius.</p></div><div><h3>Conclusions</h3><p>Our results suggest that changes in the melting state of meibum from fluid to solid, as well as changes in the radius of the terminal excretory duct and the force exerted by the eyelid can lead to dramatic decreases in the flow of meibum. Together these findings suggest alternative mechanisms for meibomian gland obstruction.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"31 ","pages":"Pages 56-62"},"PeriodicalIF":6.4,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Metabolic signatures of tear extracellular vesicles caused by herpes simplex keratitis 由单纯疱疹性角膜炎引起的泪液细胞外囊泡的代谢特征
IF 6.4 1区 医学 Q1 OPHTHALMOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.jtos.2023.12.005
Huixiang Ma , Tucan Chen , Chengxu Li , Hao Xu , Qingyu Feng , Yunfei Su , Jianqiu Cai , Qingfu Zhu , Fei Liu , Liang Hu

Purpose

Herpes simplex keratitis (HSK), caused by type 1 herpes simplex virus (HSV) reactivation, is a severe infectious disease that leads to vision loss. HSV can trigger metabolic reprogramming in the host cell and change the extracellular vesicles (EV) cargos; however, little is known about the EV metabolic signatures during ocular HSV infection. Here, we aimed to depict the EV-associated metabolic landscape in HSK patients’ tears.

Methods

We collected 82 samples from 41 participants with unilateral HSK (contralateral unaffected tears were set as negative control), including subtype cohorts of 13 epithelial, 20 stromal, and 8 endothelial HSK. We isolated tear EVs via our previously established platform and conducted metabolic analysis using LC-MS/MS. The metabolic signatures for recognizing HSK and subtypes were assessed through differential analysis and machine learning algorithms.

Results

Hypopsia and increased extracellular CD63 levels were observed in affected eyes. We identified 339 metabolites based on sEVs isolated from tears. Differential analysis revealed alterations in energy and amino acid metabolism, as well as the infectious microenvironment. Furthermore, we observed dysregulated metabolite such as methyldopa, which is associated with inappropriate neovascularization and corneal sensation loss, contributing to the HSK severity particularly in the stromal subtype. Moreover, machine learning classification also suggested a set of EV metabolic signatures that have potential for pan-keratitis detection.

Conclusions

Our findings demonstrate that tear EV metabolites can serve as valuable indicators for comprehending the underlying pathological mechanisms. This knowledge is expected to facilitate the development of liquid biopsy means and therapeutic target discovery.

目的由1型单纯疱疹病毒(HSV)再活引起的单纯疱疹性角膜炎(HSK)是一种导致视力丧失的严重传染病。HSV 可引发宿主细胞的代谢重编程,并改变细胞外囊泡 (EV) 的载体;然而,人们对眼部 HSV 感染期间的 EV 代谢特征知之甚少。方法 我们收集了 41 位单侧 HSK 患者的 82 份样本(对侧未受影响的泪液设为阴性对照),其中包括 13 个上皮型、20 个基质型和 8 个内皮型 HSK 亚型。我们通过先前建立的平台分离了泪液 EVs,并使用 LC-MS/MS 进行了代谢分析。通过差异分析和机器学习算法评估了识别 HSK 和亚型的代谢特征。我们根据从泪液中分离出的 sEVs 鉴定出 339 种代谢物。差异分析揭示了能量和氨基酸代谢以及感染微环境的改变。此外,我们还观察到代谢失调的代谢物,如甲基多巴(methyldopa),它与不适当的新生血管形成和角膜感觉丧失有关,导致了 HSK 的严重性,尤其是在基质亚型中。此外,机器学习分类还提出了一组具有泛角膜炎检测潜力的 EV 代谢特征。我们的研究结果表明,泪液 EV 代谢物可作为了解潜在病理机制的重要指标,这一知识有望促进液体活检手段的开发和治疗目标的发现。
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引用次数: 0
Gene expression changes in conjunctival cells associated with contact lens wear and discomfort 与隐形眼镜佩戴和不适有关的结膜细胞基因表达变化。
IF 6.4 1区 医学 Q1 OPHTHALMOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.jtos.2023.12.004
Andrés Ángel Calderón-García , Laura Valencia-Nieto , Cristina Valencia-Sandonis , Alberto López-de la Rosa , Marta Blanco-Vazquez , Itziar Fernández , Carmen García-Vázquez , Cristina Arroyo-del Arroyo , María J. González-García , Amalia Enríquez-de-Salamanca

Purpose

This study aimed to analyze the differences in the expression of pain-related genes in conjunctival epithelial cells among symptomatic contact lens (CL) wearers (SCLWs), asymptomatic CL wearers (ACLWs), and non-CL wearers (non-CLWs).

Methods

For this study, 60 participants (20 non-CLWs, 40 CLWs) were enrolled. The CLW group comprised 20 ACLWs and 20 SCLWs according to the Contact Lens Dry Eye Questionnaire short form©. Conjunctival cells were collected using impression cytology, and RNA was isolated and used to determine the expression levels of 85 human genes involved in neuropathic and inflammatory pain. The effects of CL wear and discomfort were evaluated using mixed-effects ANOVA with partially nested fixed-effects model. Gene set enrichment analysis was performed to assign biological meaning to sets of differentially expressed genes.

Results

Six genes (CD200, EDN1, GRIN1, PTGS1, P2RX7, and TNF) were significantly upregulated in CLWs compared to non-CLWs. Eleven genes (ADORA1, BDKRB1, CACNA1B, DBH, GRIN1, GRM1, HTR1A, PDYN, PTGS1, P2RX3, and TNF) were downregulated in SCLWs compared to ACLWs. These genes were mainly related to pain, synaptic transmission and signaling, ion transport, calcium transport and concentration, and cell-cell signaling.

Conclusions

CL wear modified the expression of pain- and inflammation-related genes in conjunctival epithelial cells. These changes may be in part, along with other mechanisms, responsible for CL discomfort in SCLWs.

目的:本研究旨在分析有症状隐形眼镜佩戴者(SCLWs)、无症状隐形眼镜佩戴者(ACLWs)和非隐形眼镜佩戴者(non-CLWs)结膜上皮细胞中疼痛相关基因表达的差异:本研究共招募了 60 名参与者(20 名非 CLW,40 名 CLW)。根据隐形眼镜干眼症问卷简表,隐形眼镜干眼症组包括 20 名 ACLWs 和 20 名 SCLWs。采用印模细胞学方法收集结膜细胞,并分离 RNA,用于测定涉及神经性和炎症性疼痛的 85 个人类基因的表达水平。采用混合效应方差分析和部分嵌套固定效应模型评估了CL磨损和不适的影响。进行了基因组富集分析,以确定差异表达基因组的生物学意义:结果:CLWs 中有六个基因(CD200、EDN1、GRIN1、PTGS1、P2RX7 和 TNF)比非 CLWs 中的基因明显上调。与 ACLW 相比,11 个基因(ADORA1、BDKRB1、CACNA1B、DBH、GRIN1、GRM1、HTR1A、PDYN、PTGS1、P2RX3 和 TNF)在 SCLW 中下调。这些基因主要与疼痛、突触传递和信号传导、离子转运、钙转运和浓度以及细胞-细胞信号传导有关:结论:CL磨损改变了结膜上皮细胞中疼痛和炎症相关基因的表达。这些变化和其他机制可能是造成SCLW佩戴CL后不适的部分原因。
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引用次数: 0
Ocular surface changes in mice with streptozotocin-induced diabetes and diabetic polyneuropathy 链脲佐菌素诱发糖尿病和糖尿病多发性神经病变小鼠眼表的变化
IF 6.4 1区 医学 Q1 OPHTHALMOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.jtos.2023.12.006
Martin Schicht , Jessica Farger , Saskia Wedel , Marco Sisignano , Klaus Scholich , Gerd Geisslinger , Natarajan Perumal , Franz H. Grus , Swati Singh , Afsun Sahin , Friedrich Paulsen , Elke Lütjen-Drecoll

Purpose

Diabetes mellitus (DM) is a leading risk factor for corneal neuropathy and dry eye disease (DED). Another common consequence of DM is diabetic peripheral polyneuropathy (DPN). Both complications affect around 50 % of the DM patients but the relationship between DM, DED and DPN remains unclear.

Methods

In this study, we examined mice with early onset of DM and PN after streptozotocin (STZ)-induced diabetes (DPN). We compared the early morphological changes of the sciatic nerve, dorsal root and trigeminal ganglia with the changes in the ocular surface, including tear proteomic and we also investigated respective changes in the gene expressions and morphological alterations in the eye tissues involved in tear production.

Results

The lacrimal gland, conjunctival goblet cells and cornea showed morphological changes along with alterations in tear proteins without any obvious signs of ocular surface inflammation. The gene expression for respectively altered tear proteins i.e., of Clusterin in cornea, Car6, Adh3a1, and Eef1a1 in eyelids, and Pigr in the lacrimal gland also showed significant changes compared to control mice. In the trigeminal ganglia like in the dorsal root ganglia neuronal cells showed swollen mitochondria and, in the latter, there was a significant increase of NADPH oxidases and MMP9 suggestive of oxidative and neuronal stress. In the dorsal root ganglia and the sciatic nerve, there was an upregulation of a number of pro-inflammatory cytokines and pain-mediating chemokines.

Conclusion

The early ocular changes in DM Mice only affect the lacrimal gland. Which, is reflected in the tear film composition of DPN mice. Due to the high protein concentration in tear fluid in humans, proteomic analysis in addition to noninvasive investigation of goblet cells and cornea can serve as a tools for the early diagnosis of DPN, DED in clinical practice. Early treatment could delay or even prevent the ocular complications of DM such as DED and PN.

目的糖尿病(DM)是角膜神经病变和干眼症(DED)的主要危险因素。糖尿病的另一个常见后果是糖尿病周围多发性神经病变(DPN)。这两种并发症影响了约 50% 的 DM 患者,但 DM、DED 和 DPN 之间的关系仍不清楚。方法在这项研究中,我们观察了链脲佐菌素(STZ)诱导糖尿病(DPN)后早期发病的 DM 和 PN 小鼠。我们将坐骨神经、背根和三叉神经节的早期形态学变化与眼表的变化(包括泪液蛋白组)进行了比较,并研究了参与泪液生成的眼部组织的基因表达和形态学变化。与对照组小鼠相比,泪液蛋白改变的基因表达,即角膜中的 Clusterin、眼睑中的 Car6、Adh3a1 和 Eef1a1 以及泪腺中的 Pigr 也发生了显著变化。三叉神经节和背根神经节的神经细胞一样,线粒体肿胀,后者的 NADPH 氧化酶和 MMP9 显著增加,表明存在氧化和神经元应激反应。在背根神经节和坐骨神经中,一些促炎细胞因子和介导疼痛的趋化因子上调。DPN小鼠的泪膜成分反映了这一点。由于人类泪液中蛋白质浓度较高,蛋白质组分析以及对腺泡细胞和角膜的无创检查可作为临床实践中早期诊断 DPN 和 DED 的工具。早期治疗可以延缓甚至预防DM的眼部并发症,如DED和PN。
{"title":"Ocular surface changes in mice with streptozotocin-induced diabetes and diabetic polyneuropathy","authors":"Martin Schicht ,&nbsp;Jessica Farger ,&nbsp;Saskia Wedel ,&nbsp;Marco Sisignano ,&nbsp;Klaus Scholich ,&nbsp;Gerd Geisslinger ,&nbsp;Natarajan Perumal ,&nbsp;Franz H. Grus ,&nbsp;Swati Singh ,&nbsp;Afsun Sahin ,&nbsp;Friedrich Paulsen ,&nbsp;Elke Lütjen-Drecoll","doi":"10.1016/j.jtos.2023.12.006","DOIUrl":"10.1016/j.jtos.2023.12.006","url":null,"abstract":"<div><h3>Purpose</h3><p><span>Diabetes mellitus (DM) is a leading risk factor for corneal neuropathy and dry eye disease (DED). Another common consequence of DM is diabetic peripheral </span>polyneuropathy (DPN). Both complications affect around 50 % of the DM patients but the relationship between DM, DED and DPN remains unclear.</p></div><div><h3>Methods</h3><p><span>In this study, we examined mice with early onset of DM and PN after streptozotocin (STZ)-induced diabetes (DPN). We compared the early morphological changes of the sciatic nerve, </span>dorsal root<span> and trigeminal ganglia<span><span> with the changes in the ocular surface, including tear </span>proteomic and we also investigated respective changes in the gene expressions and morphological alterations in the eye tissues involved in tear production.</span></span></p></div><div><h3>Results</h3><p>The lacrimal gland<span><span>, conjunctival goblet cells and cornea showed morphological changes along with alterations in </span>tear proteins<span><span><span> without any obvious signs of ocular surface inflammation. The gene expression for respectively altered tear proteins i.e., of </span>Clusterin in cornea, Car6, Adh3a1, and Eef1a1 in eyelids, and </span>Pigr<span> in the lacrimal gland also showed significant changes compared to control mice. In the trigeminal ganglia like in the dorsal root ganglia<span><span> neuronal cells showed swollen mitochondria and, in the latter, there was a significant increase of NADPH oxidases<span> and MMP9 suggestive of oxidative and neuronal stress. In the dorsal root ganglia and the sciatic nerve, there was an upregulation of a number of pro-inflammatory cytokines and pain-mediating </span></span>chemokines.</span></span></span></span></p></div><div><h3>Conclusion</h3><p>The early ocular changes in DM Mice only affect the lacrimal gland. Which, is reflected in the tear film composition of DPN mice. Due to the high protein concentration in tear fluid in humans, proteomic analysis in addition to noninvasive investigation of goblet cells and cornea can serve as a tools for the early diagnosis of DPN, DED in clinical practice. Early treatment<span> could delay or even prevent the ocular complications of DM such as DED and PN.</span></p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"31 ","pages":"Pages 43-55"},"PeriodicalIF":6.4,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138840003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Endogenous TSG-6 modulates corneal inflammation following chemical injury 内源性 TSG-6 可调节化学损伤后的角膜炎症
IF 6.4 1区 医学 Q1 OPHTHALMOLOGY Pub Date : 2023-12-25 DOI: 10.1016/j.jtos.2023.12.007
Sudhir Verma , Isabel Y. Moreno , Cassio Prinholato da Silva , Mingxia Sun , Xuhong Cheng , Tarsis F. Gesteira , Vivien J. Coulson- Thomas

Purpose

Tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) is upregulated in various pathophysiological contexts, where it has a diverse repertoire of immunoregulatory functions. Herein, we investigated the expression and function of TSG-6 during corneal homeostasis and after injury.

Methods

Human corneas, eyeballs from BALB/c (TSG-6+/+), TSG-6+/ and TSG-6−/− mice, human immortalized corneal epithelial cells and murine corneal epithelial progenitor cells were prepared for immunostaining and real time PCR analysis of endogenous expression of TSG-6. Mice were subjected to unilateral corneal debridement or alkali burn (AB) injuries and wound healing assessed over time using fluorescein stain, in vivo confocal microscopy and histology.

Results

TSG-6 is endogenously expressed in the human and mouse cornea and established corneal epithelial cell lines and is upregulated after injury. A loss of TSG-6 has no structural and functional effect in the cornea during homeostasis. No differences were noted in the rate of corneal epithelial wound closure between BALB/c, TSG-6+/ and TSG-6−/− mice. TSG-6−/− mice presented decreased inflammatory response within the first 24 h of injury and accelerated corneal wound healing following AB when compared to control mice.

Conclusion

TSG-6 is endogenously expressed in the cornea and upregulated after injury where it propagates the inflammatory response following chemical injury.

目的肿瘤坏死因子(TNF)刺激基因-6(TSG-6)在各种病理生理环境中上调,具有多种免疫调节功能。方法制备人角膜、BALB/c(TSG-6+/+)、TSG-6-/+ 和 TSG-6-/- 小鼠眼球、人永生化角膜上皮细胞和小鼠角膜上皮祖细胞,对 TSG-6 的内源性表达进行免疫染色和实时 PCR 分析。结果TSG-6在人和小鼠角膜及已建立的角膜上皮细胞系中内源性表达,并在损伤后上调。在角膜平衡状态下,TSG-6 的缺失对角膜的结构和功能没有影响。BALB/c 小鼠、TSG-6-/+ 小鼠和 TSG-6-/- 小鼠的角膜上皮伤口闭合率没有差异。与对照组小鼠相比,TSG-6-/-小鼠在受伤后 24 小时内的炎症反应减弱,AB 后角膜伤口愈合加快。
{"title":"Endogenous TSG-6 modulates corneal inflammation following chemical injury","authors":"Sudhir Verma ,&nbsp;Isabel Y. Moreno ,&nbsp;Cassio Prinholato da Silva ,&nbsp;Mingxia Sun ,&nbsp;Xuhong Cheng ,&nbsp;Tarsis F. Gesteira ,&nbsp;Vivien J. Coulson- Thomas","doi":"10.1016/j.jtos.2023.12.007","DOIUrl":"10.1016/j.jtos.2023.12.007","url":null,"abstract":"<div><h3>Purpose</h3><p>Tumor necrosis factor<span> (TNF)-stimulated gene-6 (TSG-6) is upregulated in various pathophysiological contexts, where it has a diverse repertoire of immunoregulatory functions. Herein, we investigated the expression and function of TSG-6 during corneal homeostasis and after injury.</span></p></div><div><h3>Methods</h3><p><span>Human corneas, eyeballs from BALB/c (</span><em>TSG-6</em><sup><em>+/+</em></sup>), <em>TSG-6<sup>+</sup></em><sup><em>/</em></sup><sup>−</sup> and <em>TSG-6</em><sup><em>−/−</em></sup><span><span> mice, human immortalized corneal epithelial cells and murine corneal epithelial progenitor cells were prepared for immunostaining and </span>real time PCR<span><span> analysis of endogenous expression of TSG-6. Mice were subjected to unilateral corneal debridement or alkali burn (AB) injuries and wound healing assessed over time using </span>fluorescein stain, </span></span><em>in vivo</em><span> confocal microscopy and histology.</span></p></div><div><h3>Results</h3><p><span>TSG-6 is endogenously expressed in the human and mouse cornea and established corneal epithelial cell lines and is upregulated after injury. A loss of TSG-6 has no structural and functional effect in the cornea during homeostasis. No differences were noted in the rate of corneal epithelial wound closure between BALB/c, </span><em>TSG-6</em><sup>+</sup><sup><em>/</em></sup><sup>−</sup> and <em>TSG-6</em><sup><em>−/−</em></sup> mice. <em>TSG-6</em><sup><em>−/−</em></sup><span> mice presented decreased inflammatory response within the first 24 h of injury and accelerated corneal wound healing following AB when compared to control mice.</span></p></div><div><h3>Conclusion</h3><p>TSG-6 is endogenously expressed in the cornea and upregulated after injury where it propagates the inflammatory response following chemical injury.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"32 ","pages":"Pages 26-38"},"PeriodicalIF":6.4,"publicationDate":"2023-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139034825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A PEDF peptide mimetic effectively relieves dry eye in a diabetic murine model by restoring corneal nerve, barrier, and lacrimal gland function 一种 PEDF 肽模拟物通过恢复角膜神经、屏障和泪腺功能,有效缓解糖尿病小鼠模型的干眼症
IF 6.4 1区 医学 Q1 OPHTHALMOLOGY Pub Date : 2023-12-14 DOI: 10.1016/j.jtos.2023.12.002
Shuangping Chen , Colin James Barnstable , Xiaomin Zhang , Xiaorong Li , Shaozhen Zhao , Joyce Tombran-Tink

Purpose

The study investigated effectiveness of a novel PEDF peptide mimetic to alleviate dry eye-like pathologies in a Type I diabetic mouse model established using streptozotocin.

Methods

Mice were treated topically for 3–6 weeks with Ppx (a 17-mer PEDF mimetic) 2x/day or vehicle. Corneal sensitivity, tear film, epithelial and endothelial injury were measured using Cochet-Bonnet esthesiometer, phenol red cotton thread wetting, fluorescein sodium staining, and ZO1 expression, respectively. Inflammatory and parasympathetic nerve markers and activation of the MAPK/JNK pathways in the lacrimal glands were measured.

Results

Diabetic mice exhibited features of dry eye including reduced corneal sensation and tear secretion and increased corneal epithelium injury, nerve degeneration, and edema. Ppx reversed these pathologies and restored ZO1 expression and morphological integrity of the endothelium. Upregulation of IL-1β and TNFα, increased activation of P-38, JNK, and ERK, and higher levels of M3ACHR in diabetic lacrimal glands were also reversed by the peptide treatment.

Conclusion

The study demonstrates that topical application of a synthetic PEDF mimetic effectively alleviates diabetes-induced dry eye by restoring corneal sensitivity, tear secretion, and endothelial barrier and lacrimal gland function. These findings have significant implications for the potential treatment of dry eye using a cost-effective and reproducible approach with minimal invasiveness and no obvious side effects.

目的 本研究探讨了一种新型 PEDF 肽模拟物在使用链脲佐菌素建立的 I 型糖尿病小鼠模型中缓解干眼症样病变的有效性。使用 Cochet-Bonnet 眼压计、酚红棉线润湿、荧光素钠染色和 ZO1 表达分别测量角膜敏感性、泪膜、上皮和内皮损伤。结果糖尿病小鼠表现出干眼症的特征,包括角膜感觉和泪液分泌减少、角膜上皮损伤加重、神经变性和水肿。Ppx 逆转了这些病理现象,并恢复了 ZO1 的表达和角膜内皮的形态完整性。多肽治疗还逆转了糖尿病泪腺中 IL-1β 和 TNFα 的上调、P-38、JNK 和 ERK 的活化增加以及 M3ACHR 水平的升高。这些发现对于采用一种具有成本效益、可重复、微创且无明显副作用的方法治疗干眼症具有重要意义。
{"title":"A PEDF peptide mimetic effectively relieves dry eye in a diabetic murine model by restoring corneal nerve, barrier, and lacrimal gland function","authors":"Shuangping Chen ,&nbsp;Colin James Barnstable ,&nbsp;Xiaomin Zhang ,&nbsp;Xiaorong Li ,&nbsp;Shaozhen Zhao ,&nbsp;Joyce Tombran-Tink","doi":"10.1016/j.jtos.2023.12.002","DOIUrl":"10.1016/j.jtos.2023.12.002","url":null,"abstract":"<div><h3>Purpose</h3><p><span>The study investigated effectiveness of a novel PEDF peptide mimetic to alleviate dry eye-like pathologies in a Type I diabetic mouse model established using </span>streptozotocin.</p></div><div><h3>Methods</h3><p><span><span><span>Mice were treated topically for 3–6 weeks with Ppx (a 17-mer PEDF mimetic) 2x/day or vehicle. Corneal sensitivity, tear film, epithelial and endothelial injury<span> were measured using Cochet-Bonnet esthesiometer, </span></span>phenol red cotton thread wetting, </span>fluorescein sodium<span> staining, and ZO1 expression, respectively. Inflammatory and parasympathetic nerve markers and activation of the MAPK/JNK pathways in the </span></span>lacrimal glands were measured.</p></div><div><h3>Results</h3><p>Diabetic mice exhibited features of dry eye including reduced corneal sensation and tear secretion<span><span> and increased corneal epithelium<span> injury, nerve degeneration, and edema. Ppx reversed these pathologies and restored ZO1 expression and morphological integrity of the endothelium. Upregulation of IL-1β and TNFα, increased activation of P-38, JNK, and ERK, and higher levels of M3ACHR in diabetic lacrimal glands were also reversed by the peptide </span></span>treatment.</span></p></div><div><h3>Conclusion</h3><p>The study demonstrates that topical application<span> of a synthetic PEDF mimetic effectively alleviates diabetes-induced dry eye by restoring corneal sensitivity, tear secretion, and endothelial barrier and lacrimal gland function. These findings have significant implications for the potential treatment of dry eye using a cost-effective and reproducible approach with minimal invasiveness and no obvious side effects.</span></p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"32 ","pages":"Pages 1-12"},"PeriodicalIF":6.4,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138713963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Ocular Surface
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